harmadik rész - cancer, mitochondria, mithochondria, modelling

Transcription

A RÁK MITOKONDRIÁLIS ELMÉLETE III. rész - 1 oldal / 102
- FÜGGELÉK KÖSZÖNETNYÍLVÁNÍTÁSOK – ACKNOWLEDGMENTS (Dr. Czimbalmos-Kozma Ferenc, Dr. Papp Erika)
(szerkesztés alatt)
véletlenszerű sorrendben, csak nevek, fokozatok, címek nélkül:
PAPP ZOLTÁN
JUNG JÁNOS
MÜLLER MIHÁLY†
CZÉGENI JÓZSEF†
KISS JÓZSEF
FILEP ETELKA†
KIS ISTVÁN†
BEDŐ MARGIT
BÁBA ZOLTÁN
PÁLFFY BÉLA†
LÁSZLÓ JÓZSEF
PIROS SANDA
DOMOKOS LAJOS†
DÓSA JENŐ
NÉMETH PÉTER
ENGELMANN PÉTER
SÁNDOR ZOLTÁN
SZŐKE ÉVA
PÁPA LÁSZLÓNÉ
LUIGI MATTURRI
FURIO SILVESTRI
FILEP GYŐZŐ
KEREK ISTVÁN†
KOROM GYULA
GOLOVNÉ WOSSINSZKY RITA
GÁLL MÁRTA
PÓTÓ LÁSZLÓ
NÁDLER GÁBOR
ŐRI LÁSZLÓ
FREY ISTVÁN
SULYOK ENDRE
OHMACHT RÓBERT
SERESS LÁSZLÓ
KŐNIGNÉ PÉTER ANIKÓ
CSÍKY ZOLTÁN
DIACONESCU CLAUDIU
HECSER LÁSZLÓ
VARGA LEVENTE
a névsor nem teljes, a kézirat leadásakor még szerkesztés alatt!
TheMitochondrial Theory of Cancer © Copyright 2008. Czimbalmos-Kozma, Ferenc, MD., GP., DCH., Dr. Papp, Erika MD.,
(excluding from © some NOTICES and WIKIPEDIA and other images!) - page 1 / 102
JEGYZETEK, HIVATKOZÁSOK ÉS BIBLIOGRÁFIÁK (Dr. Czimbalmos-Kozma Ferenc, Dr. Papp Erika és
hivatkozás külső forrásokra)
l. idézet, hivatkozás saját forrásra magyarázat céljából 01
A szerzők
A tanulmány egyes fejezeteit a szerzők különböző arányban együtt gondolták ki és írták meg. A
fejezetcímek után feltüntetett nevek inkább arra utalnak, hogy ki mozog otthonosabban a vonatkozott terület
háttérinformációinak tömkelegében. Egy ilyen gondolat, mint ez a tanulmány, nem egyemberes munka, ilyet
egyedül nem igazán lehet megalkotni. A tanulmány kifejezetten az intuíciónak és a koncepciók ütköztetésének, az
együttgondolkodásnak az eredménye. Olyan értelemben nem sok köze van az előtanulmányokhoz, szorgalomhoz,
tanuláshoz és kitartáshoz, hogy az előtanulmányok, a szorgalom, a tanulás és a kitartás önmagukban sohasem
bizonyultak volna elegendőnek a tanulmányban vázolt koncepció létrejöttéhez - ahhoz ugyanis ezek kellettek ugyan
(másodsorban), de kellett hozzá valami egyéb, amit nem lehet sem kitartással, sem vasakarattal, sem pénzzel, sem
semmiképpen megszerezni: ezt a valamit, aminek nevet sem lehet igazán találni (minden hasonlat csak tünékeny
közelítés) csak érdemtelenül megkapni lehet. Szinte mindenki megkapja ezt a tálentumot, de legtöbben eldobják,
vagy feláldozzák az éppen aktuális estabilishment iránti szolgalelkűség szennyes pogány oltárán, aztán van aki
elássa, esetleg jobb esetben odaadja a pénzváltóknak, hadd fialtassák. Ahhoz, hogy valaki úgy használja fel, hogy
kedvében járjon annak, aki adta, sok alázat kell. Hálával kell elfogadni, és amikor megcsillan, minden egyebet
hagyni kell, hogy növelhessük. De csak akkor, amikor megcsillan, és ezt nem lehet kiprovokálni. Erőlködni kár: Aki
adta, gondoskodik erőről ahhoz, hogy ha kell éjjel is, holtfáradtan is könnyedén félóra alatt annyit lehessen építeni,
mint előtte egy év alatt. Persze, az agresszív külvilág törpéi, hangyafocira kényszerítve azt, aki merészelt nem
leragadni a sárba melléjük, képesek ideig óráig megzavarni azt a folyamatot, amelyet nem is az indított el, aki az
egészet bevállalta (ő lévén csak munkatárs, aki igent mert mondani vétkes néma cinkosok gyűrűjében). De jaj nekik
-gáncsoskodóknak és konformistáknak, magukat büntetve látni fogják meghalni azokat, akik az általuk okozott
késedelem áldozatai. Vérük, morfiuminjekcióik, citosztatikumos infúzióik üveg alján maradt cseppjei, hányadékuk és
szüleik, gyermekeik könnyei mind - mind a lelkükön fognak száradni, és örökkön égő tüzüktől csak az a
megbocsátás szabadíthatja meg őket, amelyet csak attól remélhetnek, aki egyedül adhat ilyen megbocsátást. Ez a
tanulmány is sokkal hamarabb megszülethetett volna, azzal együtt, hogy sokáig kellett csiszolni. Nem lehetett látni
az értelmét az elején annak, hogy miért kell Dr. C. K. F. felsőbb matematikával foglalkozzon már jó tíz év óta
(egyesk szerint ez “izéljük a rezet” kategória: ugyan milyen, hamis mammonban itt most és azonnal materializálható
értéke van az ilyesminek?!). Képzettség és járatosság nélkül, látszólag ok nélkül, ellendrukkerek között.
Összefüggés nélkül következett a növények aspektusával és extrém körülmények közötti túlélésével kapcsolatos
információk iránti érdeklődés, majd bizonyos növények tumorgátló hatásainak megismerésekor képbe kerültek a
mitokondriumok. Dr. P. E. eleinte nehezen hihetőnek értékelte az tumorképző mitokondriumok elméletét, de a
koncepció végül csak ellenvetéseinek kereszttüzében, közös gondolatként állhatott össze. Ezután már Dr. P. E. jött
rá arra, hogy számos olyan szövetszaporulat van a szervezetben, amely nem malignus tumor, de non-self
információ nélkül aligha jöhetnének létre. Többek között, ismerve az atheroscleroticus plakk és egyes intracelluláris
kórokozók közt gyanított összefüggést, már évekkel ezelőtt tanulmányozta a Helicobacter pylori gyakoriságát
coronariabetegeken, ami most szintén beleillett a képbe. A non-self információ és a malignus tumorok közti
összefüggés lehetősége kikényszerítette a matematikai modellezést, amelyet Dr. C. K. F. a Turing-gép modell és
Neumann és Nash elvei alapján vázolt fel. A malignus szövetkultúrákkal történő kísérletezés során Dr. P. E. látva
egy felülfertőzött kultúra pusztulását, felvetette a bakteriális toxinokkal történő mitokondriumgátlás lehetőségét, mint
tumor-okozó mitokondriumok elleni bacteriális eredetű antibiotikumok felhasználását. Az előzetes tesztek során a
streptolisin gátolta a malignus sejtkultúrát. Dr. C. K. F. a Castanea sativa extractum vizsgálata során tapasztalt
malignus sejtkultúrát gátló hatást. A munka minden fázisa együttgondolkodás volt, különböző, de utólag
elválaszthatatlan arányban, ennek utólag nincs is jelentősége: egyedül egyikük sem jutott volna a végére.
SZAKMAI ÖNÉLETRAJZOK
Dr. PAPP ERIKA
Mottó:
Adatok:
Személyi adatok: Sz. 1972. december 18. Nagybánya, Baia Mare, Erdély, Románia.
Elérhetőségek :
E-mail:
Végzettségem: belgyógyász szakorvos.
Foglalkozásom: Jelenleg Mohács Város Kórházában (7700 Mohács, Szepessy út 7 sz.) dolgozom.
Főigazgató: Dr. Dénes László.
Tanulmányaimat szülővárosomban, Erdélyben, Nagybányán kezdtem, itt érettségiztem és programozó –
szoftverüzemeltető és számitógépkezelő végzettséget szereztem. Ezután tanulmányaimat a Marosvásárhelyi
Orvosi és Gyógyszerészeti Egyetemen folytattam, itt szereztem orvosi diplomámat 1998-ban, a magyar
tagozaton, majd marosvásárhelyi egyetemi klinikákon töltöttem egy orvosgyakornokévet. Egyetemi tanulmányaim
közben pedagógiai diplomát is szereztem.
Az orvosi diplomát átadja Prof. Dr. Jung János
A 2000 – 2005-ös időszakban marosvásárhelyi és kolozsvári egyetemi klinikákon az 5 éves képzési terv alapján
ötéves belgyógyász rezidensi képzést teljesítettem, ezalatt kilenc posztuniversitáris kurzuson vettem
részt Magyarországon és ösztöndíjjal dolgoztam két hónapot Budapesten, a II. sz. Belgyógyászati Klinikán
(Igazgató: Prof. Dr. Tulassay Zsolt, o. vez. Dr. Herszényi László Ph.D. adjunctus).
A 2005 március 16 – 24 közötti vizsgaidőszakban a Kolozsvári III. sz. Belklinikán (szakvizsgabizottsági elnök: Prof.
Dr. Mircea Grigorescu) belgyógyász szakorvosi diplomát szereztem. Részt vettem több magyarországi
orvoskongeresszuson és több romániai orvoskongresszuson.
Egyéb tevékenységeim:
Az egyetemi évek alatt és utána tagja voltam annak a marosvásárhelyi teamnek, amely Romániában az elsők közt
hajtott végre sikeres stem-sejt transzplantációt malignus haematologiai megbetegedések therapiája során. 1996-tól
a Marosvásárhelyi Katolikus Egyetemisták Egyesületének (MA-FIA) alapitó tagja vagyok, melynek keretében részt
vettem árvák és idősek megsegitését célzó programokon és szervezésükben is közremüködtem, valamint részt
vettem az Egyesület által szervezett szociális és spirituális kongresszusokon, konferenciákon, összejöveteleken.
Elő ző munkahelyek:
1999. 01. 01. – 2000. 02. 28 – orvosgyakornokidő:
Marosvásárhely: Megyei Klinikai Kórház - III Belklinika.
2000. 03. 01 – 2005. 04. 30. – rezidensképzés:
Marosvásárhely: Megyei Klinikai Kórház (belgyógyászat, anesztézia - intenzív
terápia, endokrinológia, hematológia, diabetológia).
Kolozsvár: Megyei Klinikai Kórház (gasztroenterológia,nefrológia, fertőző), Egyetemi Vasútkórház – IV. Belklinka
(belgyógyászat).
2005. 05.01 - 09. 30. között Erdélyben, Kapnikbányán (Máramaros megye), a Városi Kórház belgyógyászati
osztályán dolgoztam, mint kórházi belgyógyász szakorvos.
2005 októberében családi okból Magyarországra költöztem, hivatalos magyar munkavállalási engedély és hivatalos
magyar munkavállalási vízum birtokában dolgozni kezdtem Mohács Város Kórházában (7700 Mohács, Szepessy út
7 sz.) a Belosztályon, Dr. Dénes László főigazgató úr személyes irányításával, közalkalmazotti munkaszerződéssel.
Marosvásárhelyen szerzett orvosi diplomám honosítását kezdeményeztem a M.E.I.K.-nél, ahonnan az előírt vizsgák
sikeres letétele után az orvosi egyetemi végzettségem és orvosi diplomám elismerését tanusító okiratot megkaptam,
az Orvosok Országos Nyilvántartásába felvettek, a Magyar Orvosi Kamarába és a működési nyilvántartásába,
valamint az OFTEX-re regisztráltak. 2007. 01. 22-én Magyarországon végleges letelepedési engedélyt kaptam és
állandó lakcímet jelentettem be.
Eddigi munkámról és tevékenységemről referenciák szerezhetők:
Dr. Dénes László főigazgató, Mohács Város Kórháza 7700 Mohács, Szepessy út 7
sz. tel: 0669 - 511150;
Dr. Herszényi László Ph.D. adjunctus, o. vez. főorvos , SOTE II. sz. Belgyógyászati Klinika, 1088 Budapest,
Szentkirályi út 46, tel: 061-266-0926, mellék: 5529
Dr. Fodor Géza, M.O.GY.E. - U.M.F. Târgu Mureş - Clinica Medicală III, tel: +40-265-214503;
Conf. Dr. Vasile Negrean, Spitalul Universitar C.F. Cluj - Clinica Medicală IV, tel: +40-264-59996/230;
Bara László, egyetemi lelkész, Marosvásárhely, tel: +40-265-265923.
Nyelvismeretem: anyanyelvem magyar, ezenkívül felsőfokú román nyelv és
felsőfokú román orvosi szaknyelv, valamint középfokú angol, alapfokú olasz.
Terveimben a jelen munka témája mellett szerepel diabetológiai szakvizsga megszerzése, amely területen
szeretnék a jövőben tovább tevékenykedni.
Publikációk:
1. Papp Erika „ Esetismertetés: Colon Carcinoma in Situ” Esetismertetés a
Kolozsvári Gasztroenterológiai Napokon, 2005 március 20.
2. Papp Erika, V. Negrean, A. Draghici, Ioana Suciu – „ A dohányzás hatása a
hemorrheológiai tényez ő kre diabetes mellitusban. ” –előadás a Magyar
Diabetes Társaság XVII. Kongresszusán, 2004.04. 22 - 25, Tihany, Absztrakt:
Diabetologia Hungarica, vol XII, Supplimentum nr. 1, 98 – 99.
3. M. Adam, Erika Papp, Teodora Alexescu, V. Negrean, A. Draghici, Ioana
Suciu, Iulia Biro - „Leukocita adhézió változásai diabetes mellitusan”
(„Modificări ale adezivitătii leucocitare în diabetul zaharat”) – poszterbemutató a
Román Diabetes Szövetség - Federatia de Diabet, Nutritie si Boli Metabolice, III.
Nemzeti Kongresszusán, 2004.11. 10 - 11, Arad, Románia.
4. V. Negrean, Erika Papp, Teodora Alexescu, A. Draghici, Ioana Suciu, Simina
tărmure „A dohányzás hatása a hemorrheológiai tényező kre diabetes
mellitusban” ( - poszter a Román Diabetes Szövetség - Federatia de Diabet,
Nutritie si Boli Metabolice, III Nemzeti Kongresszusán, 2004 nov. 10 - 11, Arad,
Románia.
5. Ioana Suciu, V. Negrean, D. Sâmpălean, Erika Papp, Nicoleta Leach, Iulia
Biro, M. Adam - „Időskori nephropathia diabetica” ( „Nefropatia diabetică la
vârstnici” ) - poszter a Román Diabetes Szövetség - Federatia de Diabet, Nutritie si
Boli Metabolice, III. Országos Kongresszusán, 2004. 11. 10 - 11, Arad, Románia.
6. V. Negrean, Papp Erika, A. Draghici, Camelia Borza, Simina tărmure, Teodora
Alexescu - „Obezitás - kardiovaszkuláris rizikótényez ő a közlekedésbiztonsági
dolgozóknál.” ( „Obezitatea - factor de risc pentru bolile cardiovasculare la
angajatii din Siguranta Circulatiei”) - poszterbemutató, LXIII. Országos Kardiológiai
Kongresszus, 2004. 09. 15 - 18, Brassó Poiana, Románia, absztrakt - Revista
Română de Cardiologie, vol XIX, nr. 3, 101.
7. Ina Kacso, Anca Cristea, C. Spânu, Papp Erika, Simona Răcăsan, I. M. Patiu,
Crina Popa, Mirela Gherman-Căprioară - „A nagyon kis molekulasúlyú fehérjék
és morfopathológiai elváltozások közötti összefüggések glomeruláris
nefropáthiákban.” ( „Corelatii între prezenta proteinelor urinare de greutate
moleculară foarte mică si leziuni morfopatologice la pacientii cu nefropatii
glomerulare”) –előadás, III. Országos Nefrológia Kongresszus , 2003.05.01.-04,
Kolozsvár, Románia.
8. G. Fodor, Papp Erika, Pop P. Diana, Redis Rodica, A. Alecu, A. Nagy, Kovács
Ágnes "Helicobacter Pylori = Ischaemiás Cardiopathia?” ( „Helicobacter Pylori
= Cardiopatie Ischemica?”) – előadás, Erdélyi Múzeum Egyesület - Orvostudományi
és Gyógyszerészeti Szakosztály X. Tudományos Ülesszaka, 11.05. - 13.05.2000.
05.11 - 13, Székelyudvarhely, Románia.
9. G. Fodor, Papp Erika, Pop P. Diana, Redis Rodica – „Rizikófaktorok a
hasnyálmirigy daganatok ethiopathogenézisében” ( „Factori etiopatogenici în
cancerul pancreatic”) – elöadás, Erdélyi Múzeum Egyesület - Orvostudományi és
Gyógyszerészeti Szakosztály IX. Tudományos Ülesszaka ,1999. 04. 13 – 15,
Gyergyószentmiklós, Románia.
10. Papp Erika – „A szabad és letokolt hasű ri folyadékgyülem ultrahangos
differenciál diagnosztikája.” („Diagnosticul diferential ultrasonografic al lichidului
abdominal liber i închistat”) – bemutató, Marosvásárhelyi Magyar Diákszövetség V.
Tudományos Ülésszaka, 1998. 05. 15 – 16, Marosvásárhely, Románia.
11. Papp Erika – orvosegyetemi államvizsgadolgozat „A pancreasfej
carcinoma ultrahangdiagnosztikai kritériumai”
SZAKMAI ÖNÉLETRAJZ
Dr. CZIMBALMOS-KOZMA FERENC
vagy:
ADATOK:
E-mail:
SZ. 1961.OKT.15., MAROSVÁSÁRHELY, ERDÉLY.
SZŰLŐK:
DALMA, ASSZISZTENSNŐ (MAROSVÁSÁRHELYI ORVOSI ÉS GYÓGYSZERÉSZETI EGYETEM,
ENDOKRINOLÓGIAI KLINIKA) ;
FERENC, TÖRTÉNELEM-FILOZÓFIA SZAKOS TANÁR, ÚJSÁGÍRÓ, (MAROSVÁSÁRHELY, NÉPÚJSÁG
/VOLT "VÖRÖS ZÁSZLÓ", TÖRTÉNELEM ÉS TERMÉSZETVÉDELEM/ ROVATSZERKESZTŐJE)
ELEMI ISKOLA: 10. SZ. ÁLT. ISK. MAROSVÁSÁRHELY, MAGYAR TAGOZAT.
KÖZÉPISKOLA: BOLYAI FARKAS LÍCEUM, MAROSVÁSÁRHELY, MAGYAR TAGOZAT,
1978-IG. (II. GIMNÁZIUMI OSZTÁLYBAN FEGYELMI OKBÓL ELTANÁCSOLVA A GIMNÁZIUMBÓL).
1978-1980 (ÉRETTSÉGIIG) BIOLÓGIA-KÉMIA LÍCEUM, MAROSVÁSÁRHELY, MAGYAR TAGOZAT.
A KÖZÉPISKOLÁBAN TÖBBSZÖR MEGBUKOTT FÉLÉVRE, FŐLEG MATEMATIKÁBÓL, OROSZBÓL,
IRODALOMBÓL. KÉMIÁBÓL A LEGKIVÁLÓBB ÉRETTSÉGI DOLGOZATOT ÍRTA A GIMNÁZIUMBAN 1980-BAN.
1980-BAN ELSŐ PRÓBÁLKOZÁSRA SIKERES FELVÉTELI VIZSGA A MAROSVÁSÁRHELYI ORVOSI ÉS
GYÓGYSZERÉSZETI EGYETEM MAGYAR TAGOZATÁRA. (UTOLSÓ ELŐTTI BEJUTÓ).
1980-81 TELÉN SORKATONA BACAU-BAN. 380 ORVOSJELÖLT KÖZÜL MÁSODMAGÁVAL NEM KAP
ŐRMESTERI RANGOT CSAK SZAKASZVEZETŐIT - AZ OK POLITIKAI MEGBÍZHATATLANSÁG. EGY ÍZBEN
DEZERTÁLÁS GYANÚJA MIATT FOGDÁBA IS KERÜL.
1981-1987: ORVOSTANHALLGATÓ. TÖBBSZÖR LETARTÓZTATJA ÉS KIHALLGATJA A SECURITATE.
(MAGYAR HIMNUSZ ÉNEKLÉSE MIATT). ELSŐ ÉVEN PÓTVIZSGÁRA BUKIK MARXIZMUS - LENINIZMUSBÓL.
MÁSODÉVTŐL PROF. DR. PAP ZOLTÁN IRÁNYÍTÁSÁVAL RÉSZT VESZ A CÖLIÁKIA KUTATÁSÁBAN.
EZÉRT TÖBB ORSZÁGOS DIÁKKÖRI TUDOMÁNYOS KONFERENCIÁN ELISMERÉSBEN ÉS ÖSZTÖNDÍJBAN
RÉSZESÜL.1985-TŐL DIÁKKÉNT TAGJA EGY KUTATÓCSOPORTNAK.
1982-BEN ALAPÍTÓ TAGJA A MAROSVÁSÁRHELYI KATOLIKUS FOKOLÁRÉ CSOPORTNAK.
1984-BEN MEGNŐSÜL, AKKORI FELESÉGE GÉTZI ADRIENN, AKKOR FOGORVOSTANHALLGATÓNŐ.
1987-BEN DIPLOMÁZIK.
1987-BEN VISSZAUTASÍTJA A KÉNYSZERREL KIJELÖLT MUNKAHELYET MOLDOVÁBAN, AKKORI
FELESÉGÉVEL EGYÜTT KILÉP A KISZ-BŐL ÉS BEADJA EMIGRÁCIÓS KÉRVÉNYÉT. SZÜLEIT
KÉNYSZERNYUGDÍJBA KÜLDI A SECURITATE.
1988-BAN ELHELYEZKEDIK MINT HARANGOZÓ A SEPSISZENTGYÖRGYI SZENT GELLÉRT RÓMAI
KATOLIKUS PLÉBÁNIÁN. ORVOSI ELŐADÁSOKAT TART FIATALOKNAK.
1988 VÉGÉTŐL RENDŐRI FELÜGYELET ALATT ÁLL. KÖZBEN HELYETTES KÖRORVOS.
1989 DECEMBER 22-25 KÖZT FEGYVERES CIVILKÉNT RÉSZT VESZ AZ ANTIKOMMUNISTA
LÁZADÁSBAN, ROMÁNIÁBAN.
1990-BEN EMIGRÁL ERDÉLYBŐL MAGYARORSZÁGRA, AZÓTA MECSEKNÁDASDON KÖRZETI HÁZI
GYERMEKORVOS.
1990-93 KÖZT A PÉCSI BARANYA MEGYEI KERPEL-FRONIUS ÖDÖN GYERMEKKÓRHÁZBAN
KIEGÉSZÍTŐ TANULMÁNYOKAT VÉGEZ PROF. DR. SULYOK ENDRE VEZETÉSÉVEL. 1993 DECEMBERÉBEN
SZAKVIZSGÁZIK BUDAPESTEN, A PROF. DR. FEKETE - PROF. DR. PÉTER - PROF. DR. TULASSAY
BIZOTTSÁG ELŐTT.
2003-BAN DR. GÉTZI ADRIENN SAJÁT KEZDEMÉNYEZÉSRE ELVÁLIK DR. CZIMBALMOS-KOZMA
FERENCTŐL (2003-BAN DE FACTO, 2005-BEN DE JURE IS BEADJA ELLENE A VÁLÓPERT).
2005-BEN MEGISMERKEDIK DR. PAPP ERIKÁVAL, AZÓTA PÉCSETT ÉLNEK.
A PTE-ÁOK KÜLÖNBÖZŐ INTÉZETEIBEN „KÜLSŐSKÉNT” FOLYTATOTT CÖLIÁKIÁVAL, SIDS-EL,
ONCOPHARMACOLOGIÁVAL KAPCSOLATOS KUTATÁSOKAT.
Önéletrajz:
Első mestereim középiskolás koromban kezdtek tanítani. Első mesterem, Kiss József kiváló gimnáziumi
tanár tanított biológiából, kémiából a Bolyaiban, Marosvásárhelyen. Kisebb diákköri kutatólaboratóriumot hozott létre
a Bolyai gimnázium üvegházában, ahol Dr. Vécsei András jelenlegi parajdi háziorvossal akkoriban a hangyák
tájékozódási szokásait vizsgáltuk, majd Dr. Csíki Zoltán jelenlegi debreceni egyetemi oktatóval akkor a Maros folyó
kagylóinak szövettanával kezdtünk foglalkozni, a jelenlegi Prof. Dr. Jung János kórbonctani intézetében az Orvosi
Egyetemen. Itt rövidesen elkezdtünk bejárni boncolásokra. Czégeni József, a Gyógyszerészeti Fakultás
szerveskémia egyetemi oktatója magántanítványa voltam gimnazistaként, ő szervetlen és szerves kémiát, fizikai
kémiát, atomfizikát, csillagászatot valamint elméleti fizikát és kozmológiát tanított nekem. Kiváló, szuperintelligens
ember és tanár volt, különleges humorérzékkel, optimizmussal és a gyerekek, az elesettek, nehéz sorsúak iránti
tevőleges szeretettel, önzetlenséggel és jósággal megáldva. Egy bérelt szobában élt egyedül, egy ágy, egy asztal,
két szék, egy szekrény, egy sparhelt és egy kb. tízezer kötetes, stószokba tornyosuló könyvtár valamint egy
kakukkos óra társaságában a marosvásárhelyi Bolyai utcában, szabad idejében ingyen tanított diákokat és
ismeretterjesztő előadásokat tartott. Ő a második, meghatározó mesterem, szombatonként délután hattól sokszor
éjfélig tartott nála a néha kocsmázással záródó magántanítás. Ő ismetetett meg Müller Mihály tanárral, a Pedagógiai
Főiskola fizikus főiskolai oktatójával, magántanítványa voltam gimnazistaként, ő fizikát tanított nekem. Kiváló, jó
humorérzékű, kedves ember volt, sokszor a Maros volgyében, Gödemesterházán lévő kis házában málnabor mellett
magyarázta a fénytant, elektromosságtant, atomfizikát, vagy az erdőben sétálva botjával a patakpart fövényébe írta
a képleteket. Kiváló, felejthetetlen tanár volt, ő a harmadik mesterem. Közben rendszeresen bejártunk a
korbonctanra boncolni, itt Jung professzor magántanítványa lettem gimnazistaként biológiából, anatómiából,
élettanból. Ő a negyedik mesterem. Az egyetem évei alatt végig bejártam intézetébe (sok szeretettel emlékszem
azokra az évekre, 1982-ben egyetemistaként azt a bonctechnikai jegyzetet illusztráltam részben, amiből később
vizsgáznom kellett...). A Bolyaiban az osztályfőnöknőmmel, annak intoleráns és autokratikus magatartása és az én
azon igényem miatt, hogy megkapjam mástól azt a tiszteletet, amelyet én megelőlegeztem, konfliktusba kerültem és
gyakorlatilag eltávolítottak, pontosabban az igazgató jószándékának köszönhetően el tudtam menni egy másik
iskolába (akkori nevén Unirea), ahol biológia-kémia szakon érettségiztem. Itt kiváló tanáraim voltak: Kiss István
(kémia), Bába Zoltán (kémia), Piros Sanda (mikrobiológia), Bedő Margit (laboratóriumi kémia), Dósa Jenő
(pszichológia) – az oktatás részben az Orvosi Egyetemen folyt, Prof. Dr. László Jánosnak, az Egyetem akkori
rektorának köszönhetően (ő az, aki valójában felfedezte a B-hepatitis vírusát, nem azok, akik megelőzték a
bejelentéssel). Az orvosi egyetemet Erdélyben, Marosvásárhelyen az Orvosi és Gyógyszerészeti Egyetemen (akkor:
IMF, most: UMF, magyar rövidítéssel: MOGYE), a magyar szekción, gyermekgyógyász ráépített profilon kezdtem
1980-ban és végeztem 1987-ben. Az első éven nagy hatást tettek rám Filep Győző biofizikai előadásai, és abban a
szerencséban volt részem, hogy orvosi elektronikát tanulhattam elméletben és gyakorlatban is Prof. Dr. László
Józseftől. 1982 után kezdtem bejárni a Szívsebészeti Klinika intenzív therapiás osztályára, időrendben az ötödik
mestermnek néhai Dr. Kerek Istvánt, a kiváló, felejthetetlen, hihetetlen tudással és memóriával megáldott orvost
tekintem (jelszava „sokat, gyorsan és jól” volt). 1982-83-ban kezdtem a gluten-sensitiv enteropathia allergénjeinek
kimutatásával foglalkozni, időrendben hatodik, meghatározó mesterm, Prof. Dr. Papp Zoltán, a híres klinikavezető
gyermekgyógyász egyetemi tanár mellett. Este, mikor fehér köpenyben ketten jártuk végig – sokszor órákig – a
klinka kórtermeit, rengeteget tanultam tőle, és mellette éreztem először azt a felejtehetetlen élményt, hogy milyen
érzés orvosnak lenni. 1986-ra dolgoztam ki új eljárást a GSE antitestjeinek immunfluorescens és ELISA eljárásos
kimutatására, kevéssel azután, hogy az ELISA eljárás terjedni kezdett. 1987-ben diplomáztam, de mivel
szembefordultam a kommunista rezsimmel és kiléptem a KISZ-ből, rendőri felügyelet alá vontak a romániai
kommunista hatóságok. Az 1989-es romániai antikommunista fegyveres lázadásban való (számomra: sajnos
csekély, a szekusok számára: szerencséjükre csekély) részvételem után 1990-ben egzisztenciális okokból
Magyarországra költöztem, elvállaltam a gyermekorvosi praxist Mecseknádasdon, ahol jelenleg is dolgozom. 1990től időrendben hetedik mesterem, Prof. Dr. Sulyok Endre mellett dolgoztam Pécsett, körzeti gyermekorvosi praxisom
mellett, majd 1993-ban Budapesten az akkori OTE-n szakorvosi diplomát szereztem csecsemő és
gyermekgyógyászatból. 1995-2000 közt Pécsett, körzeti gyermekorvosi praxisom mellett, Prof. Dr. Ohmacht Róbert
és Prof. Dr. Németh Péter intézeteiben kidolgoztm a gluten-sensitiv enteropathia antigén-fractioinak Elisa és
immunprecipitatiós kimutatását (http://www.geocities.com/drcfhu/glutfrhu/index.html). 2000-2002 közt, körzeti
gyermekorvosi praxisom mellett, együttműködésben Prof. Dr. Luigi Matturri (Universita degli Studi di Milano, Istituto
di Anatomia Patologica) intézetével a SIDS (bölcsőhalál) ethiopathogenesisével és neurohistopathologiájával
foglalkoztam, majd publikáltam az első pozitív hisztológiai diagnózist Magyarországon SIDS esetben.
(http://www.geocities.com/drcfhu/sids/index.html). Az elmúlt években egyes antibiotherapia és allergologia
témakörben tartott előadásaimat pontszerzőként akkreditálták. Jelenleg, körzeti gyermekorvosi praxisom mellett, a
genericumok mellékhatásprofiljának kialakításáért felelős reziduumfractiók analitikájával és bizonyos cytotoxicus
phytopharmakonk tumorsejtnecrosist okozó hatásával foglalkozok PTE Pharmacologiai intézete és Immunológiai és
Biotechnológiai Intézete segítségével, valamint rendszeresen látok el ügyeletet Pécsváradon.
l. idézet, hivatkozás saját forrásra magyarázat céljából 02
Esszé
Dr. Czimbalmos-Kozma Ferenc
Az alkotásról
Sokszor olvastam és hallottam azt a nagy marhaságot, miszerint a tehetség a fegyelemmel, szorgalmas
tanulással, kitartó munkával párosulva az egyedüli út a felfedezés, eredmény, siker eléréséhez, a tudomány
előrehaladásához. Sőt, szegény gyermekeket is ezzel a félrevezető és hazug, képmutató csalással (rosszabb
esetben lelki vagy akár testi terrorizálással) késztetik arra, hogy egészséges ösztöneiken erőszakot téve az éppen
aktuális, magát erkölcsösnek hazudó, de valójában mindig nagyon is mulandó, tehát: pillanatnyilag valahol éppen
hatalmon lévő estabilishment (oldaltól, történelmi kortól, földrésztől függetlenül) szájíze szerint biflázzon be
mindenféle hülye tananyagot. A valahogyan mindig kéznél lévő korifeusok és őket szajkózva a társadalom többsége
még attól sem riad vissza (sokan tudatlanságukban nem is hibásak érte, habár, ha az értelmes ember
utánagondol...), hogy nagy felfedezőket , tudósokat hozzanak fel “jó példának” . Pedig a mindenki által jólismert
valóság bizony, bizony, nagyon de nagyon más! Az emberiség kultúrájának jelenlegi, meglepően magas fejlettségét
nagyobb részt nem a sok, szorgalmas, kitartó, becsületes embernek köszönhetjük, hanem főleg a néhány, sorból
kilógó, merőben újat alkotó, olykor eléggé lökött géniusznak. Nélkülük becsületesen, szorgalmasan, öntudatosan és
eltökölten túrnánk a földet faekével a mai napig is a Tigris és az Eufrátész közt, és ibolyánk nem volna az
ősrobbnásról. Vegyük csak a matematikát példának: az igazi nagy “durranást” jelentő dolgokat egytől egyig nem
profi és hivatalos szakmabeli tudósok hozták össze! Évezredekig fejődött különféle helyszíneken a számolás és
mindenféle mérés tudománya, de a filozófus Euklidész kellett hozzá, hogy az Elemek megírásával megalkossa az
absztrakt matematikát, mint rendszert és tudományt. Aztán bő kétezer évig semmi igazán nagy (értsd: sohasemvolt
új) dolog nem történt, amígnem a hadmérnök Bolyai János egy-két utazás és egy-két párbaj közt valami rohadt
kaszárnyában lazán leírta 12 oldalban (!!!) a gömbi geometriákat. Ne is mondja senki, hogy a Bolyai 12 oldalas
zseniális alkotásával akár csak egy napon is együtt lehetne emlegetni súlycsoport szerint mindazt ami Euklidész és
Bolyai közt született. Hacsak nem a főügyész Pierre de Fermat könyvmargókra firkált nagy sejtését esetleg... Mert a
többi mind a korábbiak továbbfejlesztése volt, és nem valami olyan új, mint például a festészetben egy Boticelli
festette szexi csaj egy sötét középkori krónika iniciáléján gubbasztó legörbült szájú királyhoz képest. Aztán megint
egy darabig nem sok történt, közben pedig, állítólag (sok jel mutat erre!) egy bajuszos férfi inkognitóban állítólag
többször járt Marosvásárhelyen a Teleki Tékában, élénken érdeklődve és tanulmányozva Bolyai János több ládányi
kiadatlan kézirathagyatékát, majd publikálta a... relativitáselméletet. Szeretném védelmembe venni a fentebbi
megállapításaimat. Sok értékes dolog született a köztes időkben, de kevés eredeti, lényegesen-forradalmian új.
Nagyon becsülöm Willest a nagy Fermat sejtés megoldásáért, de... találta volna ki ő! Igazán nagy elme Riemann, de
a lényegre mégiscsak Bolyai János jött rá (Rieman inkább a zéta függvény zérushelyei nem triviális valós gyökei
dolgában látott meg valamit, amiből még lehet nagy durranás). Ezért nagyobb ő, mint például a minden
megbecsülést és tiszteletet megérdemlő Hilbert. Más dolog ugyanis szorgos munkával elsajátítani az elődök tudását
és azt továbbfejleszteni, megbecsült tudóssá válva és a köztiszteletet jogosan kiérdemelve önzetlenül sokat tenni a
tudományért és megintcsak teljesen más a zseniális elme gyökeresen új alkotása. Felsőbbrendű. Ebbe a körbe sem
szorgalom, sem pénz, sem munka árán nincs belépés. Ebbe a körbe tartozni nem érdem, nem szerencse, nem
belépő ide a hivatástudat sem. Tálentum dolga mindössze, melyet sokan eltékozolnak. Szinte igazságtalannak tűnik
a dolog: az érdemtelennek úgy adatik meg a zsenialitás, hogy sokszor semmit sem tett érte, a szorgalmasnak nyúlik
a nyaka az erőfeszítéstől és avval marad. Ilyen lehangoló lenne a kép? Nem egészen! Feltűnő a számbeli
aránytalanság a humán és reálszféra géniuszainak száma közt a humánszféra javára. Vajon miért van ez? Azért
dinamikusabb a humán kultúra, mert a mővészoid emberek szabadabb lelkületüek a reálosoknál? Részben ez
lehet a válasz. A kötöttség a zsenialitás sárbataposása. A hasznosuló reál-zsenialitás pedig nem kellene ilyen ritka
legyen, én a kérdésben teljesen Pygmalion-párti vagyok! G. B. Shaw lángelméje nagy igazságra hívta fel a
figyelmet. Szerinte egyenesen minden emberben(!) világít az isteni szikra! Nagy kár, nagy bűn eltaposni. Ha
mindenkiben kifejlődhetne, amennyire csak lehet, talán nem is volna ilyen irigység tárgya, mint ma. Kiderülne, hogy
egészen hétköznapi, normális emberek is alkotnak néha gyökeresen új dolgokat és még csak nem is nyögnek
hozzá az erőlködéstől. Amikor a diszkrét mezőelméletről és az azt leíró apparátusról, a kvantummatematikáról esik
szó, nem tudok elhallgatni néhány tényt. Az igaz, hogy mindig is, kisgyermek koromtól érdekelt a tudomány , de az
iskolában semmi jelét nem mutattam különleges képességeknek, inkább közepesen tudtam csak megfelelni az
ottani és akkori követlményeknek. Sőt, harmadik-negyedikben olyan hülye voltam, hogy az még nekem is feltűnt:
nem értettem például az asszociativitás és kommutativitás közti különbséget az alapműveleteknél! Lehet, az orrpolip
okozta hipoxia ártott az agyamnak, amígnem a kedves és kiváló humorérzékő Dizmatsek doktor meg nem operált,
aztán helyrejött az eszem is úgy ötödikes koromra, csak éppen nem használtam, mert Kiss Jóska bácsi tantárgyain
kívül eléggé utáltam minden egyebet, főleg az elborult agyú kritikusok hülye förmedvényeit a magyar irodalom
nagyjairól, amit nem átallotak műelemzésnek aposztrofálni az akkori ízlésdiktátorok. Igazság szerint nem is illett
volna megtűrjenek engem a marosvásárhelyi híres Bolyaiban, csak a volt kollégái tisztelték az apámat, aki inkább
kirúgatta magát a tanfelügyelői vezető állásából, de még a szemét vaddisznó tetűláda hatalom elvárása ellenére
sem bántott soha senkit. Kétszer is álltam bukásra matematikából, bonyolult számításokra ma sem vagyok képes, a
számtant legfeljebb középszinten ha ismerem. Pár éve, a 6-os főúton autózva, kb. A 172-es km. szelvénynél
(valahogy megmaradt bennem ez az emlék), anélkül, hogy szándékosan ezirányban szellemi erőfeszítést tettem
volna, fölmerült bennem az a gondolat, hogy a Hilbert-féle axiómaredszer alapelemeinek konvencionálisan kijelölt
tulajdonságai közül a dimenziószámra más konvenciót alkalmazva, jelesül a lehetséges dimenziószámok közül a
nullát kizárva egy teljesen új matematika születik. Megálltam utána valahol az apátvarasdi eltérő parkolójában, egy
üres orvosi recept hátoldalára leírtam a főbb fogalmakat (az egész kvantummatematika lényege nagyjából ráfért) és
továbbmentem dolgomra. Pár nap múlva elővettem és rendesen leírtam, majd továbbfejlesztettem a dolgot, de az
már csak favágás volt, míg a lényeg, magának az új rendszer megalkotásának folyamata egy laza, egy-két perces
tőnődés csupán. Lehet, hogy kiábrándító, de semmiféle pátoszt és meghatottságot nem éreztem. Nem sokkal
később, a Genova melletti Camogli halászfalu kikötőjének világítótornya alatt halkonzerv evése és Moretti sör (6 és
fél decis, nem három, természetesen, az olaszokban van fantázia) ivása közben vetődött fel bennem annak a
gondolata, hogy az absztrakt tér kvantumos modellje lehet a létező reális fizikai térnek. A gondolaton egy
háromnegyed üveg sör megivásáig terjedő időn keresztül rágódtam egy kicsit, közepes erőbedobással, majd
emlékezetből pár hét után leírtam a diszkrét mezőelméletet. Utána életem legnagyobb, hetekig tartó és a
meghülyülésig kifárasztó szellemi erőfeszítése árán, Wolfram sejtautomata elméletétől (NKS) inspirálva jöttem rá az
elméletben kulcsfontosságú toposz-transzformáció fogalmának szükségességére az elmélet általánosíthatóságának
érdekében. Semmi lobogó hajú, tüzes tekintető, elszállt agyú zseni: egy átlagos, környezete szerint normális orvost
lehetett csak akkor ott látni. Volt, aki kertelés nélkül zseniálisnak nevezte a kvantummatematika és a diszkrét
mezőelmélet megírását (www.geocities.com/quanmatworkshop). Amennyiben igaznak és használhatónak
bizonyulnának, talán lenne is benne valami igazság. De ha bárki is azt a marhaságot mondaná, hogy mindez
szorgalmamnak, kitaró munkámnak, matematikai és fizikai felkészültségemnek köszönhető, szemberöhögném. Ha
pedig valakinek az jönne ki a fejéből a száján keresztül, hogy eredményeim abban a tudásban gyökereznek, amit
valamely neves tanintézményben (ahová fölvettek, mert jótanuló voltam) sajátítottam el szorgalmas memorizálással,
akkor egyenesen röhögőgörcsöt kapnék. A dolog valójában tragikomikus. Körzeti orvosként 19 éve egyedül
dolgozok, hibát, bajt nem csináltam, szeretet övez (pár embernek nem tetszem, mert nagypofájú vagyok és
magasról teszek a hatalomra és a tekintélyre, de ez szerintem így a jó) és nem tartanak rossz orvosnak, kollégáim
megbecsülnek (néhány kivétellel, de ezzel én is így vagyok, úgyhogy kvittek vagyunk). Állítom, hogy mindazon
összes tudást, amivel ma rendelkezem, tíz év alatt simán elsajátítottam volna. Ha békén hagytak volna a válogatott
baromságaikkal, 16-18 éves koromra minden további nélkül vizsgázott szakorvosként képes lettem volna úgy
gyógyítani, mint ma, ha bejárhattam volna tanulni oda, ahová én láttam volna jónak. És humán kultúra tekintetében
sokkal műveltebb lennék, mint ma vagyok, a gőzös agyú hülyék rámerőltetett kényszere miatt fölöslegesen elizélt
rengeteg drága idő alatt elvégeztem volna a teológiát, fizikát, tudnék latinul, héberül, görögül. Még jó, hogy amint a
rühes kutya a szőrét, úgy le tudtam vedleni a sok maszlagot, amit egyes „alma materekben” próbáltak a legdurvább
módon (az egzisztencia, a fizikai szabadság, a továbbtanulás lehetőségének elvesztésével fenyegetve) rám
kényszeríteni, és sikerül semmire sem emlékezni, ami fölösleges hülyeség. A talentum pedig amúgy inkább
felelősség, mint ok a büszkeségre, netán gőgre. Milyen jogon nézné le az érdem nélkül talentummal
megajándékozott a szorgalmasan munkálkodót? Csak mert nagyobb elismerést arat? Nem lenne etikus. Sokkal
inkább helyes, ha az, aki érez magában valamilyen képességet, ne hagyja veszendőbe menni. Mindezt már az
iskolában el kellene kezdeni, bátorítva a gyermekekben az intuíciónak legalább a használatát, nem pedig eltaposni
azt, ha már létrehozni ilyet úgyse tudunk. Amelyik gyermek valamiben különleges tehetséget mutat, annak szabad
utat kellene adni, hogy kötöttség nélkül fejlődhessen. Azt jelentené mindez, hogy javasolnám az iskolarendszer
felszámolását és azt, hogy hagyjuk saját kedvük szerint söpredékké zülleni a fiatalokat? Nem, korántsem. Szükség
van a jó iskolarendszerre, amely megadja a nékülözhetetlen ismereteket a felnövekvőknek. Az iskolarendszer képes
kellene legyen arra, hogy hat és tizenhat éves kor közt mindenkit megtanítson arra, hogy amikorra tizenhat éves
lesz, tökéletesen és helyesen tudjon anyanyelvén írni és olvasni, jól beszéljen két idegen nyelven (jól
kommunikáljon, és ne a tízféle pászt tenszet tudja, a derdídászt pedig ösztönből használja, ne listabiflázásból), tudja
azt, mit jelent adott nemzetéhez tartozni, tudjon jól számolni (alapműveletek, százalék, gyökvonás, területszámítás,
de nem integálás és kotangens alfa), ismerje a csillagos eget és a térképet, az égi mozgásokat és az elekromosság,
kémia, természetrajz alapjait, no meg tudjon jól úszni, megbízhatóan vezetni gépjármővet, tudjon bánni a
lőfegyverrel és életben maradni pár napig extrém helyzetben (a lányok is), tudjon ehető krumplilevest főzni,
csecsemőt pelenkázni, normálisan inget kimosni és sliccgombot varrni (a fiúk is), tudjon kicserélni egy
villanykapcsolót és installálni egy videokártyát (a lányok is), képes legyen a mesterséges légzésre, szívmasszázsra
és vérzéscsillapításra, ne öntsön sósavas vízkőoldót a hipós budiba, ne dugjon két kilowattos vasalót a
szünetmentes tápba (fiúk is, lányok is...), ésatöbbi... És ahogy az alapokat elsajátította valaki és felsőbb
tanulmányokba kezd, amennyiben jelét mutatja valamilyen extra képességnek, teljesen szabadon kellene hagyni,
hogy kifussa magát, támogatni mindennel, csak annyit kérve, hogy a szűk területét művelje szorgalmasan.
Kevesebb eltaposott tehetség és jobb világ lenne az eredmény. Tudom, ez a vélemény sokaknak nem tetszik, de azt
hiszem, mégis igaz és jó szívvel kiállok vitára a védelmében.
Pécs, 2006 február 23.
JEGYZETEK, HIVATKOZÁSOK, BIBLIOGRÁFIÁK:
jegyzetek, hivatkozások: 03, forrás: www.wikipedia.hu
Fogalmak a Turing-gépről
A Turing-gép fogalmát 1936-ban megjelent cikkében dolgozta ki a matematikai számítási eljárások, algoritmusok precíz leírására,
tágabb értelemben pedig mindenfajta „gépies” problémamegoldó folyamat, pl. a számítógépek működésének modellezésére. Erre az időszakra,
a II. világháború környékére tehető az ilyesfajta, a számítási eljárásokat azok különféle modelljein keresztül vizsgáló kutatások fellendülése,
melyek végül a valódi számítógépek építésébe torkollottak (Turing maga is részt vett egy valódi gép, a Colossus megépítésében).
A Turing-gép úgynevezett absztrakt automata: a valóságos digitális számítógépek nagyon leegyszerűsített virtuális modellje. További
jelentőségét az ún. Church–Turing-tézis adja, amely szerint univerzális algoritmikus modell. Az ilyen egyszerű számítógépmodellek matematizált
elméleteivel a matematika számítógép-tudománynak nevezett eléggé fiatal tudományágának olyan részterületei foglalkoznak, mint például a
számításelmélet.
Turing-gép elve (beillesztve szerző ábrája)
P: vezérlőprocesszor, M: memória, W: író, R: olvasó, < >: továbbító, D: adathordozó szalag.
A fogalom értelmezései, modelljei
Ha elfogadjuk igaznak azt a kijelentést, hogy a Turing-gép nem más, mint az egyszerű számítógépek modellje, a Turing-gép
kifejezésen még mindig két különféle, bár szorosan összetartozó dolgot is érthetünk, és általában szokás az is, hogy a kifejezésbe mindkét
értelmet egyszerre belelássuk (de ez nem szükséges és nem is minden szerző teszi):
A nem formális – informatikai modell: A Turing-gép jelentheti az egyszerű számítógépek informatikai modelljét. Ebben a felfogásban a Turinggépet olyan fizikailag is megvalósítható egyszerű automata formájában szokás interpretálni, mely három, fizikailag létező tárgyként elképzelt,
hardveres egységből áll: a szalagtárból (memória és input-output-perifériák), a vezérlőegységből (CPU) és az író-olvasó fejből (buszrendszer). Itt
látszik, hogy a Turing-gép mennyire hasonlít a számítógépek felépítéséhez.
Matematikailag a Turing-gépet mint egy öt-tíz elemből álló halmazrendszert szokás definiálni. Ebben az esetben a „hardveres” interpretáció
elhagyható, és a Turing-gépek és a vele kapcsolatos fogalmak elmélete a valóságos világhoz kapcsolódó minden „szennyes” hasonlóságtól
megtisztított, formális elméletként közölhető.
A matematikai modell és egy valós gép között az a lényeges különbség van, hogy a fizikai gépek memóriája véges. Egy érdekes
lehetőség, hogy a fizikai és az absztrakt modell is szimulálható akár egyszerű PC-k segítségével is.
A klasszikus Turing-gép informatikai modellje
A Turing-gépnek rengetegféle változata van, e szócikk az ún. klasszikus változattal (teljes nevén szalagtáras, egyszalagos, egyfejes,
relatív címzésű, három címes, statikus programozású, véges ábécéjű, véges (állapotú) determinisztikus absztrakt automata). Bizonyított
matematikai tételek szerint a többi változat nagy része, legalábbis ama tekintetben, hogy mit tud kiszámolni, ekvivalens a klasszikus változattal.
Ahogy fentebb mondtuk, e felfogásban a Turing-gépet fizikailag is megvalósítható egyszerű automata formájában képzeljük el, mely
három nagyobb fizikai egységből („hardver”) áll:
1.egy cellákra osztott végtelenített papírszalag formában létező memóriából (szalagmemória, szalagtár, társzalag); minden cellában a gép által
megértett nyelv betűi, azaz a Tár-abc egy-egy betűje van írva;
2.egy vezérlőegységből, mely a gép programját tartalmazza; a vezérlőegység különböző időpillanatokban különféle belső állapotokban létezhet;
3.egy író-olvasó fejből (I/O-fej), mely szimbólumokat ír vagy olvas a szalag celláira (ahogy a valóságos számítógépek betűket írnak ki a monitorra
vagy a nyomtatóban lévő papírívre).
továbbá egy „szoftveregységből”, ez az átmenettábla, ami vezérli a gép működését, megadva, hogy adott szimbólum beolvasásának hatására
adott állapotban mit tegyen: hogyan mozogjon, milyen szimbólumot írjon a tárra, és milyen belső állapotba kerüljön.
A Turing-gép működése: A Turing gépnek minden időben van egy aktuális pozíciója a memóriaszalagon, amely pozíciónál az aktuális
cella helyezkedik el. Minden időben van egy állapota, amely az aktuális állapot. Az aktuális állapotok definiálása része a gép programozásának.
A gép minden lépésben beolvas egy szimbólumot a társzalag aktuális cellájából, ezután a program attól függően, hogy az aktuális
állapota milyen és a beolvasott szimbólum a gép abc-jének melyik betűje, a következő három lehetőség közül az egyiket írja elő:
1). az aktuális cellába beír egy meghatározott szimbólumot,
2). az olvasófej a társzalagon balra vagy jobbra lép, esetleg helyben marad,
3). a gép (vezérlőegysége) átvált az éppen aktuális állapotból (amelyben éppen van, abból) egy másikra (az új állapot persze lehet ugyanaz mint
az aktuális). Egy speciális állapot a „stop-állapot”, amely után a Turing-gép a programozása szerint megáll.
Az időbeli lefutást leírva a gép beolvas, változtat, mozog, és aztán ez a ciklus újra kezdődik: azon a cellán, amelyre mozgott, ismét
beolvas, változtat, majd lép. Így megy ez, s eme folyamatnak a gép programozásától és az elvégzendő feladattól függően kétféle kimenetele
lehet:
Szabályos megállás (terminálás): a gép leálló belső állapotba („stop-állapot”) kerül;
„Elszállás”: a gép végtelen ideig fut. A legegyszerúbb módon ez úgy lehet, hogy egy végtelen ciklusba kerül, de más módon is futhat
végtelen ideig, mert egyszerűen sosem kerül stop állapotba.
A játékelmélet
A játékelmélet a matematika egyik, interdiszciplináris jellegű (tudományágak közé egyértelműen nehezen besorolható, leginkább talán
a kombinatorika részeként tárgyalható) ága, mely azzal a kérdéssel foglalkozik, hogy mi a racionális (ésszerű) viselkedés olyan helyzetekben,
ahol minden résztvevő döntéseinek eredményét befolyásolja a többiek lehetséges választása, vagyis a játékelmélet a stratégiai problémák
elmélete.
A játékelmélet alapjait Neumann János rakta le egy 1928-as munkájában, majd az Oskar Morgenstern neoklasszikus matematikusközgazdásszal közösen írt „Játékelmélet és gazdasági viselkedés” című (The Theory of Games and Economic Behavior, 1944) művében. A
matematika, a közgazdaságtan, a szociológia, a pszichológia, és a számítástechnika a játékelmélet által legérintettebb tudományok. A
mesterségesintelligencia kutatás is felhasználja eredményeit. 1994-ben Harsányi János magyar származású közgazdász, másokkal megosztva
közgazdasági Alfred Nobel-emlékdíjat kapott játékelméleti kutatásaiért (A magyar mozik nemrég játszották az ,,Egy csodálatos elme'' című
amerikai játékfilmet, amely John F. Nash matematikus életéről szól, aki Harsányi Jánossal és Reinhard Selten-nel együtt 1994-ben elnyerte a
közgazdasági Nobel-díjat. A nagy sikerű film azonban nem annyira Nash munkásságával, sokkal inkább betegségével foglalkozott, így kevés
derült ki arról, miért is kapott Nash Nobel-díjat).
Alapfogalmak
• A Játék a játékosok lehetséges viselkedését és lényeges körülményeket
meghatározó szabálysor által leírt folyamat.
• Az információs halmaz (ismeret) meghatározó. Például a játék tökéletes
információs, amennyiben a résztvevők birtokolják az összes vonatkozó adatot
(szabályok, lehetséges választások, eddigi események), és a játék véges.
• A stratégia a szabályokat alkalmazó, az ellenfél érzékelt hibáit felhasználó –
győzelemre, de minimum döntetlenre segítő módszer.
• Zéró összegű az a játék, amelyben a játékosok csak egymás kárára
növelhetik nyereségüket.
• Nem zéró összegű játszma az, mikor a két fél nemcsak egymástól, hanem
egymással együttműködve valamilyen külső forrásból is nyerhet.
• Egy játék lehet két-, vagy többszemélyes.
• Kooperatív a játék akkor, ha a játékosok között kialakul az együttműködés.
• Nem kooperatív játék esetén a játékosok versengenek egymással.
• A Nash-egyensúly az összes játékos összes stratégiájának olyan együttesét
jelenti, amelyben egyik játékosnak sem származik előnye abból, ha
stratégiáján változtat, amíg a többi játékos azonos módon játszik tovább.
Nem-kooperatív játékelmélet
Nash fő eredményét a nem kooperatív játékelmélet területén érte el, amely olyan stratégiai játékokkal (más néven: szituációkkal)
foglalkozik, ahol a játékosokról (más néven: aktorokról) feltesszük, hogy nem kötnek megállapodásokat egymással, más szóval az egyes
játékosokat, nem pedig csoportjaikat tesszük a vizsgálat tárgyává. Feltesszük továbbá, hogy minden játékos ismeri a saját maga és a többi
játékos által választható lehetőségeket (más néven: stratégiákat), és az ezekhez a lehetőségekhez tartozó hasznosságokat (más néven:
kifizetéseket). Emellett minden szereplő tudja mindezt, sőt azt is, hogy ezeknek az információknak a többi játékos is birtokában van.
A játékokat leggyakrabban úgynevezett normál (egyes irodalmakban: stratégiai) alakban írják fel, ahol egy táblázatban jelölik azt, hogy
az egyes stratégiák választása mekkora hasznosságot eredményez az azt választó játékos számára.Nem-kooperatív játékelmélet: Nash fő
eredményét a nem kooperatív játékelmélet területén érte el, amely olyan stratégiai játékokkal (más néven: szituációkkal) foglalkozik, ahol a
játékosokról (más néven: aktorokról) feltesszük, hogy nem kötnek megállapodásokat egymással, más szóval az egyes játékosokat, nem pedig
csoportjaikat tesszük a vizsgálat tárgyává. Feltesszük továbbá, hogy minden játékos ismeri a saját maga és a többi játékos által választható
lehetőségeket (más néven: stratégiákat), és az ezekhez a lehetőségekhez tartozó hasznosságokat (más néven: kifizetéseket). Emellett minden
szereplő tudja mindezt, sőt azt is, hogy ezeknek az információknak a többi játékos is birtokában van.)
Megállapítások
Valamennyi kétszemélyes zéró összegű játékban létezik mindkét fél számára optimális stratégia, mégpedig az egyéni tiszta stratégiák
tervezetten véletlen keveréke.Ésszerű feltételezni, hogy minden játékos a lehető legnagyobb nyereség elérésére, és a veszteség kockázatának
minimalizálására törekszik.
Minden véges játék legalább egy egyensúllyal rendelkezik. (Ezt az eredményt John Nash bizonyította be az 1950-es években.)
Feldolgozott játékhelyzetek
Kétszemélyes, kétválasztásos szimmetrikus játékok
A kétszemélyes, kétlépéses (mindkét játékosnak csupán két lépéslehetősége van)
játékoknak 78 fajtája létezik. Célunk, hogy a játékosok döntéslehetőségeit elemezzük s megtaláljuk a lehetséges legoptimálisabb megoldást.
Mivel mindkét játékos kétféleképpen dönthet, négy lehetséges kimenetele van a játékoknak, ezek mindegyike pedig a két játékos számára eltérő
értékű. Ez tehát azt jelenti, hogy át kell tekinteni az összes olyan táblázatot, amelyben az 1, 2, 3, 4 számok különféle kombinációkban
helyezkednek el az egyik, illetve a másik játékos számára leosztva. A 78, egymástól lényegesen különböző táblázat vizsgálatából kiderült, hogy
közülük 12-ben a két játékos szimmetrikus helyzetben van. Ezek közül pedig négy tekinthető csapdahelyzetnek. Nem csapda típusú játékra
példa:
• (1. játékos – 1. stratégia, 2. játékos – 1. stratégia) = 4,4
Ebben a játékban nyilvánvaló, hogy mindkét játékosnak csakis az 1. stratégiát érdemes választania, a másikkal mindenképpen rosszabbul jár.
Ezzel automatikusan, konfliktusmentesen el is érik a közös optimumot, csapdáról szó sincs. A kétszemélyes, kétválasztásos, szimmetrikus
játékoknak négy csapdatípusa a Fogolydilemma, Nemek harca, Vezérürü és a Gyáva nyúl fantázianevű játékok. A játszmák nevüket azokról a
(ma már klasszikusnak számitó) példákról kapták, amelyeken keresztül a legtalálóbban lehet őket bemutatni. Azoknak a kétszemélyes
játszmáknak, ahol a játékosoknak már fejenként három választási lehetőségük van, sokkal több, közel kétmilliárd változata van. Ezek
csapdahelyzeteit senki nem térképezte még fel, mivel nagyon valószínű, hogy megegyeznek a négy alapjátékéval. Az alapvető
csapdamechanizmusokat ez a négy játék megmutatja – a tényleges, életbeli konfliktusok általában e négy alaptípus bonyolult, kusza
kombinációiból épülnek fel.
Fogolydilemma
• Alaphelyzet: van két fogoly; ha az egyik vall, de a másik nem, akkor a vallomást
tevő elmehet, míg a másik 10 évet kap; ha egyik sem vall, akkor 6-6 hónapot
kapnak, ha mindketten, akkor 6-6 évet.
• Ez nem zéró összegű játék.
• A nehézség: a játék "megoldása", a domináns stratégiák melletti egyensúly az,
hogy mindketten valljanak. Bármit is tesz a másik, a játékos jobban jár, ha vall.
Mégis mindketten jobban járnának, ha egyikük sem vallana.
• A fogolydilemma jelentőségét e paradox tulajdonsága adja, vagyis hogy az
egyensúly paretói értelemben rossz eredményt idéz elő. E tulajdonsága miatt a
"láthatatlan kéz" ellenpontjának tekinthető. Itt ugyanis az önérdek követése nem
segíti elő a közérdeket.
Nemek harca
• Alaphelyzet: egy fiatal pár reggel összeveszik az esti programon: focimeccs vagy
színház. Reggel nincs idő a megbeszélésre, este későn végeznek a munkájukkal,
és ekkor kell dönteni ki hova menjen. A felek preferenciái: elsősorban együtt tölteni
az estét, másodsorban az általa kedvelt helyen.
• Ez nem zéró összegű játék.
• A játéknak két egyensúlya van tiszta stratégiákkal (mindketten színházba mennek, illetve mindketten focimeccsre mennek). Létezik egy
harmadik egyensúly is kevert stratégiákkal.
Vezérürü
• Alaphelyzet: két szuperjólnevelt ember egymást tessékeli előre az ajtóban.
• A nehézség: ha mindketten ragaszkodnak ahhoz, hogy a másik menjen előre,
örökre az ajtó előtt ragadnak. Ha az egyikük enged, fennáll a veszélye, hogy emiatt
a másik modortalannak tartja majd.
Gyáva nyúl (chicken run, csibefutam)
• Alaphelyzet: Két kocsi száguld egymás felé, az veszít, aki hamarabb félrekapja a
kormányt.
• A nehézség: Ha egyikük sem kapja félre mindketten meghalnak, de egyik sem
tudhatja, hogy a másik mennyit kockáztat még.
A közlegelő problémája
• Alaphelyzet: a falu legelőjének nagy része kiszárad; a gazdák megbeszélik, hogy a maradékra mindenki csak 1 tehenet vihet be.
• Ezt azonban senki sem tartja be, mert a gazdák egyenként profitálnak abból, ha
eggyel több állatot hajtanak ki a legelőre, így a legelő elfogy és minden tehén
elpusztul. Ez a klasszikus közjószág-probléma.
Szarvasvadászat
• Két vadásznak azt kell eldöntenie, hogy szarvasra vagy nyúlra akar-e vadászni. A
szarvast csak akkor tudják levadászni, ha kooperálnak, a döntést azonban egyedül
kell meghozniuk, és a másik döntéséről nem tudnak.
A Nash-egyensúly
A játékelméletben Nash-egyensúlynak nevezzük azt a stratégiaegyüttest, amelyre igaz, hogy a játékosok kölcsönösen a legjobb
választ adják egymás stratégiáira. Ez azt jelenti, hogy amennyiben a többi játékos nem változtat stratégiáján, az adott játékosnak sem érdemes
változtatnia.
Névadója
Nevét az őt felfedező John Forbes Nash amerikai matematikusról kapta, aki ezért az eredményéért a magyar származású Harsányi Jánossal és
Reinhard Seltennel közösen 1994-ben Közgazdasági Alfred Nobel-emlékdíjat kapott.
Matematikai definíciója
Egy n-szereplős J- játékot adottnak tekintünk, ha adottak a Σi stratégiahalmazok
(
),
valamint az ezeken értelmezett Hi(σ1,...,σi,...,σn) hasznosságfüggvények
(
).
Ha létezik
stratégiapont, amely mellett minden
szereplőre igaz az, hogy
bármely
stratégiára, a pontot Nash-egyensúlynak nevezzük.
Egy játéknak lehet Nash-egyensúlya a tiszta stratégiák halmazán, vagy lehet Nash-egyensúlya a kevert stratégiák (azaz amikor bizonyos fix
gyakorisággal az egyik, bizonyos fix gyakorisággal pedig egy másik stratégiát játszik a szereplő) halmazán.
Létezése
Nash bebizonyította, hogy ha a kevert stratégiákat is figyelembe vesszük, akkor minden n-szereplős játéknak, amelyben a stratégiák száma
véges, létezik Nash-egyensúlya.
Egyértelműsége
Bár az egyik legismertebb játék, a fogolydilemma csak egyetlen egyensúlyi ponttal rendelkezik, a legtöbb játéknak több Nash-egyensúlyi pontja is
van, így az egyensúly általában nem egyértelmű.
Alkalmazásai
A Nash-egyensúly legfőbb alkalmazási területe a közgazdaságtudomány, ahol megjelenése számos kérdés tárgyalását forradalmasította. Olyan
helyzetek megoldására ad ugyanis eszközt, ahol az egyes gazdasági szereplők döntései befolyásolják mások döntéseit, és ezt tudják is
magukról (stratégiai szituációk).
Néhány konkrét alkalmazási terület:
Árverések
Iparági formák (duopólium, oligopólium modellek)
Piaci kudarcok (közjószág, externália)
Példa:
Nemek harca
Vegyük például a következő játékot, amelynek angol neve „battle of sexes” (magyarra talán családi vitaként, vagy nemek harcaként
fordíthatnánk): Anti és Bea együtt járnak, és szombat esti programjukat tervezik. Anti rockkoncertre szeretne menni, Bea viszont otthon szeretne
maradni, hogy tanuljon. Egyikük sem szeretné azonban a másik nélkül tölteni az estét. A játékot az alábbi táblázatban foglalhatjuk össze (a
sorokban Anti, az oszlopokban Bea választható stratégiáit tüntettük fel, az első szám Anti, a második szám pedig Bea hasznossága):
Bea koncertre
megy
Bea otthon
marad
2, 1
0, 0
Anti otthon marad 0, 0
1, 2
Anti koncertre
megy
Ez a játék ismét egy szimmetrikus, nem zérus összegű játék. Ha a hasznosságokat alaposan szemügyre vesszük, láthatjuk, hogy egyik
játékosnak sincs olyan stratégiája, amely jobb lenne a másiknál függetlenül attól, hogy mit választ a másik játékos. Ezért egyik stratégia sem
dominálja a másikat, így domináns egyensúly sincs.
Mit gondolunk, mi lesz a megoldás? Ha Bea tanulni fog, Antinak is érdemesebb otthon maradnia. Ha viszont Anti otthon marad, Beának is
érdemes tanulnia. Találtunk tehát egy olyan pontot, amely stabil: egyik játékosnak sem érdemes más stratégiát választania, kilépnie az
egyensúlyi pontból (vajon van más ilyen pont is?). Az ilyen egyensúlyt nevezzük Nash-egyensúlynak.
Külső hivatkozások
Radnai Márton: Egy csodálatos elmélet – a Nash-egyensúly, Középiskolai Matematikai Lapok, 2002/6.
A lap eredeti címe "http://hu.wikipedia.org/wiki/Nash-egyens%C3%BAly"
jegyzetek, hivatkozások: 06, forrás: www.wikipedia.org
Lynn Margulis,
and the endosymbiont theory of the phylogenesis of the mitochondria
The endosymbiont theory of the phylogenesis of the mitochondria was described by Lynn Margulis.
Dr. Lynn Margulis (born March 15, 1938) is a biologist and University Professor in the Department of Geosciences at the University of
Massachusetts Amherst.[1] She is best known for her theory on the origin of eukaryotic organelles, and her contributions to the endosymbiotic
theory—which is now generally accepted for how certain organelles were formed.
Research
Endosymbiotic theory
Lynn Margulis attended the University of Chicago as an undergrad and received her Ph.D. in 1963 from UC Berkeley. In 1966, as a
young faculty member at Boston University, she wrote a theoretical paper entitled The Origin of Mitosing Eukaryotic Cells.[2] The paper however
was "rejected by about fifteen scientific journals," Margulis recalled.[3] It was finally accepted by The Journal of Theoretical Biology and is
considered today a landmark in modern endosymbiotic theory. Although it draws heavily on symbiosis ideas first put forward by mid-19th century
scientists and by Merezhkovsky (1905) and Wallin (1920) in the early-20th century, Margulis's endosymbiotic theory formulation is the first to rely
on direct microbiological observations (as opposed to paleontological or zoological observations which were previously the norm for new works in
evolutionary biology). The paper was initially heavily rejected, as symbiosis theories had been dismissed by mainstream biology at the time.
Weathering constant criticism of her ideas for decades, Margulis is famous for her tenacity in pushing her theory forward, despite the opposition
she faced at the time.
The underlying theme of endosymbiotic theory, as formulated in 1966, was interdependence and cooperative existence of multiple
prokaryotic organisms; one organism engulfed another, yet both survived and eventually evolved over millions of years into eukaryotic cells. Her
1970 book, Origin of Eukaryotic Cells, discusses her early work pertaining to this organelle genesis theory in detail. Currently, her endosymbiotic
theory is recognized as the key method by which some organelles have arisen (see endosymbiotic theory for a discussion) and is widely
accepted by mainstream scientists. The endosymbiotic theory of organogenesis gained strong support in the 1980s, when the genetic material of
mitochondria and chloroplasts was found to be different from that of the symbiont's nuclear DNA.[4]
Theory of symbiotic relationships driving evolution
In 1995, prominent Neo-Darwinist evolutionary biologist Richard Dawkins had this to say about Lynn Margulis and her work:
She later formulated a theory to explain how symbiotic relationships between organisms of often different phyla or kingdoms are the
driving force of evolution. Genetic variation is proposed to occur mainly as a result of transfer of nuclear information between bacterial cells or
viruses and eukaryotic cells. While her organelle genesis ideas are widely accepted, symbiotic relationships as a current method of introducing
genetic variation is something of a fringe idea. However, examination of the results from the Human Genome Project lends some credence to an
endosymbiotic theory of evolution—or at the very least Margulis's endosymbiotic theory is the catalyst for current ideas about the composition of
the human genome. Significant portions of the human genome are either bacterial or viral in origin—some clearly ancient insertions, while others
are more recent in origin. This strongly supports the idea of symbiotic—and more likely parasitic—relationships being a driving force for genetic
change in humans, and likely all organisms. It should be noted that while the endosymbiotic theory has historically been juxtaposed with Neo-
Darwinism, the two theories are not incompatible and the truth is likelier to be that natural szelekción works on many levels (genetic up to the
ecosystem) and variation is introduced both at the genetic and the cellular level.
She does, however, hold a negative view of Neo-Darwinism, as she believes that history will ultimately judge the theory as "a minor
twentieth-century religious sect within the sprawling religious persuasion of Anglo-Saxon Biology."[6] She also believes that proponents of the
standard theory "wallow in their zoological, capitalistic, competitive, cost-benefit interpretation of Darwin - having mistaken him... Neo-Darwinism,
which insists on (the slow accrual of mutations), is a complete funk."[7]
Controversy
Margulis' present day efforts, in the form of books and lectures, strongly stress a symbiotic—and cooperative—relationship between all
organisms and a strong leaning toward Gaia theory. Her advocacy outside the realm of biology and toward more sociopolitical ends has been
criticized by more mainstream scientists—somewhat similar to criticisms aimed toward Carl Sagan's latter day ideas.
Recently, Margulis has leant her support to 9/11 conspiracy theories, calling the September 11, 2001 attacks a "false-flag" operation of
the United States government itself.[8],[9]
Other
Margulis was elected to the National Academy of Sciences in 1983 and served as Chairman of the Academy’s Space Science Board Committee
on Planetary Biology and Chemical Evolution.
She was inducted into the World Academy of Art and Science, the Russian Academy of Natural Sciences, and the American Academy of Arts and
Sciences between 1995 and 1998.
In 1998 the Library of Congress, Washington, DC, announced that it would permanently archive Dr. Margulis' papers.
In 1999 she received the Proctor Prize for scientific achievement.
In 1999, she was awarded the National Medal of Science by President William J. Clinton.
She is also a proponent and co-developer of the modern version of Gaia hypothesis, based on an idea developed by the English atmospheric
scientist James Lovelock.
She is profiled in a book published in 2006 by Resurgence Magazine in the UK, called Visionaries: The 20th Century's 100 Most Important
Inspirational Leaders.
In 2006 with her son Dorion, she founded Sciencewriters Books, an imprint of Chelsea Green Publishing for science books.
Personal
She was the first wife of astronomer Carl Sagan and is the mother of Dorion Sagan, popular science writer and co-author; Jeremy Sagan,
software developer and founder of Sagan Technology; Zachary Margulis-Ohnuma, New York City Criminal Defense lawyer; and Jennifer
Margulis, teacher and author.
See also
Symbiogenesis
From Wikipedia, the free encyclopedia
Symbiogenesis is the merging of two separate organisms to form a single new organism. The idea originated with Konstantin
Mereschkowsky in his 1926 book Symbiogenesis and the Origin of Species, which proposed that chloroplasts originate from cyanobacteria
captured by a protozoan.[1] Today both chloroplasts and mitochondria are believed to have such an origin; this is the endosymbiotic theory.
In Acquiring Genomes: A Theory of the Origins of Species, biologist Dr. Lynn Margulis argued that symbiogenesis is a primary force in
evolution. According to her theory, acquisition and accumulation of random mutations are not sufficient to explain how inherited variations occur;
rather, new organelles, bodies, organs, and species arise from symbiogenesis.[2] Whereas the classical interpretation of evolution (the modern
evolutionary synthesis) emphasizes competition as the main force behind evolution, Margulis emphasizes cooperation.[3]
Many ecologists agree, but this idea has little support from other evolutionary biologists. They see little evidence that symbiogenesis
has had a major impact on eukaryotic life, or that much of its diversification can be attributed to it. Other than the two examples of mitochondria
and chloroplasts, there is no clear evidence of other major traits or transitions that can be attributed to symbiogenesis.
A fundamental principle of modern evolutionary theory is that mutations arise one at a time and either spread through the population or
not, depending on whether they offer an individual fitness advantage. Nevertheless, this general case may not apply to all examples of
evolutionary change. Indeed, genome mapping techniques have revealed that family trees of the major taxa appear to be extensively cross-linked
- possibly due to lateral gene transfer.[4]
References
^ Sapp J, Carrapiço F, Zolotonosov M (2002). "Symbiogenesis: the hidden face of Constantin Merezhkowsky". History and philosophy of the life
sciences 24 (3-4): 413–40. doi:10.1080/03919710210001714493. PMID 15045832.
^ Margulis L (1993). "Origins of species: acquired genomes and individuality". BioSystems 31 (2-3): 121–5. doi:10.1016/0303-2647(93)90039-F.
PMID 8155844.
^ Margulis L, Bermudes D (1985). "Symbiosis as a mechanism of evolution: status of cell symbiosis theory". Symbiosis 1: 101–24. PMID
11543608.
^ de la Cruz F, Davies J (2000). "Horizontal gene transfer and the origin of species: lessons from bacteria". Trends Microbiol. 8 (3): 128–33.
doi:10.1016/S0966-842X(00)01703-0. PMID 10707066.
[edit] Important publications
Konstantin Mereschkowsky. Symbiogenesis and the Origin of Species. 1926.
Lynn Margulis. Symbiotic Planet: A New Look at Evolution. Amherst, MA: Perseus Books Group, 1998. ISBN 0-456-07271-2.
Lynn Margulis, Dorion Sagan. Acquiring Genomes: A Theory of the Origins of Species. Amherst, MA: Perseus Books Group, 2002. ISBN
0-465-04391-7.
Retrieved from "http://en.wikipedia.org/wiki/Symbiogenesis"
Categories: Evolutionary biology
Publications and bibliography
Margulis, Lynn and Dorion Sagan, 2007, Dazzle Gradually: Reflections on the Nature of Nature, Sciencewriters Books, ISBN
978-1-933392-31-8
Margulis, Lynn and Eduardo Punset, eds., 2007 Mind, Life and Universe: Conversations with Great Scientists of Our Time,
Sciencewriters Books, ISBN 978-1-933392-61-5
Margulis, Lynn, 2007, Luminous Fish: Tales of Science and Love, Sciencewriters Books, ISBN 978-1-933392-33-2
Margulis, Lynn and Dorion Sagan, 2002, Acquiring Genomes: A Theory of the Origins of Species, Perseus Books Group, ISBN
0-465-04391-7
Margulis, Lynn, et al., 2002, The Ice Chronicles: The Quest to Understand Global Climate Change, University of New Hampshire, ISBN
1-58465-062-1
Margulis, Lynn, 1998, Symbiotic Planet : A New Look at Evolution, Basic Books, ISBN 0-465-07271-2
Margulis, Lynn and Karlene V. Schwartz, 1997, Five Kingdoms: An Illustrated Guide to the Phyla of Life on Earth, W.H. Freeman &
Company, ISBN 0-613-92338-3
Margulis, Lynn and Dorian Sagan, 1997, What Is Sex?, Simon and Shuster, ISBN 0-684-82691-7
Margulis, Lynn and Dorion Sagan, 1997, Slanted Truths: Essays on Gaia, Symbiosis, and Evolution, Copernicus Books, ISBN
0-387-94927-5
Margulis, Lynn, 1992, Symbiosis in Cell Evolution: Microbial Communities in the Archean and Proterozoic Eons, W.H. Freeman, ISBN
0-7167-7028-8
Margulis, Lynn, ed, 1991, Symbiosis as a Source of Evolutionary Innovation: Speciation and Morphogenesis, The MIT Press, ISBN
0-262-13269-9
Margulis, Lynn and Dorion Sagan, 1991, Mystery Dance: On the Evolution of Human Sexuality, Summit Books, ISBN 0-671-63341-4
Margulis, Lynn and Dorion Sagan, 1987, Microcosmos: Four Billion Years of Evolution from Our Microbial Ancestors, HarperCollins,
ISBN 0-04-570015-X
Margulis, Lynn and Dorion Sagan, 1986, Origins of Sex : Three Billion Years of Genetic Recombination, Yale University Press, ISBN
0-300-03340-0
Margulis, Lynn, 1982, Early Life, Science Books International, ISBN 0-86720-005-7
Margulis, Lynn, 1970, Origin of Eukaryotic Cells, Yale University Press, ISBN 0-300-01353-1
References
•^ Lynn Margulis biography at U. Mass. (Accessed July 15, 2006)
•^ Lynn Sagan (1967). On the origin of mitosing cells. J. Theoretical Biology 14(3), 255-274. PMID 11541392 doi:10.1016/0022-5193(67)90079-3
•^ John Brockman, The Third Culture, New York: Touchstone, 1995, 135.
•^ Acceptance Doesn't Come Easy (Accessed July 15, 2006)
•^ John Brockman, The Third Culture, New York: Touchstone, 1995, 144.
•^ Mann, C. (1991) "Lynn Margulis: Science's Unruly Earth Mother," Science, 252
•^ Mann, C. (1991) "Lynn Margulis: Science's Unruly Earth Mother," Science, 378-381
•^ statement by Lynn Margulis, [1](Accessed November 17, 2007)
•^ [www.911truth.org/article.php?story=2007082682539691](Accessed November 18, 2007)
External links
1.UMass Bio Dept. (includes a partial list of technical publications) (Accessed March 3, 2005)
2.UMass Geo Dept. (Accessed March 3, 2005)
3.http://www.immaculata.edu/bioinformatics/esehi/lynn%20margulis.htm (Accessed March 3, 2005)
4.San Jose Science, Technology and Society, 2004-2005 Linus Pauling Memorial Lectures (Accessed March 3, 2005)
5.The Endosymbiotic Theory (Accessed March 3, 2005)
6.Gaia Is a Tough Bitch
7.Interview with Lynn Margulis on Gaia 5 minute MP3 from October 2005
Retrieved from "http://en.wikipedia.org/wiki/Lynn_Margulis"
jegyzetek, hivatkozások: 07
H-1096 Budapest, Nagyvárad tér 2., Hungary
Idézet:
Summary
A nanobaktériumok világa
Bókkon István
Fodor József Országos Közegészségügyi Központ,
Országos Kémiai Biztonsági Intézet, 1096 Budapest,
Nagyvárad tér 2.
Összefoglalás
A cikk összefoglaló képet nyújt – saját gondolatokkal
tűzdelve – a nanobaktériumok érdekes, még
mikrobiológusok által is alig ismert világáról. A
nanobaktériumok szokatlan tulajdonságai jó példát
szolgáltatnak arra, hogy a természet számos esetben
rácáfol arra, amire mi, kutatók azt mondjuk,
nem lehetséges.
Bókkon, I.
National Institute of Chemical Safety,
This article provides an overview – along with
certain own ideas – on the interesting world of
nanobacteria hardly known even by microbiologists.
The unusual features of nanobacteria
beautifully illustrate that nature can confute us,
researchers in numerous cases, when we believe
certain phenomena impossible.
Bevezetés
A nanobaktériumok felfedezése a geológiai kutatásokkal
kapcsolatos. Robert L. Folk a Texasi Egyetem
geológusa két évtizeddel ezelőtt arról számolt
be, hogy talaj- és kőzetminták mikroszkópos képein
100 nanométernél kisebb átmérőjű baktériumok
találhatók [1]. Az elméleti számítások szerint ekkora
baktériumok nem létezhetnek, mivel a baktériumok
esetében maga a sejtfal 10 nm vastag, és a
riboszóma, amelyen a proteinek szintézise történik,
25 nm nagyságú. Akárhogy is, a nanobaktérium
fosszíliák jelenléte ma már tény a több milliárd éves
dolomitokban és mészkövekben [2,3]. Folk szerint
ezek a baktériumok jelentős szerepet játszhattak a
földkőzetek létrejöttében, mivel képesek különféle
ásványokat precipitálni. Folk geológusként még
nanoplanktonoknak nevezte a felfedezett kisméretű
baktériumokat. R.Y. Morita a Kanadai Mikrobiológiai
Folyóiratban (Canadian Journal of Microbiology)
nevezi e képződményeket először nanobaktériumoknak
[4]. A nanobaktériumok történetéhez
tartozik a NASA egy kutatócsoportjának beszámolója
arról, hogy az Antarktisz jegében talált és bizonyítottan
a Marsról származó ALH84001 meteoritban
20–50 nm átmérőjű – ekkor már terminus technicusként
használt – nanobaktérium fosszíliákat
találtak [5].
A nanobaktériumokkal szorosan egybefonódik E.
Olavi Kajandernek, a finn Kuopio Egyetem biológusának
neve. Kajander a kilencvenes évek legelején
egy kísérletsorozata során emlőssejteket tenyésztett,
amelyek nem a szokásos módon szaporodtak.
A sejtek nagyon lassan növekedtek és citoplazmájuk
abnormális vakuolákat tartalmazott. Az
emlőssejteket általában a borjúvérrel kiegészített
táptalajon tenyésztik. A táptalaj legtöbbször steril,
bár néha (fertőzés kapcsán) tartalmaz vírusokat és
mikoplazmákat (sejtfal nélküli baktériumok), amelyek
nehézségeket okozhatnak a sejtek tenyésztésekor.
Kajander és kollégái elektronmikroszkóp segítségével
próbálták kideríteni a szaporodás gátlásának
okát, de nem találtak a sejttenyészetekben vírusokat
és mikoplazmákat sem. Ugyanakkor számos
sejtben kis baktériumokat figyeltek meg. A felfedezést
követően éveken keresztül tanulmányozták
az 50–500 nm nagyságú, nanobaktériumoknak keresztelt
mikroorganizmusokat. Kajander vizsgálatai
kimutatták, hogy a borjúszérum és ritkábban az
emberi vér is tartalmaz vírus nagyságú nanobaktériumokat.
Kajander eredményei – hasonlóan Folk
kőzetekben talált nanobaktériumaihoz – frusztrálták
a legtöbb biológust, akik nem vették komolyan
állításait. A nanobaktériumok esete hasonló a
Helicobacter pylorihoz. A tudósok sok évig nem
fogadták el azt a ma már tényként ismert jelenséget,
hogy a fekélyek nagy részét a Helicobacter
baktériumok okozzák.
1998. július 7-én Kajander és kollégái újabb felfedezésről
számoltak be a finnországi Nemzeti Tudományos
Akadémián [6]. A beszámoló szerint az
emberi vizeletben nanobaktériumok élnek, amelyek
kalciumot és más ásványi anyagokat választanak
ki maguk körül úgy, hogy kristályosodási magot
képezve indukálják a vesekőképződést. Akutatásaik
szerint egyes antibiotikumok meggátolhatják
a krónikus vesekőképződéseket. Ananobaktériumok
okozta vesekőképződés elmélete már számos
kutatónak felkeltette az érdeklődését. A nanobaktériumok
javasolt tudományos neve: Nanobacterium
sanguineum, utalva kis méretükre, előfordulási
helyükre és egészségkárosító voltukra.
Szaporodás és táplálkozás
Miért nem fedezték fel a mikrobiológusok mostanáig
a nanobaktériumokat? Az egyik ok a már
említett tényező, hogy elméletileg nem létezhetnek
ilyen kis méretű baktériumok. Amásik, hogy tradicionális
fénymikroszkópokkal nem nagyon lehet
észrevenni őket, valamint a szokásos sejtfalfestékek
sem kötődnek hozzájuk. A nanobaktériumok alakja
legtöbbször gömbölyű vagy ovális, de a körülményektől
függően számos növekedési formát,
alakot és közösségi formát mutatnak. A közösségi
formák főleg környezeti stressz esetén képződnek.
A nanobaktériumok gyakran formálnak fehér biofilmeket,
amikor szérumban egyedül vagy emlőssejtekkel
együtt növesztik őket.
Míg a közönséges baktériumok általában óránként
vagy kisebb időintervallumban osztódnak, addig
a nanobaktériumok 1–5 naponként duplázódnak
meg, ami különösen nehézzé teszi a metabolizmusuk
tanulmányozását [7]. A baktériumtenyésztésnél
alkalmazott közegekben a nanobaktériumok
nem szaporodnak. Tenyésztésük emlőssejtekkel
vagy azok nélkül, borjúvérszérumban, 5–10% széndioxid
jelenlétében lehetséges. Az eddig ismert legkisebb
baktériumok a Mycoplasma, Chlamydia és
Rickettsia szintén az emlőssejtek tenyésztésének
feltételeit igénylik, és csak a Mycoplasma képes
autonóm is növekedni.
A tenyésztés alatt a nanobaktériumok mérete nő,
amelyet a sejt körül kialakuló vastag szervetlen
precipitátum okoz, amely egyben láthatóvá is teszi
a fénymikroszkóp alatt. Akörülményektől függően
drasztikusan változik egyedi méretük. Kedvezőtlen
körülmények esetén hatalmas, több milliméter
nagyságú multicelluláris egységeket alkotnak. A
nanobaktériumok – a mikoplazmákhoz hasonlóan
– képesek pszeudokolóniákat alkotni. Alkalmas
feltételek esetén önállóan replikálódnak, míg kedvezőtlen
feltételek esetén szaporodásuk vírusszerű.
A szaporodás detektálható specifikus ELISA teszttel,
optikai denzitásméréssel, mikroszkópos számolással,
SDS-PAGE gélelektroforézissel vagy jelölt
metionin és uridin beépülésének követésével. A
szaporodás gátolható nagy dózisú aminoglikozid
antibiotikummal, EDTA-val, citozin-arabinózzal és
gammasugárzással. Az emlős sejtkultúrák 80%-ánál
mutattak ki nanobaktériumokat, amelyek csak
akkor okoznak problémát, ha elég nagy relatív koncentrációban
vannak jelen a sejtekhez képest. Ez
főleg sejtklónozáskor és hosszú ideig tartó kísérletek
esetén fordul elő.
1. ábra „Hajszerű” apatit kristályréteggel borított, osztódásban lévő nanobaktérium transzmissziós elektronmikroszkópos képe. (Az ábra jobb alsó
sarkában jelzett szakasz hossza 100 nm.) Engedélyezett újraközlés / reproduced with permission, Kajander and Çiftçioglu (1998) Proc. Natl.
Acad. Sci. USA, 95: 8275 [7].
Bókkon István 1989-ben mint vegyészmérnök, 1991-ben mint okleveles biológus mérnök végzett a Budapesti Műszaki Egyetemen.
Környezetvédőként, majd magántanárként dolgozott. Jelenleg az Országos Közegészségügyi Központ kutatója. Tudományos tevékenységében
egymástól távol álló tudományterületek témáit törekszik összefoglalni, átlátni, és új gondolatokat felvetni adott témával kapcsolatban.
Foglalkozott többek között az elektromágneses sugárzás biokémiai hatásaival, az agy információtárolásának új szemléletű vizsgálatával,
endotoxinokkal, antioxidánsokkal.
A normál baktériumok komplex metabolikus rendszerek,
amelyek fennmaradásukhoz aktív transzportot
és mozgásokat igényelnek. A koncentrált
metabolitok miatt a belső nyomás 3–5 bar, és a
metabolizmus gyors. Kedvezőtlen feltételek között
ezek a nagy baktériumok elpusztulnak, mert nem
tudják fenntartani az iongradiensüket. A nanobaktériumokban
a sejten belüli ozmotikus nyomás
kicsi, így lassú a metabolizmus. A lassú metabolizmus
megengedi, hogy minimális számú enzimet
használjanak, mert számos reakciót nem kell katalizálni.
Ahol mégis szükséges a katalizálás, megtörténhet
fémek és ásványok segítségével is. Kis méretük
miatt a táplálkozásban a diffúzió és Brownmozgás
lehet a meghatározó, amely megmagyarázhatja
a forrásponthoz közeli hőmérséklettel szemben
tanúsított ellenállásukat [8]. A nanobaktériumok
a kész aminosavakat és zsírsavakat a környezetből
(pl. médiumból) veszik fel. Abban az esetben,
ha zsírsavakat nem képesek felvenni, akkor a
membránban lévő lipidjeiket részlegesen apatittal
képesek helyettesíteni.
Litogenezis
A precipitáció során egy adott só koncentrációja
eléri az oldatban a telítettségi, majd a túltelítettségi
szintet. Az utóbbi termodinamikailag nem stabil,
ezért nuklealizációhoz vezet, amit az oldat szabadenergiája
biztosít. A nuklealizáció eredményeként
csökken a szabad energia, és termodinamikailag
stabil állapot alakul ki. A nuklealizációt követő
aggregáció a kristálynövekedés meghatározó lépése.
A vesekövek esetében további lényeges faktor,
hogy az urothelium visszatarthatja a képződött
mikrokristályokat [9]. A röviden vázolt precipitációs
folyamat a valóságban sokkal bonyolultabb,
melyben genetikai, mikrobiológiai, táplálkozási és
környezeti faktorok érvényesülnek, mint fő meghatározók.
Természetesen a fontosabb faktorok kölcsönösen
befolyásolják egymást. Például, az egyed
válasza adott mikrobiológiai kihívásra függ az
egyén genetikai determináltságától.
A patológiai litogenezis – sokrétűsége ellenére – a
legtöbb esetben összefüggésbe hozható valamilyen
mikroba jelenlétével. Az analitikai elemzések már
régen rávilágítottak arra, hogy a nagy kristályok kisebb
krisztallitokból állnak, közöttük szerves mátrixszal
[10]. Ez a szerves mátrix számos esetben mikroba
eredetű. Biokémiailag a vesekövek mukoproteineket,
mukopoliszacharidokat, szervetlen anyagokat
és kötött vizet tartalmaznak. Az élő (funkcionáló)
és nem élő (sejtdegradációs termék) szerves
makromolekuláknak döntő szerepük lehet a
sejteken belüli, illetve kívüli kőképződésben. Aproteolipidet
tartalmazó membránok mint kiindulási
magok működhetnek a kőképződésben [11]. A
kísérletek szerint a mitokondriumok és a sejtközötti
állományban lévő ciszták/hólyagocskák membránjai
gyakran indukálnak patológiás kalcifikációt
[12]. Ha ezt gondolatban összekapcsoljuk azzal,
hogy az endoszimbiózis révén létrejött eukarióta
sejtek több lépcsőben anaerob prokariótákból alakultak
ki, akkor valószínű, hogy a litogenezisben is
azonos és egyszerű mechanizmusok működnek.
Pontosabban, azonos mechanizmusok dolgozhatnak
a patogén mikrobák által okozott kalcifikáció,
valamint a sejt mitokondriumok és sejtmembránok
által okozott kalcifikációja esetében.
A mitokondriumok intracelluláris, míg a külső hólyagocskák
extracelluláris kalcifikációt iniciálhatnak.
A mitokondriumok és ciszták esetében a kőképződést
a membránhoz kötött foszfatáz enzimek
és kalciumkötő foszfolipidek közötti kölcsönhatás
váltja ki. Extracelluláris kalcifikáció esetében iniciáló
folyamatként a mátrix hólyagocskák savas foszfolipidjei
vonzzák a kalciumot, amely komplexet
képez a foszfáttal és proteinnel [13]. A továbbiakban
a hólyagocskák körüli mátrix körülményei határozzák
meg a kristály proliferációját. A proteoglikánok,
a pirofoszfát, a g-karboxi-glutaminsavat
tartalmazó proteinek és foszfoproteinek az anion
alcsoportjaikkal, kalciumot tartalmazó közegben
megkötik a Ca2+-ionokat, így ezek akadályozzák a
hidroxi-apatit képződését és növekedését in vitro.
Ugyanakkor a kollagén elősegíti az apatitképződést.
Extracelluláris patológiás kalcifikációk találhatók
az érelmeszesedés, csont- és ízületi gyulladás,
középfülgyulladás, szívbillentyű-meszesedés
stb. betegségek esetében. Szövetsérülés, sejtmembrándegradációs termékek (foszfolipidek és különösen
a foszfatidil-szerin) szintén indukálhatnak litogenezist,
mert a degradációs makromolekulák
gócként szolgálhatnak a kalcium-apatit nuklealizációjához
[14]. A membrán belső felületén lévő foszfatidilszerinnek nagy az affinitása a kalciumhoz.
Ha a sejt sérül, a foszfatidil-szerin érintkezhet az
extracelluláris folyadékkal, amely felelőssé tehető a
disztrofikus kalcifikációért.
2. ábra A szérummentes közegben tenyésztett nanobaktériumok a tenyésztőedény aljához kötődnek, és kicsiny apatitgömböcskéket hoznak létre
maguk körül. Az ábrán a gömböcskék pásztázó elektronmikroszkópos képe látható. A nanobaktériumok a lyukakban helyezkednek el. (Az ábra
jobb alsó sarkában jelzett szakasz hossza 100 mm.) Engedélyezett újraközlés / reproduced with permission, Kajander and Çiftçioglu (1998) Proc.
Natl. Acad. Sci. USA, 95: 8277 [7].
A nanobaktériumok esetében a precipitáció indukálásáért
szintén makromolekulák tehetők felelőssé.
Az elképzelések szerint a nanobaktériumok úgy
katalizálják a precipitációt, hogy a negatívan töltött
sejtfalukhoz vonzzák a kationokat, ami szubmikrométer
alatti skálán túltelítettséghez vezet, és elindítja
a CaCO3 vagy CaPO4 (apatit) kicsapódását. A
nanobaktériumok táplálkozása kapcsán már említett,
nagyon érdekes megfigyelés, hogy amennyiben
nem képesek zsírsavakat felvenni, a membránjukban
lévő lipideket részlegesen apatittal helyettesíthetik.
Jelenleg ismeretlen, hogy miért alakítanak
ki a precipitáció indukálása mellett ásványburkokat
(Kajander kifejezésével „castles”) maguk körül
a nanobaktériumok. Méghozzá olyan ásványburkolatot,
amelyből kitenyészthetők, és ami jelzi,
hogy nem szunnyadó állapotban léteznek a veseköveken
belül.
A nanobaktériumokat befedő karbonát-apatit ásványi
rétege emlékeztet a csont struktúrájára, bár
utóbbi hidroxi-apatitból épül fel. A karbonát-apatit
ugyanazon anyag, amelyből a legtöbb kalcifikáció
és kő is kialakul az abnormális szövetekben. Úgy
tűnik, hogy a csontképződés és kőképződés között
azonos mechanizmusok működhetnek. Miért kaphatnak
a litogenezisben különös hangsúlyt a nanobaktériumok?
Azért, mert a legősibb és nagyon
egyszerű anyagcseréjű prokariótákhoz tartoznak,
így egy egyszerű és közös mechanizmust szolgáltathatnak
a kőképződést illetően. Egyre több patológiás
litogenezisben igazolható a jelenlétük, vagy
kimutatható az antigénjük. Képesek szaporodni a
sejteken belül és kívül is. Méretüknél fogva a szervezetben
mindenhova képesek eljutni áthatolva
még a vér–agy gáton is. Végezetül igen ellenállóak
mindenféle extrém körülménnyel szemben.
Citotoxicitás
A marhaembrió-szérumot tartalmazó médiumban
növő sejttenyészetek 80%-ában mutatták ki nanobaktériumok
jelenlétét. Normális esetben az emlőssejtek
nem engedik, hogy beléjük baktériumok
inkorporeáljanak. Kísérletek során minimális tápanyagösszetételű médiumban tenyésztett fibroblast
sejtkultúrát nanobaktériummal fertőztek,
majd elektronmikroszkóp és monoklonális antitestek
segítségével kimutatták, hogy a nanobaktériumok
a fibroblastok felületére kötődtek [15]. A
fibroblastsejtek – receptormediált endocitózissal
vagy ehhez közeli mechanizmussal – internalizálták
a nanobaktériumokat. Az internalizáció után
a fibroblastsejtek abnormális apoptózist, illetve a
sejtek halálát mutatták, 100 nanobaktérium/sejt
koncentráció esetében. Az apoptózis indukálása
megmagyarázza az emlőssejtek tenyésztésekor tapasztalt
növekedésgátlást: a sejtekbe internalizált
nanobaktériumok citotoxikusak a sejtek számára.
Okozhatnak sejtvakualizációt, váratlan sejtlízist és
egyéb problémákat a sejtek tenyésztésekor. Szerencsére
a legtöbb sejtvonal gyorsabban osztódik, mint
e baktériumok, így a citotoxikus hatás sokszor elkerülhető.
Az RNS, a DNS, és a fehérjék
szerveződése
Az rRNS gén szekvenciaeredményei alapján a
Nanobacterium a Protobacteria alfa-2 alcsoportba
sorolható. Ebbe a csoportba tartozik a Brucella és a
Bartonella is, melyekről tudjuk, hogy néhány fajtája
fertőzi az állatok és az emberek vérét. Valószínűsíthető
a nem tradicionális DNS jelenléte is [16].
A nanobaktériumok DNS-e – a mitokondriumokéhoz
hasonlóan – fluorkrómmal festhető. A nanobaktériumok
DNS-mérete a mikoplazmák és mitokondriumok
között helyezkedhet el. A Mycoplasma
genitalium genommérete 0,58 MB, szemben az
Escherychia coli 4,6 MB genomméretével. A
Saccharomyces élesztő mitokondriumában 35, nukleáris
genomjában körülbelül 290 gén van [17]. A
mitokondriumok valószínűleg számos gént veszítettek
el az eukarióta sejtekbe történő domesztifikációjuk
közben. Ez jelzi, hogy a metabolikus együttműködés
a baktériumok vagy a baktériumok és
más organizmusok között szignifikánsan csökkentheti
a szükséges genomméretet. A metabolikus
együttműködés további magyarázatot szolgáltat
arra, hogy a nanobaktériumok igen egyszerű
anyagcseréjük ellenére mégis létezhetnek.
A nanobaktériumok SDS-PAGE gélelektroforézise
több mint 30 proteinsávot mutatott [Kajander és
mtsai, valamint James Coulton (McGill Egyetem),
nem publikált eredmény]. Igazolták a muraminsav
jelenlétét (tipikus komponense a peptidoglikánnak),
amely az összes valódi baktérium sejtfalában
megtalálható. Valamint 6 protein aminoterminális
szekvenciáját elemezve megállapították, hogy a hat
közül az egyik a porin protein működéséhez szükséges.
A porin proteinek tipikusan a Gram-negatív
baktériumokat jellemzik: a külső membránban helyezkednek
el, és lehetővé teszik, hogy a viszonylag
kicsiny és vízoldékony molekulák keresztüljussanak
rajta. Ennek alapján a nanobaktériumok sejtfala
Gram-negatív jellegű, bár ultrastruktúrájuk
különleges, és változik a növekedési fázis alatt.
A poliaminok a sejtek osztódásához általában
esszenciálisak. A baktériumok poliaminja a putreszcin
és a spermidin, bár tartalmazhatnak kb. 30
egyéb di- és poliamint. Ezeket mint filogenetikus
eszközöket használják [18]. A putreszcin és spermidin
génjei hiányoznak a Mycoplasma genitalium,
Borrelia burgdorferi és Treponema pallidum baktériumokból.
A Haemophilus influenzae putreszcint, a
Helicobacter pyroli, a Mycobacterium tubercolosis és az
E. coli putreszcint és spermidint is képesek előállítani.
A nanobaktériumok nem képeznek putreszcint
és spermidint sem, ehelyett egy speciális poliamint
a kadaverint szintetizálják, amit számos
eubaktérium használ mint a peptidoglikánnak egy
kovalensen kötött komponensét.
A nanobaktériumok lehetséges szerepe a
patogén kalcifikációkban
Speciális antitestekkel igazolták, hogy a finn lakosság
5%-a fertőzött nanobaktériumokkal. Úgy tűnik,
hogy a nanobaktériumok összefüggésbe hozhatók
a különféle szövetekben előforduló megmagyarázatlan
patológiás extraszkeletális kalcifikációkkal,
mint az arteriosclerosis, arthritis és dementiák
[19,20]. Nanobaktériumokból származó proteineket
találtak emberi vérben és vérszérummintákban,
de nem a vér az elsődleges előfordulási helyük.
Állatokba injektálva gyorsan a vesékbe, majd a
vizeletbe migrálnak, sőt egy év után a gerincvelői
folyadékból is kimutatható a jelenlétük.
Kajander és munkatársai finn betegekből származó
72 vesekövet vizsgáltak [21]. A kísérlet során a köveket
1 N sósavban oldották fel. A nanobaktériumok
meglepően rezisztensek voltak a sósavra, mert
a kövek 91,3%-ából kitenyészthetőek voltak. A
nanobaktériumokon kívül, csak a struvit (ammóniummagnézium-foszfát) kövekben találtak közönséges
baktériumokat Az apatit kövek nagyobb antigénjelet
adtak, mint a más típusúak, és a nanobaktériumantigének
jelenléte nem függött a kő típusától.
További kísérletek során Kajander és munkatársai
nanobaktériumokat, illetve antigénjeiket mutatták
ki a policisztás vesebetegeknél, valamint májcisztafolyadékból
és vizeletből [22]. A nanobaktériumok
valószínűleg jelen vannak a sejtkultúrák segítségével
készített vakcinákban, a g-globulin- és
más antitestkészítményekben. Mivel lassan osztódnak,
jelenlétük esetleg krónikus autóimmun betegségekkel
is összefüggésbe hozható.
3. ábra Nanobaktériumok extra- és intracelluláris kalcifikációja.
Fetális marhaszérumból tenyésztett (A) és demineralizált vesekőben kimutatott nanobaktériumok (B) TEM mikrográfiás képe. A vesekőből
származó, apatitréteggel körülvett nanobaktérium morfológiáját tekintve hasonlít a szérumból kitenyésztett, maguk körül szintén apatitréteget
létrehozó nanobaktériumokhoz. (Az ábrák jobb alsó sarkában jelzett szakaszok hossza A: 200 nm, B: 50 nm.) Engedélyezett újraközlés /
reproduced with permission, Kajander and Çiftçioglu (1998) Proc. Natl. Acad. Sci. USA, 95: 8278 [7]
A nanobaktériumok növekedésének
gátlása, sterilizálásuk
A szokásos sterilizálási folyamatokkal szemben a
nanobaktériumok ellenállóak. Avírusokhoz hasonlóan
1 Mrad sugárzást képesek elviselni. Emellett –
valószínűleg ásványi burkuk miatt – ellenállóak a
legtöbb antibiotikummal szemben is, de kis dózisú
tetraciklin (akkumulálódik az apatiton és koncentrálódhat
a baktérium közelében) vagy nagy koncentrációjú
aminoglikozid antibiotikummal növekedésük
gátolható (mindkét antibiotikum a bakteriális
proteinszintézisre hat riboszóma szinten). A
tetraciklin és a citrát in vitro gátolta a nanobaktériumok
növekedését [22], de hatásosak továbbá a citozin
arabinozid és fluorouracil antimetabolitok is,
amelyek az összes sejttípusban gátolják a nukleinsavszintézist.
A klinikai kísérletek igazolták, hogy nincs szignifikáns
kapcsolat a C- és a B6-vitamin napi felvétele és
a vesekőképződés között [23]. Sőt Cathcart szerint
– aki 11000 betegének adott 1969-től kezdve nagy
dózisú (1–2 gramm/nap) C-vitamint – a C-vitamin
képes meggátolni a vesekőképződést [24]. A nagy
dózisú aszkorbinsav bevitele növeli az aszkorbinsavkiválasztást a vizeletbe, és valószínűleg elpusztítja
a baktériumokat, emellett komplexet képez a
vizeletben lévő Ca2+-ionokkal, csökkentve így a
kalcium-oxalát-képződés lehetőségét [25], harmadsorban
pedig növeli az immunrendszer hatékonyságát.
Cathcart szerint a nagy dózisú aszkorbát
szervezetbe juttatása a nanobaktériumok esetében
is hatásos. Az emelt szintű folyadékbevitel a nanobaktériumok
okozta kőképződés esetében is javasolt,
mert a hidratáció hatásos a kőképződés megelőzésében.
In vitro kísérletek szerint a magnézium gátolja a
heterogén apatitképződést [26]. Mivel a magnézium
kalciumantagonista, és több mint 300 enzim
működésében vesz részt, valószínű, hogy a nanobaktériumok
okozta kőképződésben is hatásos lehet
a megnövelt Mg-felvétel.
Bár a nanobaktériumok körül még számos ellentmondás
mutatkozik, lényeges lenne további kutatásokat
végezni e témában, mert ezen ősi baktériumok
olyan egyszerű biomechanizmusokra szolgáltathatnak
adatokat, amelyek elősegíthetik az
alapvető sejtbiológiai folyamatok megértését és
ezen keresztül a gyógyítást. Bárhogy legyen is,
Bennett L. cikke [27] – Are all diseases infectious? címmel
– elgondolkoztató, hiszen a biológiai kutatások
eredményei egyre inkább azt jelzik, hogy a legtöbb
betegség összefüggésbe hozható valamilyen mikroba
jelenlétével.
Irodalomjegyzék
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[13] Anderson, H. C. (1981) Normal and abnormal mineralization in
mammals. Trans. Am. Soc. Artif. Intern. Organs., 27: 702-708.
[14] Kim, K. M. (1983) Lipid matrix of dystrophic calcification and
urinary
stone. Scan. Electron. Microsc., 1983: 1275-1284.
[15] Ciftcioglu, N., Kuronen, K., Akerman, K., Hiltunen, E., Laukkanen,
J., Kajander, O. (1997) New potential threat in antigen and antibody
products: Nanobacteria. In: Vaccines 97 (Brown, F., Burton,
D., Doherty, P., Mekalanos, J., Norrby, E., Eds) (Cold Spring Harbor
Laboratory Press, Cold Spring Harbor. New York), pp. 99-103.
[16] Kajander, E. O., Kuronen, I., Akerman, K., Peltteri, A., Ciftcioglu,
N. (1997) Nanobacteria from blood, the smallest culturable,
autonomously
replicating agent on Earth. Proc. SPIE, 3111: 420-428.
[17] Hodges, P. E., Payne, W. E., Garrels, J. I. (1998) Yeast protein
database
(YPD): a database for complete proteome od Saccharomyces
cerevisiae. Nucleic Acids Res., 26: 68-72.
[18] Hamana, K., Matsuzaki, S. (1992) Polyamines as a
chemotaxonomic
marker in bacterial systematics. Crit. Rev. Microbiol., 18: 261-283.
[19] Carson, D. A. (1998) An infectious origin of extra skeletal
calcification.
Proc. Natl. Acad. Sci. U. S. A., 95: 7846.
[20] Miller-Hjelle, M. (1999) Living nanobacteria recovered from human
cystic kidney and liver fluids. 99th General Meeting, Amer. Soc.
Microbiol., May 30-Jun 3. Chicago, Illinois. Session 112, Paper C193.
[21] Ciftcioglu, N., Bjorklund, M., Kuorikiski, K., Bergstrom, K.,
Kajander, E. O. (1999) Nanobacteria: An infectious cause for kidney
stone formation. Kidney Int., 56: (5) 1893-1898.
[22] Hjelle, J. T., Miller-Hjele, M. A., Poxton, I. R., Kajander, E. O.,
Ciftcioglu, N., Jones, M. L., Caughey, R. C., Brown, R., Millikin, P.
D., Darras, F. S. (2000) Endotoxin and nanobacteria in polycystic
kidney disease. Kidney Int., 57: 2360-2374.
[23] Curhan, G., Willett, W., Rimm, E., Stampfer, M. (1996) A
prospective
study of the intake if vitamins C and B6 and the risk of kidney
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[24] Cathcart, R. F. (1985) Vitamin C: the nontoxic, nonrate-limited,
antioxidant free radical scavenger. Medical Hypotheses., 18: 61-77.
[25] Lewin, S. (1976) In: Vitamin C: Its molecular biology and medical
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Internetes Irodalom:
http://www.nationalacademies.org/ssb/nanopanel2kajander.htm
http://naturalscience.com/ns/articles/01-03/ns_folk.html
Idézet vége.
Systems theory
Systems theory is an interdisciplinary field of science and the study of
the nature of
complex systems in nature, society, and science. More specificially, it is
a
framework by which one can analyze and/or describe any group of
objects that work
in concert to produce some result. This could be a single organism, any
organization or society, or any electro-mechanical or informational
artifact. Systems
theory as a technical and general academic area of study
predominantly refers to
the science of systems that resulted from Bertalanffy's General System
Theory
(GST), among others, in initiating what became a project of systems
research and
practice. It was Margaret Mead and Gregory Bateson who developed
interdisciplinary perspectives in systems theory (such as positive and
negative
feedback in the social sciences).
Overview
Margaret Mead was an influential figure in systems theory.
Ideas from systems theory have grown with diversified areas,
exemplified by the
work of Béla H. Bánáthy, ecological systems with Howard T. Odum,
Eugene Odum
and Fritjof Capra, organizational theory and management with
individuals such as
Peter Senge, interdisciplinary study with areas like Human Resource
Development
from the work of Richard A. Swanson, and insights from educators
such as Debora
Hammond.
As
a
transdisciplinary,
interdisciplinary
and
multiperspectival domain,
the area brings together principles and concepts from ontology,
philosophy of
science, physics, computer science, biology, and engineering as well
as geography,
sociology, political science, psychotherapy (within family systems
therapy) and
economics among others. Systems theory thus serves as a bridge for
interdisciplinary dialogue between autonomous areas of study as well
as within the
area of systems science itself.
In this respect, with the possibility of misinterpretations, Bertalanffy [1]
believed a
general theory of systems “should be an important regulative device in
science,” to
guard against superficial analogies that “are useless in science and
harmful in their
practical consequences.” Others remain closer to the direct systems
concepts
developed by the original theorists. For example, Ilya Prigogine, of the
Center for
Complex Quantum Systems at the University of Texas, Austin, has
studied
emergent properties, suggesting that they offer analogues for living
systems. The
theories of Autopoiesis of Francisco Varela and Humberto Maturana
are a further
development in this field. Important names in contemporary systems
science
include Russell Ackoff, Bela Banathy, Stanford Beer, Mandy Brown,
Peter
Checkland, Robert Flood, Fritjof Capra, Michael C. Jackson, and
Werner Ulrich,
among others.
With the modern foundations for a general theory of systems following
the World
Wars, Ervin Laszlo, in the preface for Bertalanffy's book Perspectives
on General
System Theory, maintains that the translation of "general system
theory" from
German into English has "wroth a certain amount of Havoc" [2]. The
preface
explains that the original concept of a general system theory was
"Allgemeine
Systemtheorie (or Lehre)," pointing out the fact that "Theorie" (or
"Lehre") just as
"Wissenschaft" (translated Scholarship), "has a much broader meaning
in German
than the closest English words ‘theory’ and ‘science'" [3]. With these
ideas referring
to an organized body of science and "any systematically presented set
of concepts,
whether they are empirical, axiomatic, or philosophical," "Lehre" is
associated with
theory and science in the etymology of general systems, but also does
not translate
from the German very well; "teaching" is the closest equivalent [4].
While many of
the root meanings for the idea of a “general systems theory” might
have been lost in
the translation and many[attribution needed] were led to believe that
the systems
theorists had articulated nothing but a pseudoscience, systems theory
became a
nomenclature that early investigators used to describe the
interdependence of
relationships in organization by defining a new way of thinking about
science and
scientific paradigms.
A system from this frame of reference is composed of regularly
interacting or
interrelating groups of activities. For example, in noting the influence in
organizational psychology as the field evolved from “an individually
oriented
industrial psychology to a systems and developmentally oriented
organizational
psychology,” it was recognized that organizations are complex social
systems;
reducing the parts from the whole reduces the overall effectiveness of
organizations
[5]. This is at difference to conventional models that center on
individuals,
structures, departments and units separate in part from the whole
instead of
recognizing the interdependence between groups of individuals,
structures and
processes that enable an organization to function. Laszlo [6] explains
that the new
systems view of organized complexity went "one step beyond the
Newtonian view of
organized simplicity" in reducing the parts from the whole, or in
understanding the
whole without relation to the parts. The relationship between
organizations and their
environments became recognized as the foremost source of complexity
and
interdependence. In most cases the whole has properties that cannot
be known
from analysis of the constituent elements in isolation. Bela H. Banathy,
who argued
- along with the founders of the systems society - that “the benefit of
humankind” is
the purpose of science, has made significant and far-reaching
contributions to the
area of systems theory. For the Primer Group at ISSS, Banathy defines
a
perspective that iterates this view:
The systems view is a world-view that is based on the discipline of
SYSTEM INQUIRY. Central to systems inquiry is the concept of
SYSTEM.
In the most general sense, system means a configuration of parts
connected and joined together by a web of relationships. The Primer
group defines system as a family of relationships among the members
acting as a whole. Bertalanffy defined system as "elements in standing
relationship." [7]
Similar ideas are found in learning theories that developed from the
same
fundamental concepts, emphasizing that understanding results from
knowing
concepts both in part and as a whole. In fact, Bertalanffy’s organismic
psychology
paralleled the learning theory of Jean Piaget (Bertalanffy 1968).
Interdisciplinary
perspectives are critical in breaking away from industrial age models
and thinking
where history is history and math is math segregated from the arts and
music
separate from the sciences and never the twain shall meet [8]. The
influential
contemporary work of Peter Senge [9] provides detailed discussion of
the
commonplace critique of educational systems grounded in
conventional
assumptions about learning, including the problems with fragmented
knowledge and
lack of holistic learning from the "machine-age thinking" that became a
"model of
school separated from daily life." It is in this way that systems theorists
attempted to
provide alternatives and an evolved ideation from orthodox theories
with individuals
such as Max Weber, Emile Durkheim in sociology and Frederick
Winslow Taylor in
scientific management, which were grounded in classical assumptions
[10]. The
theorists sought holistic methods by developing systems concepts that
could be
integrated with different areas.
The contradiction of reductionism in conventional theory (which has as
its subject a
single part) is simply an example of changing assumptions. The
emphasis with
systems theory shifts from parts to the organization of parts,
recognizing
interactions of the parts are not "static" and constant but "dynamic”
processes.
Conventional closed systems were questioned with the development of
open
systems perspectives. The shift was from absolute and universal
authoritative
principles and knowledge to relative and general conceptual and
perceptual
knowledge [11], still in the tradition of theorists that sought to provide
means in
organizing human life. Meaning, the history of ideas that preceded
were rethought
not lost. Mechanistic thinking was particularly critiqued, especially the
industrial-age
mechanistic metaphor of the mind from interpretations of Newtonian
mechanics by
Enlightenment philosophers and later psychologists that laid the
foundations of
modern organizational theory and management by the late 19th
century [12].
Classical science had not been overthrown, but questions arose over
core
assumptions that historically influenced organized systems, within both
social and
technical sciences.
History
TIMELINE
• 1820-1903 Herbert Spencer
• 1882-1950 Nicolai Hartmann
• 1848-1923 Vilfredo Pareto
• 1888-1917 Emile Durkheim
• 1912-1917 Alexander Bogdanov publishes Tectology in Russian
(translated
to German in 1928)
• 1929-1951 Robert Maynard Hutchins, University of Chicago
• 1931 Interdisciplinary Division of the Social Sciences, U. of Chicago
• 1931 Bertalanffy presents General Systems Theory, U. of Chicago
• 1939-1945 World War II
• 1946-1953 Macy conferences
• 1948 Norbert Wiener publishes Cybernetics or Control and
Communication
in the Animal and the Machine
• 1955 W. Ross Ashby publishes Introduction to Cybernetics
• 1956 Ludwig von Bertalanffy, Anatol Rapoport, Ralph W. Gerard,
Kenneth
Boulding establish Society for the Advancement of General Systems
Theory.
• 1970-1980s Second-order cybernetics developed by Heinz von
Foerster,
Gregory Bateson, Humberto Maturana and others
• 1970s Catastrophe theory (René Thom, E.C. Zeeman) Dynamical
systems
in mathematics.
• 1980s Chaos theory David Ruelle, Edward Lorenz, Mitchell
Feigenbaum,
Steve Smale, James A. Yorke
• 1988 International Society for Systems Science
• 1990 Complex adaptive systems (CAS) John H. Holland, Murray GellMann,
Harold Morowitz, W. Brian Arthur
Whether considering the first systems of written communication with
Phoenician
cuneiform to Mayan numerals, or the feats of engineering with the
Egyptian
pyramids, systems thinking in essence dates back to antiquity.
Differentiated from
Western rationalist traditions of philosophy, C. West Churchman often
identified
with the I Ching as a systems approach sharing a frame of reference
similar to preSocratic philosophy and Heraclites [13]. Bertalanffy traced systems
concepts to the
philosophy of G.W. von Leibniz and Nicholas of Cusa’s Coincidentia
Oppositorum.
While modern systems are considerably more complicated, today’s
systems are
embedded in history.
Systems theory as an area of study specifically developed following the
World Wars
from the work of Ludwig von Bertalanffy, Anatol Rapoport, Kenneth E.
Boulding,
William Ross Ashby, Margaret Mead, Gregory Bateson, C. West
Churchman and
others in the 1950s, specifically catalyst from the Macy conferences.
Cognizant of
advances in science that questioned classical assumptions in the
organizational
sciences, Bertalanffy's idea to develop a theory of systems began as
early as the
interwar period, publishing "An Outline for General Systems Theory" in
the British
Journal for the Philosophy of Science, Vol 1, No. 2, by 1950. Where
assumptions in
Western science from Greek thought with Plato and Aristotle to
Newton’s Principia
have historically influenced all areas from the social to hard sciences,
the original
theorists explored the implications of twentieth century advances in
terms of
systems.
Subjects like complexity, self-organization, connectionism and adaptive
systems
had already been studied in the 1940s and 1950s. In fields like
cybernetics,
researchers like Norbert Wiener, William Ross Ashby, John von
Neumann and
Heinz von Foerster examined complex systems using mathematics and
no more
than pencil and paper. John von Neumann discovered cellular
automata and selfreproducing
systems, again with only pencil and paper. Aleksandr Lyapunov and
Jules Henri Poincaré worked on the foundations of chaos theory
without any
computer at all. At the same time Howard T. Odum, the radiation
ecologist,
recognised that the study of general systems required a language that
could depict
energetics and kinetics at any system scale. Odum developed a
general systems,
or Universal language, based on the circuit language of electronics to
fulfill this role,
known as the Energy Systems Language. Between 1929-1951, Robert
Maynard
Hutchins at the University of Chicago had undertaken efforts to
encourage
innovation and interdisciplinary research in the social sciences, aided
by the Ford
Foundation with the interdisciplinary Division of the Social Sciences
established in
1931 (Hammond 2003: 5-9). Numerous scholars had been actively
engaged in
ideas before (Tectology of Alexander Bogdanov published in
1912-1917 is a
remarkable example), but in 1937 Bertalanffy presented the general
theory of
systems for a conference at the University of Chicago.
The systems view was based on several fundamental ideas. First, all
phenomena
can be viewed as a web of relationships among elements, or a system.
Second, all
systems, whether electrical, biological, or social, have common
patterns, behaviors,
and properties that can be understood and used to develop greater
insight into the
behavior of complex phenomena and to move closer toward a unity of
science.
System philosophy, methodology and application are complementary to
this science
[14]. By 1956, the Society for General Systems Research was
established,
renamed the International Society for Systems Science in 1988. The
Cold War had
its affects upon the research project for systems theory in ways that
sorely
disappointed many of the seminal theorists. Some began to recognize
theories
defined in association with systems theory had deviated from the initial
General
Systems Theory (GST) view (Hull 1970). The economist Kenneth
Boulding, an early
researcher in systems theory, had concerns over the manipulation of
systems
concepts. Boulding concluded from the effects of the Cold War that
abuses of
power always prove consequential and that systems theory might
address such
issues [15]. Since the end of the Cold War, there has been a renewed
interest in
systems theory with efforts to strengthen an ethical view.
Developments in system theories
General systems research and systems inquiry
Many early systems theorists aimed at finding a general systems
theory that could
explain all systems in all fields of science. The term goes back to
Bertalanffy's book
titled General System Theory. von Bertalanffy's objective was to bring
together
under one heading the organismic science that he had observed in his
work as a
biologist. His desire was to use the word "system" to describe those
principles which
are common to systems in general. In GST, he writes:
...there exist models, principles, and laws that apply to generalized
systems or their subclasses, irrespective of their particular kind, the
nature of their component elements, and the relationships or "forces"
between them. It seems legitimate to ask for a theory, not of systems of
a
more or less special kind, but of universal principles applying to
systems
in general.[16]
Ervin Laszlo [17] in the preface of von Bertalanffy's book Perspectives
on General
System Theory.. [18]
Thus when von Bertalanffy spoke of Allgemeine Systemtheorie it was
consistent with his view that he was proposing a new perspective, a
new
way of doing science. It was not directly consistent with an
interpretation
often put on "general system theory," to wit, that it is a (scientific)
"theory
of general systems." To criticize it as such is to shoot at straw men.
Von
Bertalanffy opened up something much broader and of much greater
significance than a single theory (which, as we now know, can always
be
falsified and has usually an ephemeral existence): he created a new
paradigm for the development of theories.
Ludwig von Bertalanffy outlines systems inquiry into three major
domains:
Philosophy, the Science, and Technology. In his work with the Primer
Group, Bela
H. Banathy generalized the domains into four integratable domains of
systemic
inquiry:
1. Philosophy, the ontology, epistemology, and axiology of systems;
2. Theory, a set of interrelated concepts and principles applying to all
systems;
3. Methodology, the set of models, strategies, methods, and tools that
instrumentalize systems theory and philosophy; and
4. Application the application and interaction of the domains.
These operate in a recursive relationship, he explained. Integrating
Philosophy and
Theory as Knowledge, and Method and Application as action, Systems
Inquiry then
is knowledgable action.[19]
Cybernetics
Cybernetics is the study of feedback and derived concepts such as
communication
and control in living organisms, machines and organisations. Its focus
is how
anything (digital, mechanical or biological) processes information,
reacts to
information, and changes or can be changed to better accomplish the
first two
tasks.
The terms "systems theory" and "cybernetics" have been widely used
as synonyms.
Some authors use the term cybernetic systems to denote a proper
subset of the
class of general systems, namely those systems that include feedback
loops.
However Gordon Pask's differences of eternal interacting actor loops
(that produce
finite products) makes general systems a proper subset of cybernetics.
According to
Jackson (2000), Bertalanffy promoted an embryonic form of general
system theory
(GST) as early as the 1920s and 1930s but it was not until the early
1950s it
became more widely known in scientific circles.
Threads of cybernetics began in the late 1800s that led toward the
publishing of
seminal works (eg., Wiener’s Cybernetics in 1946 and von Bertalanffy’s
General
Systems Theory in 1968). Cybernetics arose more from engineering
fields and GST
from biology. If anything it appears that although the two probably
mutually
influenced each other, cybernetics had the greater influence.
Bertalanffy (1969)
specifically makes the point of distinguishing between the areas in
noting the
influence of cybernetics: "Systems theory is frequently identified with
cybernetics
and control theory. This again is incorrect. Cybernetics as the theory of
control
mechanisms in technology and nature and founded on the concepts of
information
and feedback, is but a part of a general theory of systems;” then
reiterates: "the
model is of wide application but should not be identified with 'systems
theory' in
general," and that "warning is necessary against its incautious
expansion to fields
for which its concepts are not made." (17-23). Jackson (2000) also
claims
Bertalanffy was informed by Alexander Bogdanov’s three volume
Tectology that
was published in Russia between 1912 and 1917, and was translated
into German
in 1928. He also states it is clear to Gorelik (1975) that the “conceptual
part” of
general system theory (GST) had first been put in place by Bogdanov.
The similar
position is held by Mattessich (1978) and Capra (1996). Bertalanffy
never even
mentioned Bogdanov in his works, which Capra (1996) finds
"surprising".
Cybernetics, catastrophe theory, chaos theory and complexity theory
have the
common goal to explain complex systems that consist of a large
number of mutually
interacting and interrelated parts in terms of those interactions. Cellular
automata
(CA), neural networks (NN), artificial intelligence (AI), and artificial life
(ALife) are
related fields, but they do not try to describe general (universal)
complex (singular)
systems. The best context to compare the different "C"-Theories about
complex
systems is historical, which emphasizes different tools and
methodologies, from
pure mathematics in the beginning to pure computer science now.
Since the
beginning of chaos theory when Edward Lorenz accidentally
discovered a strange
attractor with his computer, computers have become an indispensable
source of
information. One could not imagine the study of complex systems
without the use of
computers today.
Complex adaptive systems
Complex adaptive systems are special cases of complex systems.
They are
complex in that they are diverse and made up of multiple
interconnected elements
and adaptive in that they have the capacity to change and learn from
experience.
The term complex adaptive systems was coined at the interdisciplinary
Santa Fe
Institute (SFI), by John H. Holland, Murray Gell-Mann and others.
CAS ideas and models are essentially evolutionary, and they take
ground in the
modern biological views on adaptation and evolution. Accordingly, the
theory of
complex adaptive systems bridges developments of the system theory
with the
ideas of 'generalized Darwinism', which suggests that Darwinian
principles of
evolution are capable to explain a range of complex material
phenomena, from
cosmic to social objects.
Applications of system theories
Living systems theory
Living systems theory is an offshoot of Bertalanffy's general systems
theory, created
by James Grier Miller, which was intended to formalize the concept of
"life".
According to Miller's original conception as spelled out in his magnum
opus Living
Systems, a "living system" must contain each of 20 "critical
subsystems", which are
defined by their functions and visible in numerous systems, from simple
cells to
organisms, countries, and societies. In Living Systems Miller provides a
detailed
look at a number of systems in order of increasing size, and identifies
his
subsystems in each.
James Grier Miller (1978) wrote a 1,102-page volume to present his
living systems
theory. He constructed a general theory of living systems by focusing
on concrete
systems—nonrandom accumulations of matter-energy in physical
space-time
organized into interacting, interrelated subsystems or components.
Slightly revising
the original model a dozen years later, he distinguished eight “nested”
hierarchical
levels in such complex structures. Each level is “nested” in the sense
that each
higher level contains the next lower level in a nested fashion.
Software and computing
In the 1960s, systems theory was adopted by the post John Von
Neumann
computing and information technology field, and, in fact formed the
basis of
structured analysis and structured design (see also Larry Constantine,
Tom
Demarco and Ed Yourdon). It was also the basis for early software
engineering and
computer-aided software engineering principles.
By the 1970s, General Systems Theory (GST) was the fundamental
underpinning of
most commercial software design techniques, and by the 1980, W.
Vaughn Frick
and Albert F. Case, Jr. had used GST to design the "missing link"
transformation
from system analysis (defining what's needed in a system) to system
design (what's
actually implemented) using the Yourdon/Demarco notation. These
principles were
incorporated into computer-aided software engineering tools delivered
by Nastec
Corporation, Transform Logic, Inc., KnowledgeWare (see Fran
Tarkenton and
James Martin), Texas Instruments, Arthur Andersen and ultimately IBM
Corporation.
Organizational theory
Sociology and Sociocybernetics
Kurt Lewin attended the Macy conferences and is commonly identified
as the
founder of the movement to study groups scientifically.
Systems theory has also been developed within sociology. An
important figure in
the sociological systems perspective as developed from GST is Walter
Buckley
(who from Bertalanffy's theory). Niklas Luhmann (see Luhmann 1994)
is also
predominant in the literatures for sociology and systems theory. Miller's
living
systems theory was particularly influential in sociology from the time of
the early
systems movement. Models for equilibrium in systems analysis that
contrasted
classical views from Talcott Parsons and George Homas were
influential in
integrating concepts with the general movement. With the renewed
interest in
systems theory on the rise since the 1990s, Bailey (1994) notes the
concept of
systems in sociology dates back to Auguste Comte in the 19th century,
Herbert
Spencer and Vilfredo Pareto, and that sociology was readying into its
centennial as
the new systems theory was emerging following the World Wars.
In sociology, members of Research Committee 51 of the International
Sociological
Association (which focuses on sociocybernetics), have sought to
identify the
sociocybernetic feedback loops which, it is argued, primarily control the
operation of
society. On the basis of research largely conducted in the area of
education, Raven
(1995) has, for example, argued that it is these sociocybernetic
processes which
consistently undermine well intentioned public action and are currently
heading our
species, at an exponentially increasing rate, toward extinction. See
sustainability.
He suggests that an understanding of these systems processes will
allow us to
generate the kind of (non "common-sense") targeted interventions that
are required
for things to be otherwise - ie to halt the destruction of the planet.
The systems framework is also fundamental to organizational theory as
organizations are complex dynamic goal-oriented processes. One of
the early
thinkers in the field was Alexander Bogdanov, who developed his
Tectology, a
theory widely considered a precursor of Bertalanffy's GST, aiming to
model and
design human organizations (see Mattessich 1978, Capra 1996). Kurt
Lewin was
particularly influential in developing the systems perspective within
organizational
theory and coined the term "systems of ideology", from his frustration
with
behavioral psychologies that became an obstacle to sustainable work
in psychology
[20]. Jay Forrester with his work in dynamics and management
alongside numerous
theorists including Edgar Schein that followed in their tradition since the
Civil Rights
Era have also been influential.
The systems approach to organizations relies heavily upon achieving
negative
entropy through openness and feedback. A systemic view on
organizations is
transdisciplinary and integrative. In other words, it transcends the
perspectives of
individual disciplines, integrating them on the basis of a common
"code", or more
exactly, on the basis of the formal apparatus provided by systems
theory. The
systems approach gives primacy to the interrelationships, not to the
elements of the
system. It is from these dynamic interrelationships that new properties
of the system
emerge. In recent years, systems thinking has been developed to
provide
techniques for studying systems in holistic ways to supplement
traditional
reductionistic methods. In this more recent tradition, systems theory in
organizational studies is considered by some as a humanistic
extension of the
natural sciences.
System dynamics
System Dynamics was founded in the late 1950s by Jay W. Forrester
of the MIT
Sloan School of Management with the establishment of the MIT
System Dynamics
Group. At that time, he began applying what he had learned about
systems during
his work in electrical engineering to everyday kinds of systems.
Determining the
exact date of the founding of the field of system dynamics is difficult
and involves a
certain degree of arbitrariness. Jay W. Forrester joined the faculty of
the Sloan
School at MIT in 1956, where he then developed what is now System
Dynamics.
The first published article by Jay W. Forrester in the Harvard Business
Review on
"Industrial Dynamics", was published in 1958. The members of System
Dynamics
Society have chosen 1957 to mark the occasion as it is the year in
which the work
leading to that article, which described the dynamics of a
manufacturing supply
chain, was done.
As an aspect of systems theory, system dynamics is a method for
understanding
the dynamic behavior of complex systems. The basis of the method is
the
recognition that the structure of any system — the many circular,
interlocking,
sometimes time-delayed relationships among its components — is
often just as
important in determining its behavior as the individual components
themselves.
Examples are chaos theory and social dynamics. It is also claimed that,
because
there are often properties-of-the-whole which cannot be found among
the
properties-of-the-elements, in some cases the behavior of the whole
cannot be
explained in terms of the behavior of the parts. An example is the
properties of
these letters which when considered together can give rise to meaning
which does
not exist in the letters by themselves. This further explains the
integration of tools,
like language, as a more parsimonious process in the human
application of easiest
path adaptability through interconnected systems.
Systems engineering
Systems Engineering is an interdisciplinary approach and means for
enabling the
realization and deployment of successful systems. It can be viewed as
the
application of engineering techniques to the engineering of systems, as
well as the
application of a systems approach to engineering efforts.[21] Systems
Engineering
integrates other disciplines and specialty groups into a team effort,
forming a
structured development process that proceeds from concept to
production to
operation and disposal. Systems Engineering considers both the
business and the
technical needs of all customers, with the goal of providing a quality
product that
meets the user needs.[22]
Systemic psychology
Systemic psychology is a branch of psychology that treats groups, and
to some
extent individuals, as systems that exhibit homeostasis. Meaning,
within open
systems they have an active method of remaining stable through the
dynamic
relationship between parts. Systemic psychology is based on the
theoretical work of
Gregory Bateson and others. Therapeutic applications were developed
by Virginia
Satir, the Milan Group, and others.
See also
• C ybernetics
• E mergence
• H olism
• M eta-systems
• M indwalk (film)
• M orphological analysis
• M ulti-agent system
• P ublications in systems theory
• S ystemantics
• S ystem engineering
• S ystem of systems
• S ystem of systems engineering
• S ystems architecture
• S ystems intelligence
• S ystems theory in archaeology
• S ystems theory in political science
• S ystems thinking
• T erms used in systems theory
• W orld-systems theory
References
1. ^ Bertalanffy (1950: 142)
2. ^ (Laszlo 1974)
3. ^ (Laszlo 1974)
4. ^ (Laszlo 1974)
5. ^ (Schein 1980: 4-11)
6. ^ Laslo (1972: 14-15)
7. ^ (Banathy 1997: ¶ 22)
8. ^ (see Steiss 1967; Buckley, 1967)
9. ^ Peter Senge (2000: 27-49)
10.^ (Bailey 1994: 3-8; see also Owens 2004)
11.^ (Bailey 1994: 3-8)
12.^ (Bailey 1994; Flood 1997; Checkland 1999; Laszlo 1972)
13.^ (Hammond 2003: 12-13)
14.^ (Laszlo 1974)
15.^ (Hammond 2003: 229-233)
16.^ (GST p.32)
17.^ http://projects.isss.org/perspectives_on_general_system_theory
18.^ von Bertalanffy, Ludwig, (1974) Perspectives on General System
Theory
Edited by Edgar Taschdjian. George Braziller, New York
19.^ http://projects.isss.org/Main/SystemsInquiry]
20.^ (see Ash 1992: 198-207)
21.^ Thomé, Bernhard (1993). Systems Engineering: Principles and
Practice of
Computer-based Systems Engineering. Chichester: John Wiley &
Sons. ISBN
0-471-93552-2.
22.^ INCOSE. What is Systems Engineering. Retrieved on 2006-11-26.
This article or section is missing citations or needs footnotes.
Using inline citations helps guard against copyright violations and
factual inaccuracies. (July 2007)
Further reading
• Ackoff, R. (1978). The art of problem solving. New York: Wiley.
• Ash, M.G. 1992. "Cultural Contexts and Scientific Change in
Psychology: Kurt
Lewin in Iowa." American Psychologist, Vol. 47, No. 2, pp. 198-207.
• Bailey, K.D. 1994. Sociology and the New Systems Theory: Toward a
Theoretical Synthesis. New York: State of New York Press.
• Banathy, B (1996) Designing Social Systems in a Changing World
New York
Plenum
• Banathy, B. ( ) Systems Design of Education. Englewood Cliffs:
Educational
Technology Publications
• Banathy, B. (1992) A Systems View of Education. Englewood Cliffs:
Educational Technology Publications. ISBN 0-87778-245-8
• Banathy, B.H. 1997. "A Taste of Systemics", The Primer Project,
Retrieved
May 14, 2007
• Bateson, G. (1979). Mind and nature: A necessary unity. New York:
Ballantine
• Bausch, Kenneth C. (2001) The Emerging Consensus in Social
Systems
Theory, Kluwer Academic New York ISBN 0-306-46539-6
• L udwig von Bertalanffy (1968). General System Theory:
Foundations,
Development, Applications New York: George Braziller
• Bertalanffy, L. von. (1950). "An Outline of General Systems Theory."
British
Journal for the Philosophy of Science, Vol. 1, No. 2.
• Bertalanffy, L. von. 1955. "An Essay on the Relativity of Categories."
Philosophy of Science, Vol. 22, No. 4, pp. 243–263.
• Bertalanffy, Ludwig von. 1968. Organismic Psychology and Systems
Theory.
Worchester: Clark University Press.
• Bertalanffy, Ludwig Von. 1974. Perspectives on General System
Theory
Edited by Edgar Taschdjian. George Braziller, New York.
• Buckley, W. 1967. Sociology and Modern Systems Theory. New
Jersey:
Englewood Cliffs.
• M ario Bunge (1979) Treatise on Basic Philosophy, Volume 4.
Ontology II A
World of Systems. Dordrecht, Netherlands: D. Reidel.
• Capra, F. (1997). The Web of Life-A New Scientific Understanding of
Living
Systems, Anchor ISBN 978-0385476768
• Checkland, P. (1981). Systems thinking, Systems practice. New York:
Wiley.
• Checkland, P. 1997. Systems Thinking, Systems Practice. Chichester:
John
Wiley & Sons, Ltd.
• Churchman, C.W. (1968). The systems approach. New York: Laurel.
• Churchman, C.W. (1971). The design of inquiring systems. New York:
Basic
Books.
• Corning, P. 1983) The Synergism Hupothesis: A Theory of
Progressive
Evolution. New York: McGRaw Hill
• Durand, D. La systémique, Presses Universitaires de France*
Hinrichsen, D.
and Pritchard, A.J. (2005) Mathematical Systems Theory. New York:
Springer. ISBN 978-3-540-44125-0
• Flood, R.L. 1999. Rethinking the Fifth Discipline: Learning within the
unknowable." London: Routledge.
• C harles François. (2004). Encyclopedia of Systems and Cybernetics,
Introducing the 2nd Volume [1] and further links to the
ENCYCLOPEDIA, K G
Saur, Munich [2] see also [3] * Kahn, Herman. (1956). Techniques of
System
Analysis, Rand Corporation* Laszlo, E. (1995). The Interconnected
Universe.
New Jersy, World Scientific. ISBN 981-02-2202-5
• François, C. (1999). Systemics and Cybernetics in a Historical
Perspective *
Jantsch, E. (1980). The Self Organizing Universe. New York:
Pergamon.
• Gorelik, G. (1975) Reemergence of Bogdanov’s Tektology in. Soviet
Studies
of Organization, Academy of Management Journal. 18/2, pp. 345-357
• Hammond, D. 2003. The Science of Synthesis. Colorado: University
of
Colorado Press.
• Hull, D.L. 1970. “Systemic Dynamic Social Theory.” Sociological
Quarterly,
Vol. 11, Issue 3, pp. 351-363.
• J ackson, M.C. 2000. Systems Approaches to Management. London:
Springer.
• Klir, G.J. 1969. An Approach to General Systems Theory. New York:
Van
Nostrand Reinhold Company.
• E rvin László 1972. The Systems View of the World. New York:
George
Brazilier.
• Laszlo, E. (1972a). The systems view of the world. The natural
philosophy of
the new developments in the sciences. New York: George Brazillier.
ISBN 08076-0636-7
• Laszlo, E. (1972b). Introduction to systems philosophy. Toward a new
paradigm of contemporary thought. San Francisco: Harper. -->
• Laszlo, Ervin. 1996. The Systems View of the World. Hampton Press,
NJ.
(ISBN 1-57273-053-6).
• Lemkow, A. (1995) The Wholeness Principle: Dynamics of Unity
Within
Science, Religion & Society. Quest Books, Wheaton.
• N iklas Luhmann. (1984). Soziale Systeme. Grundriss einer
allgemeinen
Theorie, Frankfurt, Suhrkamp.
• Mattessich, R. (1978) Instrumental Reasoning and Systems
Methodology: An
Epistemology of the Applied and Social Sciences. Reidel, Boston
• Minati, Gianfranco. Collen, Arne. (1997) Introduction to Systemics
Eagleye
books. ISBN 0-924025-06-9
• Odum, H. (1994) Ecological and General Systems: An introduction to
systems ecology, Colorado University Press, Colorado.
• Owens, R.G. (2004). Organizational Behavior in Education: Adaptive
Leadership and School Reform, Eighth Edition. Boston: Pearson
Education,
Inc.
• Pharoah, M.C. (online). Looking to systems theory for a reductive
explanation
of phenomenal experience and evolutionary foundations for higher
order
thought Retrieved Dec.14 2007.
• Schein, E.H. 1980. Organizational Psychology, Third Edition. New
Jersey:
Prentice-Hall.
• P eter Senge (1990). The Fifth Discipline. The art and practice of the
learning
organization. New York: Doubleday.
• Senge, P., Ed. 2000. Schools That Learn: A Fifth Discipline Fieldbook
for
Educators, Parents, and Everyone Who Cares About Education. New
York:
Doubleday Dell Publishing Group.
• Steiss, A.W. 1967. Urban Systems Dynamics. Toronto: Lexington
Books.
• G erald Weinberg. (1975). An Introduction to General Systems
Thinking (1975
ed., Wiley-Interscience) (2001 ed. Dorset House).
• Wiener, N. (1967). The human use of human beings. Cybernetics and
Society. New York: Avon.
External links
Look up Systems theory in Wiktionary, the free dictionary.
• P rincipia Cybernetica Web
• In ternational Society for the System Sciences
• A utopoiesis at the ACM website
• S ystems theory
• L e Village Systémique
• P ortland State University Systems Science Ph.D. Program
• N ew England Complex Systems Institute
• U CLA Human Complex Systems Program
• S ystems Department, Open University
Academic programs:
• E ngineering and Systems Division, MIT
• C enter for the Study of Complex Systems, University of Michigan
• C enter for Models of Life, Niels Bohr Institute, Copenhagen
Un-annotated external links:
• h ttp://mvhs1.mbhs.edu/mvhsproj/project2.html
• h ttp://www.geom.umn.edu/education/math5337/ds/
• h ttp://www.systemdynamics.org/
• h ttp://www.uni-klu.ac.at/users/gossimit/links/bookmksd.htm
• h ttp://www.wkap.nl/journalhome.htm/0924-6703
• h ttp://www.wkap.nl/jrnltoc.htm/0924-6703
• h ttp://www.newciv.org/ISSS_Primer/seminar.html
• h ttp://chiron.valdosta.edu/whuitt/materials/sysphil.html
• H umane Systems Design (semi-annotated)
Biological system · Complex system · Complex adaptive system ·
Conceptual system · Cultural system · Dynamical system · Economic
system · Ecosystem · Formal system · Global Positioning System ·
Human organ systems · Information systems · Legal system · Metric
system · Nervous system · Non-linear system · Operating system ·
Physical system · Political system · Sensory system · Social system ·
Solar System · System · Systems of measurement
In the natural sciences an open system is one whose border is
permeable to both
energy and mass.[2] In physics a closed system, by contrast, is
permeable to
energy but not to matter.
Open systems have a number of consequences. A closed system
contains limited
energy. The definition of an open system assumes that there are
supplies of energy
that cannot be depleted; in practice, this energy is supplied from some
source in the
surrounding environment, which can be treated as infinite for the
purposes of study.
One type of open system is the so-called radiant energy system, which
receives its
energy from solar radiation – an energy source that can be regarded as
inexhaustible for all practical purposes.
In the social sciences
In the social sciences an open systems is a process that exhange
material, energy,
people, capital and information with its environment.
Fields of theory
See also
Chaos theory · Complex systems · Control theory · Cybernetics ·
Holism
in science · Sociotechnical systems theory · Systems biology · System
dynamics · Systems ecology · Systems engineering · Systems theory ·
Systems science
• C losed system
• D ynamical system
• G lossary of systems theory
• I solated system
• M aximum power principle
• N on-equilibrium thermodynamics
• O pen system (computing)
• P hantom loop
• S ystem theory
• T hermodynamic system
Global structure in systems, systems sciences and systems scientists
Categories
Conceptual systems · Physical systems · Social systems · Systems ·
Systems science · Systems scientists · Systems theory
Systems
Systems scientists
Russell L. Ackoff · William Ross Ashby · Gregory Bateson · Stafford
Beer · Ludwig von Bertalanffy · Kenneth E. Boulding · Peter Checkland
·
C. West Churchman · Heinz von Foerster · Charles François · Jay
Wright
Forrester · Ralph W. Gerard · Debora Hammond · George Klir · Niklas
Luhmann · Humberto Maturana · Donella Meadows · Mihajlo D.
Mesarovic · Howard T. Odum · Talcott Parsons · Ilya Prigogine · Anatol
Rapoport · Francisco Varela · John N. Warfield · Norbert Wiener
Retrieved from "http://en.wikipedia.org/wiki/Systems_theory"
Categories: Articles with specifically-marked weasel-worded phrases |
Articles with
unsourced statements since July 2007 | All articles with unsourced
statements |
Wikipedia external links cleanup | Cybernetics | Branches of sociology
(interdisciplinary) | Evolution | Sociology of science | Systems |
Systems theory |
Theories of history
Open system (systems theory)
An open system is a state of a system, in which a system continuously
interacts
with its environment. Open systems are those that maintain their state
and exhibit
the characteristics of openness previously mentioned.
Open systems contrast with closed systems. Systems are rarely ever
either open or
closed but open to some and closed to other influences. [1]. Basic
characteristics of
an open system are environment, input, throughput and output. And
some control
systems with feedback. The definition of a "system" is often arbitrary; a
system may
be defined as the region of space under study being characterized by a
collection of
components or elements related in some way.
The concept of an "open system" is originally developed in
thermodynamics, and
since the 1950s also in systems theory. Nowadays the concept has its
applications
in the natural and social sciences.
In the natural sciences
References
1. ^ OPEN SYSTEM, Pricipea Cybernetica Web, 2007.
2. ^ Glossary Maxwell Demon, 1998.
Further reading
• Khalil, E.L. (1995). Nonlinear thermodynamics and social science
modeling:
fad cycles, cultural development and identificational slips. The
American
Journal of Economics and Sociology, Vol. 54, Issue 4, pp. 423-438.
• Weber, B.H. (1989). Ethical Implications Of The Interface Of Natural
And
Artificial Systems. Delicate Balance: Technics, Culture and
Consequences:
Conference Proceedings for the Institute of Electrical and Electronic
Engineers.
External links
• O PEN SYSTEM, Pricipea Cybernetica Web, 2007.
Retrieved
from
"http://en.wikipedia.org/wiki/Open_system_
%28systems_theory%29"
Categories: Systems theory stubs | Cybernetics | Physical systems
Closed system
A closed system is a system in the state of being isolated from the
environment. It
is often used to refer to a theoretical scenario where perfect closure is
an
assumption, however in practice no system can be completely closed;
there are
only varying degrees of closure.
In physics, a closed system can exchange heat and work, but not
matter, with its
surroundings. In contrast an isolated system can exchange neither
heat nor matter
with the surroundings. For a simple system, with only one type of
particle (atom or
molecule), this amounts to a constant number of particles. However, for
systems
which are undergoing a chemical reaction, there may be all sorts of
molecules being
generated and destroyed by the reaction process. In this case, the fact
that the
system is closed is expressed by saying that the total number of each
elemental
atom is conserved, no matter what kind of molecule it may be a part of.
Mathematically:
where Nj is the number of j-type molecules, aij is the number of atoms
of element i
in molecule j and bi
0 is the total number of atoms of element i in the system, which
remains constant, since the system is closed. There will be one such
equation for
each different element in the system.
In quantum mechanics confusingly, a closed system is equivalent to an
isolated
system, and a system that can exchange energy with the surroundings
is referred to
as an o pen system [ 1].
Notes
1. ^ Nielsen, M and Chuang, I (2000). Quantum Computation and
Quantum
Information.
characteristics of life and interact with their environment. This takes
place by means
of information and material-energy exchanges. Living systems can be
as simple as
a single cell or as complex as a supranational organization such as the
European
Economic Community. Regardless of their complexity, they each
depend upon the
same essential twenty subsystems (or processes) in order to survive
and to
continue the propagation of their species or types beyond a single
generation.[2].
Miller said that systems exist at eight "nested" hierarchical levels: cell,
organ,
organism, group, organization, community, society, and supranational
system. At
each level, a system invariably comprises 20 critical subsystems, which
process
matter/ energy or information except for the first two, which process
both
matter/energy and information: reproducer & boundary.
The processors of matter/energy are:
• Ingestor, Distributor, Converter, Producer, Storage, Extruder, Motor,
Supporter
The processors of information are
• Input transducer, Internal transducer, Channel and net, Timer (added
later),
Decoder, Associator, Memory, Decider, Encoder, Output transducer.
See also
Miller's Living systems theory
• G lossary of systems theory
• D ynamical system: Has components and/or flows that change over
time.
• I solated system: Has no interactions with an outside system, not
even energy
can flow into or out of an isolated system.
• O pen system: Can be influenced by events outside of the actual or
conceptual boundaries.
• T hermodynamic system
Retrieved from "http://en.wikipedia.org/wiki/Closed_system"
Living systems theory
Living systems theory is a general theory about the existence of all
living systems,
their structure, interaction, behavior and development. This work is
created by
James Grier Miller, which was intended to formalize the concept of
"life". According
to Miller's original conception as spelled out in his magnum opus Living
Systems, a
"living system" must contain each of 20 "critical subsystems", which are
defined by
their functions and visible in numerous systems, from simple cells to
organisms,
countries, and societies. In Living Systems Miller provides a detailed
look at a
number of systems in order of increasing size, and identifies his
subsystems in
each.
Living systems
Miller considers living systems as a subset of all systems. Below the
level of living
systems, he defines space and time, matter and energy, information
and entropy,
levels of organization, and physical and conceptual factors, and above
living
systems ecological, planetary and solar systems, galaxies, and so
forth.[1].
Living systems are by definition open self-organizing systems that have
the special
James Grier Miller in 1978 wrote a 1,102-page volume to present his
living systems
theory. He constructed a general theory of living systems by focusing
on concrete
systems—nonrandom accumulations of matter-energy in physical
space-time
organized into interacting, interrelated subsystems or components.
Slightly revising
the original model a dozen years later, he distinguished eight “nested”
hierarchical
levels in such complex structures. Each level is “nested” in the sense
that each
higher level contains the next lower level in a nested fashion.
His central thesis is that the systems in existence at all eight levels are
open
systems composed of 20 critical subsystems that process inputs,
throughputs, and
outputs of various forms of matter/energy and information. Two of these
subsystems—reproducer and boundary—process both matter/energy
and
information. Eight of them process only matter/energy. The other 10
process
information only.
All nature is a continuum. The endless complexity of life is organized
into
patterns which repeat themselves—theme and variations—at each
level
of system. These similarities and differences are proper concerns for
science. From the ceaseless streaming of protoplasm to the
manyvectored
activities of supranational systems, there are continuous flows
through living systems as they maintain their highly organized steady
states.[3]
Seppänen (1998) says that Miller applied general systems theory on a
broad scale
to describe all aspects of living systems” [4]
Topics in living systems theory
Miller’s theory posits that the mutual interrelationship of the
components of a system
extends across the hierarchical levels. Examples: Cells and organs of a
living
system thrive on the food the organism obtains from its suprasystem;
the member
countries of a supranational system reap the benefits accrued from the
communal
activities to which each one contributes. Miller says that his eclectic
theory “ties
together past discoveries from many disciplines and provides an
outline into which
new findings can be fitted”.[5]
Miller says the concepts of space, time, matter, energy, and information
are
essential to his theory because the living systems exist in space and
are made of
matter and energy organized by information. Miller’s theory of living
systems
employs two sorts of spaces: physical or geographical space, and
conceptual or
abstracted spaces. Time is the fundamental “fourth dimension” of the
physical
space-time continuum/spiral. Matter is anything that has mass and
occupies
physical space. Mass and energy are equivalent as one can be
converted into the
other. Information refers to the degrees of freedom that exist in a given
situation to
choose among signals, symbols, messages, or patterns to be
transmitted.
Other relevant concepts are system, structure, process, type, level,
echelon,
suprasystem, subsystem, transmissions, and steady state. A system
can be
conceptual, concrete or abstracted. The structure of a system is the
arrangement of
the subsystems and their components in three-dimensional space at
any point of
time. Process, which can be reversible or irreversible, refers to change
over time of
matter/energy or information in a system. Type defines living systems
with similar
characteristics. Level is the position in a hierarchy of systems. Many
complex living
systems, at various levels, are organized into two or more echelons.
The
suprasystem of any living system is the next higher system in which it
is a
subsystem or component. The totality of all the structures in a system
which carry
out a particular process is a subsystem. Transmissions are inputs and
outputs in
concrete systems. Because living systems are open systems, with
continually
altering fluxes of matter/energy and information, many of their equilibria
are
dynamic—situations identified as steady states or flux equilibria.
Miller identifies the comparable matter-energy and information
processing critical
subsystems. Elaborating on the eight hierarchical levels, he defines
society, which
constitutes the seventh hierarchy, as “a large, living, concrete system
with
[community] and lower levels of living systems as subsystems and
components”. [6]
Society may include small, primitive, totipotential communities; ancient
city-states,
and kingdoms; as well as modern nation-states and empires that are
not
supranational systems. Miller provides general descriptions of each of
the
subsystems that fit all eight levels.
A supranational system, in Miller’s view, “is composed of two or more
societies,
some or all of whose processes are under the control of a decider that
is
superordinate to their highest echelons” [7]. However, he contends that
no
supranational system with all its 20 subsystems under control of its
decider exists
today. The absence of a supranational decider precludes the existence
of a
concrete supranational system. Miller says that studying a
supranational system is
problematical because its subsystems
...tend to consist of few components besides the decoder. These
systems
do little matter-energy processing. The power of component societies
[nations] today is almost always greater than the power of
supranational
deciders. Traditionally, theory at this level has been based upon
intuition
and study of history rather than data collection. Some quantitative
research is now being done, and construction of global-system models
and simulations is currently burgeoning.[8]
At the supranational system level, Miller’s emphasis is on international
organizations, associations, and groups comprising representatives of
societies
(nation-states). Miller identifies the subsystems at this level to suit this
emphasis.
Thus, for example, the reproducer is “any multipurpose supranational
system which
creates a single purpose supranational organization” (p. 914); and the
boundary is
the “supranational forces, usually located on or near supranational
borders, which
defend, guard, or police them” (p. 914).
Strengths of Miller’s theory
Not just those specialized in international communication, but all
communication
science scholars could pay particular attention to the major
contributions of LST to
social systems approaches that Bailey [9] has pointed out:
• The specification of the 20 critical subsystems in any living system.
• The specification of the eight hierarchical levels of living systems.
• The emphasis on cross-level analysis and the production of
numerous crosslevel
hypotheses.
• Cross-subsystem research (e.g., formulation and testing of
hypotheses in two
or more subsystems at a time).
• Cross-level, cross-subsystem research.
Bailey says that LST, perhaps the “most integrative” social systems
theory, has
made many more contributions that may be easily overlooked, such as:
providing a
detailed analysis of types of systems; making a distinction between
concrete and
abstracted systems; discussion of physical space and time; placing
emphasis on
information processing; providing an analysis of entropy; recognition of
totipotential
systems, and partipotential systems; providing an innovative approach
to the
structure-process issue; and introducing the concept of joint subsystem
—a
subsystem that belongs to two systems simultaneously; of dispersal—
lateral,
outward, upward, and downward; of inclusion—inclusion of something
from the
environment that is not part of the system; of artifact—an animal-made
or humanmade
inclusion; of adjustment process, which combats stress in a system;
and of
critical subsystems, which carry out processes that all living systems
need to
survive.[10]
LST’s analysis of the 20 interacting subsystems, Bailey adds, clearly
distinguishing
between matter/energy processing and information-processing, as well
as LST’s
analysis of the eight interrelated system levels, enables us to
understand how social
systems are linked to biological systems. LST also analyzes the
irregularities or
“organizational pathologies” of systems functioning (e.g., system stress
and strain,
feedback irregularities, information-input overload). It explicates the
role of entropy
in social research while it equates negentropy with information and
order. It
emphasizes both structure and process, as well as their interrelations
[11]
Limitations
It omits the analysis of subjective phenomena, and it overemphasizes
concrete Qanalysis
(correlation of objects) to the virtual exclusion of R-analysis (correlation
of
variables). By asserting that societies (ranging from totipotential
communities to
nation-states and non-supranational systems) have greater control
over their
subsystem components than supranational systems have, it dodges
the issue of
transnational power over the contemporary social systems. Miller’s
supranational
system bears no resemblance to the modern world-system that
Wallerstein (1974)
described although both of them were looking at the same living
(dissipative)
structure.
References
• K enneth D. Bailey, (1994). Sociology and the new systems theory:
Toward a
theoretical synthesis. Albany, NY: SUNY Press.
• Kenneth D. Bailey (2006). Living systems theory and social entropy
theory.
Systems Research and Behavioral Science, 22, 291-300.
• James Grier Miller, (1978). Living systems. New York: McGraw-Hill.
ISBN 087081-363-3
• Miller, J.L., & Miller, J.G. (1992). Greater than the sum of its parts:
Subsystems which process both matter-energy and information.
Behavioral
Science, 37, 1-38.
• Jouko Seppänen, (1998). Systems ideology in human and social
sciences. In
G. Altmann & W.A. Koch (Eds.), Systems: New paradigms for the
human
sciences (pp. 180-302). Berlin: Walter de Gruyter.
• Wallerstein, I. (1974). The modern world-system: Capitalist agriculture
and
the origins of the European world economy in the sixteenth century.
New
York: Academic Press.
Footnotes
1. ^ Seppänen, 1998, p. 198
2. ^ Elaine Parent, [The Living Systems Theory of James Grier Miller],
Primer
project ISSS, 1996.
3. ^ (Miller, 1978, p. 1025)
4. ^ Seppänen 1998, pp. 197-198.
5. ^ (Miller, 1978, p.1025)
6. ^ Miller 1978, p. 747.
7. ^ Miller 1978, p. 903
8. ^ Miller, 1978, p. 1043.
9. ^ Kenneth D. Bailey, (2006)
10.^ Kenneth D. Bailey 2006, pp.292-296.
11.^ Kenneth D. bailey, 1994, pp. 209-210.
See also
• S ystems theory
• B iological systems
External links
• In ternational Society for the Systems Sciences
• L iving Systems Theory Of James Grier Miller
• S ymbols for drawing Living Systems Theory diagrams
Retrieved from "http://en.wikipedia.org/wiki/Living_systems_theory"
Categories: Systems theory | Biological systems | Life
Biochemical systems theory
Biochemical systems theory is a mathematical modelling framework for
biochemical systems, based on ordinary differential equations (ODE),
in which
biochemical processes are represented using power-law expansions in
the
variables of the system. This framework, which became known as
Biochemical
Systems Theory, is developed since the 1960s by Michael Savageau
and other
groups for systems analysis of biochemical processes.[1] They regard
this as a
general theory of metabolic control, which includes both metabolic
control analysis
and flux-oriented theory as special cases.[2]
Representation
The dynamics of a specie is represented by a differential equation with
the
structure:
where Xi represents one of the nd variables of the model (metabolite
concentrations,
protein concentrations or levels of gene expression). j represents the nf
biochemical
processes affecting the dynamics of the specie. On the other hand, μij
(stoichiometric coefficient), γj (rate constants) and fik (kinetic orders)
are two
different kinds of parameters defining the dynamics of the system.
The principal difference of power-law models with respect to other ODE
models
used in biochemical systems is that the kinetic orders can be noninteger numbers.
A kinetic order can have even negative value when inhibition is
modelled. In this
way, power-law models have a higher flexibility to reproduce the nonlinearity of
biochemical systems.
Models using power-law expansions have been used during the last 35
years to
model and analyse several kinds of biochemical systems including
metabolic
networks, genetic networks and recently in cell signalling.
Literature
Books:
• M.A. Savageau, Biochemical systems analysis: a study of function
and
design in molecular biology, Reading, MA, Addison–Wesley, 1976.
• E.O. Voit (ed), Canonical Nonlinear Modeling. S-System Approach to
Understanding Complexity, Van Nostrand Reinhold, NY, 1991.
• E.O. Voit, Computational Analysis of Biochemical Systems. A
Practical Guide
for Biochemists and Molecular Biologists, Cambridge University Press,
Cambridge, U.K., 2000.
• N.V. Torres and E.O. Voit, Pathway Analysis and Optimization in
Metabolic
Engineering, Cambridge University Press, Cambridge, U.K., 2002.
Scientific articles:
• M.A. Savageau, Biochemical systems analysis: I. Some mathematical
properties of the rate law for the component enzymatic reactions in: J.
Theor.
Biol. 25, pp. 365-369, 1969.
• M.A. Savageau, Development of fractal kinetic theory for enzymecatalysed
reactions and implications for the design of biochemical pathways in:
Biosystems 47(1-2), pp. 9-36, 1998.
• M.R. Atkinson et al, Design of gene circuits using power-law models,
in: Cell
113, pp. 597–607, 2003.
• F. Alvarez-Vasquez et al, Simulation and validation of modelled
sphingolipid
metabolism in Saccharomyces cerevisiae, Nature 27, pp. 433(7024),
pp. 42530, 2005.
• J. Vera et al, Power-Law models of signal transduction pathways in:
Cellular
Signalling doi:10.1016/j.cellsig.2007.01.029), 2007.
• Eberhart O. Voit, Applications of Biochemical Systems Theory, 2006.
References
1. ^ Biochemical Systems Theory, an introduction.
2. ^ Athel Cornish-Bowden, Metabolic control analysis FAQ, website 18
April
2007.
See also
• D ynamical systems
• L udwig von Bertalanffy
• S ystems theory
External links
• B iochemical Systems Theory an introduction,
• h ttp://web.udl.es/Biomath/PowerLaw/
Retrieved
"http://en.wikipedia.org/wiki/Biochemical_systems_theory"
Categories: Systems theory stubs | Systems biology
from
Dynamical system
This article is about the general aspects of dynamical systems. For
technical details,
see Dynamical system (definition). For the use of dynamical systems in
cognitive
science, see Dynamical system (cognitive science).
The Lorenz attractor is an example of a non-linear dynamical system.
Studying this
system helped give rise to Chaos theory.
The dynamical system concept is a mathematical formalization for any
fixed "rule"
which describes the time dependence of a point's position in its
ambient space.
Examples include the mathematical models that describe the swinging
of a clock
pendulum, the flow of water in a pipe, and the number of fish each
spring in a lake.
A dynamical system has a state determined by a collection of real
numbers, or more
generally by a set of points in an appropriate state space. Small
changes in the
state of the system correspond to small changes in the numbers. The
numbers are
also the coordinates of a geometrical space—a manifold. The evolution
rule of the
dynamical system is a fixed rule that describes what future states
follow from the
current state. The rule is deterministic: for a given time interval only
one future state
follows from the current state.
Overview
The concept of a dynamical system has its origins in Newtonian
mechanics. There,
as in other natural sciences and engineering disciplines, the evolution
rule of
dynamical systems is given implicitly by a relation that gives the state
of the system
only a short time into the future. (The relation is either a differential
equation,
difference equation or other time scale.) To determine the state for all
future times
requires iterating the relation many times—each advancing time a
small step. The
iteration procedure is referred to as solving the system or integrating
the system.
Once the system can be solved, given an initial point it is possible to
determine all
its future points, a collection known as a trajectory or orbit.
Before the advent of fast computing machines, solving a dynamical
system required
sophisticated mathematical techniques and could only be
accomplished for a small
class of dynamical systems. Numerical methods executed on
computers have
simplified the task of determining the orbits of a dynamical system.
For simple dynamical systems, knowing the trajectory is often
sufficient, but most
dynamical systems are too complicated to be understood in terms of
individual
trajectories. The difficulties arise because:
• The systems studied may only be known approximately—the
parameters of
the system may not be known precisely or terms may be missing from
the
equations. The approximations used bring into question the validity or
relevance of numerical solutions. To address these questions several
notions
of stability have been introduced in the study of dynamical systems,
such as
Lyapunov stability or structural stability. The stability of the dynamical
system
implies that there is a class of models or initial conditions for which the
trajectories would be equivalent. The operation for comparing orbits to
establish their equivalence changes with the different notions of
stability.
• The type of trajectory may be more important than one particular
trajectory.
Some trajectories may be periodic, whereas others may wander
through
many different states of the system. Applications often require
enumerating
these classes or maintaining the system within one class. Classifying
all
possible trajectories has led to the qualitative study of dynamical
systems,
that is, properties that do not change under coordinate changes. Linear
dynamical systems and systems that have two numbers describing a
state
are examples of dynamical systems where the possible classes of
orbits are
understood.
• The behavior of trajectories as a function of a parameter may be what
is
needed for an application. As a parameter is varied, the dynamical
systems
may have bifurcation points where the qualitative behavior of the
dynamical
system changes. For example, it may go from having only periodic
motions to
apparently erratic behavior, as in the transition to turbulence of a fluid.
• The trajectories of the system may appear erratic, as if random. In
these
cases it may be necessary to compute averages using one very long
trajectory or many different trajectories. The averages are well defined
for
ergodic systems and a more detailed understanding has been worked
out for
hyperbolic systems. Understanding the probabilistic aspects of
dynamical
systems has helped establish the foundations of statistical mechanics
and of
chaos.
It was in the work of Poincaré that these dynamical systems themes
developed.
Basic definitions
A dynamical system is a manifold M called the phase (or state) space
and a smooth
evolution function Φ t that for any element of t ∈ T, the time, maps a
point of the
phase space back into the phase space. The notion of smoothness
changes with
applications and the type of manifold. There are several choices for the
set T. When
T is taken to be the reals, the dynamical system is called a flow; and if
T is restricted
to the non-negative reals, then the dynamical system is a semi-flow.
When T is
taken to be the integers, it is a cascade or a map; and the restriction to
the nonnegative
integers is a semi-cascade.
Examples
The evolution function Φ t is often the solution of a differential equation
of motion
The equation gives the time derivative, represented by the dot, of a
trajectory x(t) on
the phase space starting at some point x0. The vector field v(x) is a
smooth function
that at every point of the phase space M provides the velocity vector of
the
dynamical system at that point. (These vectors are not vectors in the
phase space
M, but in the tangent space TMx of the point x.) Given a smooth Φ t, an
autonomous
vector field can be derived from it.
There is no need for higher order derivatives in the equation, nor for
time
dependence in v(x) because these can be eliminated by considering
systems of
higher dimensions. Other types of differential equations can be used to
define the
evolution rule:
is an example of an equation that arises from the modeling of
mechanical systems
with complicated constraints.
The differential equations determining the evolution function Φ t are
often ordinary
differential equations: in this case the phase space M is a finite
dimensional
manifold. Many of the concepts in dynamical systems can be extended
to infinitedimensional
manifolds—those that are locally Banach spaces—in which case the
differential equations are partial differential equations. In the late 20th
century the
dynamical system perspective to partial differential equations started
gaining
popularity.
Further examples
• L ogistic map
• D ouble pendulum
• A rnold's cat map
• H orseshoe map
• B aker's map is an example of a chaotic piecewise linear map
• B illiards and outer billiards
• H énon map
• L orenz system
• C ircle map
• R össler map
• L ist of chaotic maps
• S winging Atwood's machine
• Q uadratic map simulation system
• B ouncing ball simulation system
Linear dynamical systems
Linear dynamical systems can be solved in terms of simple functions
and the
behavior of all orbits classified. In a linear system the phase space is
the Ndimensional
Euclidean space, so any point in phase space can be represented by a
vector with N numbers. The analysis of linear systems is possible
because they
satisfy a superposition principle: if u(t) and w(t) satisfy the differential
equation for
the vector field (but not necessarily the initial condition), then so will u(t)
+ w(t).
Flows
For a flow, the vector field Φ(x) is a linear function of the position in the
phase
space, that is,
with A a matrix, b a vector of numbers and x the position vector. The
solution to this
system can be found by using the superposition principle (linearity).
The case b ≠ 0
with A = 0 is just a straight line in the direction of b:
When b is zero and A ≠ 0 the origin is an equilibrium (or singular) point
of the flow,
that is, if x0 = 0, then the orbit remains there. For other initial
conditions, the
equation of motion is given by the exponential of a matrix: for an initial
point x0,
When b = 0, the eigenvalues of A determine the structure of the phase
space. From
the eigenvalues and the eigenvectors of A it is possible to determine if
an initial
point will converge or diverge to the equilibrium point at the origin.
The distance between two different initial conditions in the case A ≠ 0
will change
exponentially in most cases, either converging exponentially fast
towards a point, or
diverging exponentially fast. Linear systems display sensitive
dependence on initial
conditions in the case of divergence. For nonlinear systems this is one
of the
(necessary but not sufficient) conditions for chaotic behavior.
Linear vector fields and a few trajectories.
Maps
A discrete-time, affine dynamical system has the form
with A a matrix and b a vector. As in the continuous case, the change of
coordinates
x → x + (1 - A) –1b removes the term b from the equation. In the new
coordinate
system, the origin is a fixed point of the map and the solutions are of
the linear
system A nx0. The solutions for the map are no longer curves, but
points that hop in
the phase space. The orbits are organized in curves, or fibers, which
are collections
of points that map into themselves under the action of the map.
As in the continuous case, the eigenvalues and eigenvectors of A
determine the
structure of phase space. For example, if u1 is an eigenvector of A,
with a real
eigenvalue smaller than one, then the straight lines given by the points
along α u1,
with α ∈ R, is an invariant curve of the map. Points in this straight line
run into the
fixed point.
There are also many other discrete dynamical systems.
Local dynamics
The qualitative properties of dynamical systems do not change under a
smooth
change of coordinates (this is sometimes taken as a definition of
qualitative): a
singular point of the vector field (a point where v(x) = 0) will remain a
singular point
under smooth transformations; a periodic orbit is a loop in phase space
and smooth
deformations of the phase space cannot alter it being a loop. It is in the
neighborhood of singular points and periodic orbits that the structure of
a phase
space of a dynamical system can be well understood. In the qualitative
study of
dynamical systems, the approach is to show that there is a change of
coordinates
(usually unspecified, but computable) that makes the dynamical system
as simple
as possible.
Rectification
A flow in most small patches of the phase space can be made very
simple. If y is a
point where the vector field v(y) ≠ 0, then there is a change of
coordinates for a
region around y where the vector field becomes a series of parallel
vectors of the
same magnitude. This is known as the rectification theorem.
The rectification theorem says that away from singular points the
dynamics of a
point in a small patch is a straight line. The patch can sometimes be
enlarged by
stitching several patches together, and when this works out in the
whole phase
space M the dynamical system is integrable. In most cases the patch
cannot be
extended to the entire phase space. There may be singular points in
the vector field
(where v(x) = 0); or the patches may become smaller and smaller as
some point is
approached. The more subtle reason is a global constraint, where the
trajectory
starts out in a patch, and after visiting a series of other patches comes
back to the
original one. If the next time the orbit loops around phase space in a
different way,
then it is impossible to rectify the vector field in the whole series of
patches.
Near periodic orbits
In general, in the neighborhood of a periodic orbit the rectification
theorem cannot
be used. Poincaré developed an approach that transforms the analysis
near a
periodic orbit to the analysis of a map. Pick a point x0 in the orbit γ and
consider the
points in phase space in that neighborhood that are perpendicular to
v(x0). These
points are a Poincaré section S(γ, x0), of the orbit. The flow now
defines a map, the
Poincaré map F : S → S, for points starting in S and returning to S. Not
all these
points will take the same amount of time to come back, but the times
will be close to
the time it takes x0.
The intersection of the periodic orbit with the Poincaré section is a fixed
point of the
Poincaré map F. By a translation, the point can be assumed to be at x
= 0. The
Taylor series of the map is F(x) = J · x + O(x˛), so a change of
coordinates h can
only be expected to simplify F to its linear part
This is known as the conjugation equation. Finding conditions for this
equation to
hold has been one of the major tasks of research in dynamical
systems. Poincaré
first approached it assuming all functions to be analytic and in the
process
discovered the non-resonant condition. If λ1,…,λν are the eigenvalues
of J they will
be resonant if one eigenvalue is an integer linear combination of two or
more of the
others. As terms of the form λi – Σ (multiples of other eigenvalues)
occurs in the
denominator of the terms for the function h, the non-resonant condition
is also
known as the small divisor problem.
Conjugation results
The results on the existence of a solution to the conjugation equation
depend on the
eigenvalues of J and the degree of smoothness required from h. As J
does not need
to have any special symmetries, its eigenvalues will typically be
complex numbers.
When the eigenvalues of J are not in the unit circle, the dynamics near
the fixed
point x0 of F is called hyperbolic and when the eigenvalues are on the
unit circle
and complex, the dynamics is called elliptic.
In the hyperbolic case the Hartman-Grobman theorem gives the
conditions for the
existence of a continuous function that maps the neighborhood of the
fixed point of
the map to the linear map J · x. The hyperbolic case is also structurally
stable.
Small changes in the vector field will only produce small changes in the
Poincaré
map and these small changes will reflect in small changes in the
position of the
eigenvalues of J in the complex plane, implying that the map is still
hyperbolic.
The Kolmogorov-Arnold-Moser (KAM) theorem gives the behavior near
an elliptic
point.
Bifurcation theory
When the evolution map Φt (or the vector field it is derived from)
depends on a
parameter μ, the structure of the phase space will also depend on this
parameter.
Small changes may produce no qualitative changes in the phase space
until a
special value μ0 is reached. At this point the phase space changes
qualitatively and
the dynamical system is said to have gone through a bifurcation.
Bifurcation theory considers a structure in phase space (typically a
fixed point, a
periodic orbit, or an invariant torus) and studies its behavior as a
function of the
parameter μ. At the bifurcation point the structure may change its
stability, split into
new structures, or merge with other structures. By using Taylor series
approximations of the maps and an understanding of the differences
that may be
eliminated by a change of coordinates, it is possible to catalog the
bifurcations of
dynamical systems.
The bifurcations of a hyperbolic fixed point x0 of a system family Fμ
can be
characterized by the eigenvalues of the first derivative of the system
DFμ(x0)
computed at the bifurcation point. For a map, the bifurcation will occur
when there
are eigenvalues of DFμ on the unit circle. For a flow, it will occur when
there are
eigenvalues on the imaginary axis. For more information, see the main
article on
Bifurcation theory.
Some bifurcations can lead to very complicated structures in phase
space. For
example, the Ruelle-Takens scenario describes how a periodic orbit
bifurcates into
a torus and the torus into a strange attractor. In another example,
Feigenbaum
period-doubling describes how a stable periodic orbit goes through a
series of
period-doubling bifurcations.
Ergodic systems
In many dynamical systems it is possible to choose the coordinates of
the system
so that the volume (really a ν-dimensional volume) in phase space is
invariant. This
happens for mechanical systems derived from Newton's laws as long
as the
coordinates are the position and the momentum and the volume is
measured in
units of (position) × (momentum). The flow takes points of a subset A
into the points
Φ t(A) and invariance of the phase space means that
In the Hamiltonian formalism, given a coordinate it is possible to derive
the
appropriate (generalized) momentum such that the associated volume
is preserved
by the flow. The volume is said to be computed by the Liouville
measure.
In a Hamiltonian system not all possible configurations of position and
momentum
can be reached from an initial condition. Because of energy
conservation, only the
states with the same energy as the initial condition are accessible. The
states with
the same energy form an energy shell Ω, a sub-manifold of the phase
space. The
volume of the energy shell, computed using the Liouville measure, is
preserved
under evolution.
For systems where the volume is preserved by the flow, Poincaré
discovered the
recurrence theorem: Assume the phase space has a finite Liouville
volume and let
F be a phase space volume-preserving map and A a subset of the
phase space.
Then almost every point of A returns to A infinitely often. The Poincaré
recurrence
theorem was used by Zermelo to object to Boltzmann's derivation of
the increase in
entropy in a dynamical system of colliding atoms.
One of the questions raised by Boltzmann's work was the possible
equality between
time averages and space averages, what he called the ergodic
hypothesis. The
hypothesis states that the length of time a typical trajectory spends in a
region A is
vol(A)/vol(Ω).
The ergodic hypothesis turned out not to be the essential property
needed for the
development of statistical mechanics and a series of other ergodic-like
properties
were introduced to capture the relevant aspects of physical systems.
Koopman
approached the study of ergodic systems by the use of functional
analysis. An
observable a is a function that to each point of the phase space
associates a
number (say instantaneous pressure, or average height). The value of
an
observable can be computed at another time by using the evolution
function φ t.
This introduces an operator U t, the transfer operator,
By studying the spectral properties of the linear operator U it becomes
possible to
classify the ergodic properties of Φ t. In using the Koopman approach
of considering
the action of the flow on an observable function, the finite-dimensional
nonlinear
problem involving Φ t gets mapped into an infinite-dimensional linear
problem
involving U.
The Liouville measure restricted to the energy surface Ω is the basis for
the
averages computed in equilibrium statistical mechanics. An average in
time along a
trajectory is equivalent to an average in space computed with the
Boltzmann factor
e xp(−β H ) . This idea has been generalized by Sinai, Bowen, and
Ruelle (SRB) to a
larger class of dynamical systems that includes dissipative systems.
SRB measures
replace the Boltzmann factor and they are defined on attractors of
chaotic systems.
Chaos theory
Simple nonlinear dynamical systems and even piecewise linear
systems can exhibit
a completely unpredictable behavior, which might seem to be random.
(Remember
that we are speaking of completely deterministic systems!). This
unpredictable
behavior has been called chaos. Hyperbolic systems are precisely
defined
dynamical systems that exhibit the properties ascribed to chaotic
systems. In
hyperbolic systems the tangent space perpendicular to a trajectory can
be well
separated into two parts: one with the points that converge towards the
orbit (the
stable manifold) and another of the points that diverge from the orbit
(the unstable
manifold).
This branch of mathematics deals with the long-term qualitative
behavior of
dynamical systems. Here, the focus is not on finding precise solutions
to the
equations defining the dynamical system (which is often hopeless), but
rather to
answer questions like "Will the system settle down to a steady state in
the long
term, and if so, what are the possible attractors?" or "Does the longterm behavior
of the system depend on its initial condition?"
Note that the chaotic behavior of complicated systems is not the issue.
Meteorology
has been known for years to involve complicated—even chaotic—
behavior. Chaos
theory has been so surprising because chaos can be found within
almost trivial
systems. The logistic map is only a second-degree polynomial; the
horseshoe map
is piecewise linear.
Geometrical definition
A dynamical system is the tuple , with a manifold (locally a Banach
space or Euclidean space), the domain for time (non-negative reals,
the integers,
...) and an evolution rule f t (with ) a diffeomorphism of the manifold to
itself.
Measure theoretical definition
See main article measure-preserving dynamical system.
A dynamical system may be defined formally, as a measure-preserving
transformation of a sigma-algebra, the quadruplet (X,Σ,μ,τ). Here, X is
a set, and Σ
is a topology on X, so that (X,Σ) is a sigma-algebra. For every element ,
μ is
its finite measure, so that the triplet (X,Σ,μ) is a probability space. A
map
is said to be Σ-measurable if and only if, for every , one has
. A map τ is said to preserve the measure if and only if, for every
, one has μ(τ − 1σ) = μ(σ). Combining the above, a map τ is said to be
a measurepreserving
transformation of X , if it is a map from X to itself, it is Σ-measurable,
and is measure-preserving. The quadruple (X,Σ,μ,τ), for such a τ, is
then defined to
be a dynamical system.
The map τ embodies the time evolution of the dynamical system. Thus,
for discrete
dynamical systems the iterates for integer n are studied. For
continuous dynamical systems, the map τ is understood to be finite
time evolution
map and the construction is more complicated.
Examples of dynamical systems
• L ogistic map
• D ouble pendulum
• A rnold's cat map
• H orseshoe map
• B aker's map is an example of a chaotic piecewise linear map
• B illiards and Outer Billiards
• H enon map
• L orenz system
• C ircle map
• R ossler map
• L ist of chaotic maps
• S winging Atwood's Machine (SAM)
• B ouncing Ball
• M echanical Strings
See also
• O scillation
• S arkovskii's theorem
• S ystem dynamics
• S ystems theory
• L ist of dynamical system topics
• P eople in systems and control
• B ehavioral modeling
References
Further reading
Works providing a broad coverage:
• R alph Abraham and Jerrold E. Marsden (1978). Foundations of
mechanics.
Benjamin-Cummings. ISBN 0-8053-0102-X. (available as a reprint:
ISBN 0201-40840-6)
• Encyclopaedia of Mathematical Sciences (ISSN 0938-0396) has a
sub-series
on dynamical systems with reviews of current research.
• Anatole Katok and Boris Hasselblatt (1996). Introduction to the
modern
theory of dynamical systems. Cambridge. ISBN 0-521-57557-5.
• Christian Bonatti, Lorenzo J. Díaz, Marcelo Viana (2005). Dynamics
Beyond
Uniform Hyperbolicity: A Global Geometric and Probabilistic
Perspective.
Springer. ISBN 3-540-22066-6.
• D iederich Hinrichsen and Anthony J. Pritchard (2005). Mathematical
Systems
Theory I - Modelling, State Space Analysis, Stability and Robustness.
Springer Verlag. ISBN 0-978-3-540-44125-0.
Introductory texts with a unique perspective:
• V . I. Arnold (1982). Mathematical methods of classical mechanics.
SpringerVerlag. ISBN 0-387-96890-3.
• J acob Palis and Wellington de Melo (1982). Geometric theory of
dynamical
systems: an introduction. Springer-Verlag. ISBN 0-387-90668-1.
• D avid Ruelle (1989). Elements of Differentiable Dynamics and
Bifurcation
Theory. Academic Press. ISBN 0-12-601710-7.
• Tim Bedford, Michael Keane and Caroline Series, eds. (1991).
Ergodic
theory, symbolic dynamics and hyperbolic spaces. Oxford University
Press.
ISBN 0-19-853390-X.
• R alph H. Abraham and Christopher D. Shaw (1992). Dynamics—the
geometry of behavior, 2nd edition. Addison-Wesley. ISBN
0-201-56716-4.
Textbooks
• S teven H. Strogatz (1994). Nonlinear dynamics and chaos: with
applications
to physics, biology chemistry and engineering. Addison Wesley. ISBN
0-20154344-3.
• Kathleen T. Alligood, Tim D. Sauer and James A. Yorke (2000).
Chaos. An
introduction to dynamical systems. Springer Verlag. ISBN
0-387-94677-2.
• Morris W. Hirsch, Stephen Smale and Robert Devaney (2003).
Differential
Equations, dynamical systems, and an introduction to chaos. Academic
Press. ISBN 0-12-349703-5.
Popularizations:
• Florin Diacu and Philip Holmes (1996). Celestial Encounters.
Princeton. ISBN
0-691-02743-9.
• J ames Gleick (1988). Chaos: Making a New Science. Penguin. ISBN
0-14009250-1.
• Ivar Ekeland (1990). Mathematics and the Unexpected (Paperback).
University Of Chicago Press. ISBN 0-226-19990-8.
• Ian Stewart (1997). Does God Play Dice? The New Mathematics of
Chaos.
Penguin. ISBN 0140256024.
External links
• A collection of dynamic and non-linear system models and demo
applets (in
Monash University's Virtual Lab)
• A rxiv preprint server has daily submissions of (non-refereed)
manuscripts in
dynamical systems.
• D SWeb provides up-to-date information on dynamical systems and
its
applications.
• E ncyclopedia of dynamical systems A part of Scholarpedia — peer
reviewed
and written by invited experts.
• N onlinear Dynamics. Models of bifurcation and chaos by Elmer G.
Wiens
• O liver Knill has a series of examples of dynamical systems with
explanations
and interactive controls.
• S ci.Nonlinear FAQ 2.0 (Sept 2003) provides definitions, explanations
and
resources related to nonlinear science
Online books or lecture notes:
• G eometrical theory of dynamical systems. Nils Berglund's lecture
notes for a
course at ETH at the advanced undergraduate level.
• D ynamical systems. George D. Birkhoff's 1927 book already takes a
modern
approach to dynamical systems.
• C haos: classical and quantum. An introduction to dynamical systems
from the
periodic orbit point of view.
• M odeling Dynamic Systems. An introduction to the development of
mathematical models of dynamic systems.
• L earning Dynamical Systems. Tutorial on learning dynamical
systems.
Research groups:
• D ynamical Systems Group Groningen, IWI, University of Groningen.
• C haos @ UMD. Concentrates on the applications of dynamical
systems.
• D ynamical Systems, SUNY Stony Brook. Lists of conferences,
researchers,
and some open problems.
• C enter for Dynamics and Geometry, Penn State.
• C ontrol and Dynamical Systems, Caltech.
• L aboratory of Nonlinear Systems, Ecole Polytechnique Fédérale de
Lausanne
(EPFL).
• C enter for Dynamical Systems, University of Bremen
• Systems Analysis, Modelling and Prediction Group, University of
Oxford
• N on-Linear Dynamics Group, Instituto Superior Técnico, Technical
University
of Lisbon
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Human mitochondrial genetics
Contents
Mitochondrial genetics is the study of the genetics of the DNA contained in mitochondria. Mitochondria are small structures in cells that
generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell.
Mitochondrial DNA (mtDNA) is not transmitted through nuclear DNA (nDNA), and in most multicellular organisms, virtually all mitochondria are
inherited from the mother's ovum, as sperm cells do not contribute any mitochondria.
Mitochondrial inheritance is therefore non-Mendelian, as Mendelian inheritance presumes that half the genetic material of a fertilized egg (zygote)
derives from each parent.
Eighty percent of mitochondrial DNA codes for functional mitochondrial proteins, and therefore most mitochondrial DNA mutations lead to
functional problems, which may be manifested as muscle disorders (myopathies).
Understanding the genetic mutations that affect mitochondria can help us to understand the inner workings of cells and organisms, as well as
helping to suggest methods for successful therapeutic tissue and organ cloning, and to treatments or possibly cures for many devastating
muscular disorders.
Mitochondrial function and genome
Because they provide 36 molecules of ATP per glucose molecule in contrast to the 2 ATP molecules produced by glycolysis, mitochondria are
essential to all higher organisms for sustaining life. The mitochondrial diseases are genetic disorders carried specifically in mitochondrial DNA;
slight problems with any one of the numerous enzymes used by the mitochondria can be devastating to the cell, and in turn, to the organism.
Membrane complexes
The processes carried out by the electron transport chain are mediated by protein complexes (named Complexes I-V, DHO-QO, ETF-QO, and
ANT). Complex I, or NADH : coenzyme Q oxidoreductase, uses the energy in NADH to pump protons into the intermembrane space of the
mitochondrion, pumping 2 protons per electron and passing 2 electrons via coenzyme Q to complex III or coenzyme Q : cytochrome c
oxidoreductase. Complex II or succinate : coenzyme Q oxidoreductase accepts energy from succinate produced in the citric acid cycle and
passes it via coenzyme Q to complex III. Complex III pumps 1 protons per electron and passes 1 electron via cytochrome c to complex IV.
Complex IV pumps 1 protons into the space between the mitochondrion’s two membranes before passing the electron to O2 which reacts to form
water. Complex V (ATP synthase) is a rotary complex which allows approximately (determining the actual number is very difficult) 10 protons to
enter the mitochondrial matrix along their concentration gradients. It uses the energy from the gradient to form the bond between ADP and the
phosphate group to create ATP. The electron transfer flavoprotein : coenzyme Q oxidoreductase is also an electron-transporting molecule and is
involved in the breakdown of fatty acids and amino acids. ANT (adenine nucleotide translocator) is also involved in oxidative phosphorylation as
an energy carrying molecule. Each of these eight complexes plays a vital role in the health of the cell and any slight mutation in any one of the
proteins that make up these complexes can lead to cell death or stress, which can both in turn lead to a number of diseases.
Genome
Further information: Mitochondrial DNA
Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule and in most species codes for 13 or 14 proteins involved in the
electron transfer chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis). The number of proteins involved in the
electron transfer chain is much larger than 13 or 14, but the remainder is in fact coded by the nuclear DNA.
In total, the mitochondrion hosts about 3000 proteins, but only about 37 of them are coded on the mitochondrial DNA. Most of the 3000 genes are
involved in a variety of processes other than ATP production, such as porphyrin synthesis. Only about 3% of them code for ATP production
proteins. This means most of the genetic information coding for the protein makeup of mitochondria is in chromosomal DNA and is involved in
processes other than ATP synthesis. This increases the chances that a mutation that will affect a mitochondrion will occur in chromosomal DNA,
which is inherited in a Mendelian pattern. Another result is that a chromosomal mutation will affect a specific tissue due to its specific needs,
whether those may be high energy requirements or a need for the catabolism or anabolism of a specific neurotransmitter or nucleic acid. Because
several copies of the mitochondrial genome are carried by each mitochondrion (2-10 in humans), mitochondrial mutations can be inherited
maternally by mtDNA mutations which are present in mitochondria inside the oocyte before fertilization, or (as stated above) through mutations in
the chromosomes.
In humans, the heavy strand of mtDNA carries 28 genes and the light strand of mtDNA carries only 9 genes. Eight of the 9 genes on the light
strand code for mitochondrial tRNA molecules. Human mtDNA consists of 16,569 nucleotide pairs. The entire molecule is regulated by only one
regulatory region which contains the origins of replication of both heavy and light strands. The entire human mitochondrial DNA molecule has
been mapped[1][2]. The rate of mutation in mtDNA is calculated to be about ten times greater than that of nuclear DNA, possibly due to a paucity
of DNA repair mechanisms. This high mutation rate leads to a high variation between mitochondria, not only among different species but even
within the same species. It is calculated that if two humans are chosen randomly and their mtDNA is tested, they will have an average of between
fifty and seventy different nucleotides. This may not seem like much, but when compared to the total number of nucleotides of a human
mitochondrial DNA molecule (16,569), as much as .42% of the mtDNA varies between two people.
Genetic code variants
The genetic code is, for the most part, universal, with few exceptions: mitochondrial genetics includes some of these. For most organisms the
"stop codons" are “UAA”, “UAG”, and “UGA”. In vertebrate mitochondria “AGA” and “AGG” are also stop codons, but not “UGA”, which codes for
tryptophan instead. “AUA” codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA/tRNA.
There are many other variations among the codes used by other mitochondrial m/tRNA, which happened not to be harmful to their organisms,
and which can be used as a tool (along with other mutations among the mtDNA/RNA of different species) to determine relative proximity of
common ancestry of related species. (The more related two species are, the more mtDNA/RNA mutations will be the same in their mitochondrial
genome).
Using these techniques, it is estimated that the first mitochondrion evolved, was consumed, or developed around 1.5 billion years ago, as an
aerobic prokaryote in a symbiotic relationship within an anaerobic eukaryote.
Inheritance patterns
Because mitochondrial diseases (diseases due to malfunction of mitochondria) can be inherited both maternally and through chromosomal
inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic
mutations that occur in the nuclear DNA can occur in any of the chromosomes (depending on the species). Mutations inherited through the
chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows
normal Mendelian laws, despite the fact that the phenotype of the disease may be masked. Because of the complex ways in which mitochondrial
and nuclear DNA "communicate" and interact, even seemingly simple inheritance is hard to diagnose. A mutation in chromosomal DNA may
change a protein that regulates (an increase or decrease) the production of another certain protein in the mitochondria or the cytoplasm and may
lead to slight, if any, noticeable symptoms. On the other hand, there are some devastating mtDNA mutations that are easy to diagnose because
of their widespread damage to muscular, neural, and/or hepatic (among other high energy and metabolism dependent) tissues and due to the fact
that they are present in the mother and all the offspring. Mitochondrial genome mutations are passed on 100% of the time from mother to all her
offspring. Because the mitochondria within the fertilized oocyte is what the new life will have to begin with (in terms of mtDNA), and because the
number of affected mitochondria varies from cell (in this case, the fertilized oocyte) to cell depending both on the number it inherited from its
mother cell and environmental factors which may favor mutant or wildtype mitochondrial DNA, and because the number of mtDNA molecules in
the mitochondria varies from around two to ten, the number of affected mtDNA molecules inherited to a specific offspring can vary greatly. It is
possible, even in twin births, for one baby to receive more than half mutant mtDNA molecules while the other twin may receive only a tiny fraction
of mutant mtDNA molecules with respect to wildtype (depending on how the twins divide from each other and how many mutant mitochondria
happen to be on each side of the division). In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but
paternal mitochondria are actively decomposed.
Replication, repair, transcription, and translation
Mitochondrial replication is controlled by nuclear genes and is specifically suited to make as many mitochondria as that particular cell needs at
the time. Human mitochondrial DNA (mtDNA) has three promoters, H1, H2, and L (heavy strand 1, heavy strand 2, and light strand promoters).
The H1 promoter transcribes the entire heavy strand and the L promoter transcribes the entire light strand. The H2 promoter causes the
transcription of the two mitochondrial rRNA molecules. When transcription takes place on the heavy strand a polycistronic transcript is created.
The light strand produces either small transcripts, which can be used as primers, or one long transcript. The production of primers occurs by
processing of light strand transcripts with the Mitochondrial RNase MRP (Mitochondrial RNA Processing). The requirement of transcription to
produce primers links the process of transcription to mtDNA replication. Full length transcripts are cut into functional tRNA, rRNA, and mRNA
molecules. The process of transcription initiation in mitochondria involves three types of proteins: the mitochondrial RNA polymerase (POLRMT),
mitochondrial transcription factor A (TFAM), and mitochondrial transcription factors B1 and B2 (TFB1M, TFB2M). POLRMT, TFAM, and TFB1M or
TFB2M assemble at the mitochondrial promoters and begin transcription. The actual molecular events that are involved in initiation are unknown,
but these factors make up the basal transcription machinery and have been shown to function in vitro. Mitochondrial translation is still not very
well understood. In vitro translations have still not been successful, probably due to the difficulty of isolating sufficient mt mRNA, functional mt
rRNA, and possibly because of the complicated changes that the mRNA undergoes before it is translated.
Mitochondrial DNA polymerase
The Mitochondrial DNA Polymerase (Pol gamma) is used in the copying of mtDNA during replication. Because the two (heavy and light) strands
on the circular mtDNA molecule have different origins of replication, it replicates in a D-loop (displacement) configuration. One strand begins to
replicate first, displacing the other strand. This continues until replication reaches the origin of replication on the other strand, at which point the
other strand beings replicating in the opposite direction. This results in two new mtDNA molecules. Each mitochondria has several copies of the
mtDNA molecule and the number of mtDNA molecules is a limiting factor in mitochondrial fission. After the mitochondrion has enough mtDNA,
membrane area, and membrane proteins, it can undergo fission (very similar to that which bacteria use) to become two mitochondria. Evidence
suggests that mitochondria can also undergo fusion and exchange (in a form of crossover) genetic material among each other. Mitochondria
sometimes form large matrices in which fusion, fission, and protein exchanges are constantly occurring. mtDNA shared among mitochondria
(despite the fact that they can undergo fusion).
Damage and transcription error
Mitochondrial DNA is susceptible to damage from free oxygen radicals from mistakes that occur during the production of ATP through the electron
transport chain. These mistakes can be caused by genetic disorders, cancer, and temperature variations. These radicals can damage mtDNA
molecules or change them, making it hard for mitochondrial polymerase to replicate them. Both cases can lead to deletions, rearrangements, and
other mutations. Recent evidence has suggested that mitochondria have enzymes that proofread mtDNA and fix mutations that may occur due to
free radicals. It is believed that a DNA recombinase found in mammalian cells is also involved in a repairing recombination process. Deletions and
mutations due to free radicals have been associated with the aging process. It is believed that radicals cause mutations which lead to mutant
proteins, which in turn lead to more radicals. This process takes many years and is associated with some aging processes involved in oxygendependent tissues such as brain, heart, muscle, and kidney. Auto-enhancing processes such as these are possible causes of degenerative
diseases including Parkinson’s, Alzheimer’s, and coronary artery disease.
Chromosomally mediated mtDNA replication errors
Because mitochondrial growth and fission are mediated by the nuclear DNA, mutations in nuclear DNA can have a wide array of effects on
mtDNA replication. Despite the fact that the loci for some of these mutations have been found on human chromosomes, specific genes and
proteins involved have not yet been isolated. Mitochondria need a certain protein to undergo fission. If this protein (made by the nucleus) is not
present, the mitochondria grow but they do not divide. This leads to giant, inefficient mitochondria. Mistakes in chromosomal genes or their
products can also affect mitochondrial replication more directly by inhibiting mitochondrial polymerase and can even cause mutations in the
mtDNA directly and indirectly. Indirect mutations are most often caused by radicals created by defective proteins made from nuclear DNA.
Mitochondrial diseases
Mitochondrial diseases range in severity from almost not diagnosable to fatal. They also range in cause from inherited to acquired mutations
(although acquired mutations that cause disease are very rare). A certain mutation can cause several different diseases depending on the
severity of the problem in the mitochondria and the tissue the affected mitochondria are in. Conversely, several different mutations may present
themselves as the same disease. This almost patient-specific characterization of mitochondrial diseases makes them very hard to accurately
diagnose and trace. Some diseases are observable at or even before birth (most causing death) while others do not show themselves until late
adulthood. This is because the number of mutant versus wildtype mitochondria varies from cell to cell and tissue to tissue, and is always
changing. Because cells have multiple mitochondria, different mitochondria in the same cell can have different variations of the mtDNA genome.
This condition is referred to as heteroplasmy. When a certain tissue reaches a certain ration of mutant versus wildtype mitochondria, a disease
will present itself. The ration varies from person to person and tissue to tissue (depending on its specific energy, oxygen, and metabolism
requirements, and the effects of the specific mutation). Mitochondrial diseases are very numerous and different. Apart from diseases definitely
caused by abnormalities in mitochondrial DNA, many diseases are suspected to be caused in part by dysfunction of mitochondria, such as
diabetes mellitus, forms of cancer and cardiovascular disease, lactic acidosis, specific forms of myopathy, osteoporosis, Alzheimer's disease,
Parkinsons's disease, stroke, and many more. Furthermore, mtDNA mutations are believed to play a role in the aging process.
Notes
^ Societat Catalana de Neurologia. Retrieved on December 5, 2005.
^ http://www.mitomap.org/mitomapgenome.pdf. Retrieved on December 5, 2005.
See also
•Human mitochondrial DNA haplogroups
•Cambridge Reference Sequence
Sources
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Resolution. Proc. Natl. Acad. Sci. USA. Vol. 93. (dl Nov. 2004).
Naviaux, Robert. (1997) The Spectrum of Mitochondrial Disease. Exceptional Parent Magazine. Vol. 27, Issue 8.
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Nester, Anderson, Roberts, Pearsall, Nester. Microbiology, A Human Perspective. Boston: McGraw Hill Inc; 2004.
Mitochondrial inheritance tree Mitochondrial DNA genetics
Broughton R, Milam J, and Roe B. (Nov. 2001) The Complete Sequence of the Zebrafish (Danio rerio) Mitochondrial Genome and
Evolutionary Patterns in Vertebrate Mitochondrial DNA. Genome Research. Vol. 11, Issue 11. (dl Nov. 2004).
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de Neurologia. Universidad de Zaragoza. (dl Nov. 2004).
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Scheffler, Immo E. (2000) Review Article: A Century of Mitochondrial Research: Achievements and Perspectives. Elsevier Science B. V.
and Mitochondrial Research Society. (dl Nov. 2004).
Vladutiu, Georgirene D. (1997) Advances in Mitochondrial Disease Research. Exceptional Parent Magazine. Vol. 27, Issue 8.
DiMauro, Salvatore. (1997) Promising Avenues of Investigation in the Diagnosis and Treatment of Mitochondrial Defects. Exceptional
Parent Magazine. Vol. 27, Issue 8.
University of Texas Medical Branch. TX; Dec. 2003. The Mitochondrial Life Cycle. (dl Nov. 2004).
The Mitochondrial Research Society. Mitochondria Means the Most to US; 2004. (dl Nov. 2004).
Purves W, Sadava D, Orians G, Heller C. Life: The Science of Biology, Sixth Edition. Massachusetts: Sinauer Associates, Inc; 2002.
Retrieved from "http://en.wikipedia.org/wiki/Human_mitochondrial_genetics"
Category: Mitochondrial genetics
KEEPING SHARKS WARM IN THE COLD:
Duong, C. A., Sepulveda, C. A., Graham, J. B. and Dickson, K. A. (2006).
Mitochondrial proton leak rates in the slow, oxidative myotomal muscle and liver of the endothermic shortfin mako shark (Isurus oxyrinchus) and
the ectothermic blue shark (Prionace glauca) and leopard shark (Triakis semifasciata).
J. Exp. Biol. 209, 2678-2685:
Packed into our tissues, microscopic mitochondria are the body’s power-houses, consuming oxygen to generate the ATP that powers
our every move. However, warmblooded creatures (endotherms) also benefit from one of the organelle’s by-products, heat, generated when the
organelles leak protons. In fact, up to 25% of the basal metabolic rate of most warm-blooded creatures can be attributed to energy consumed
topping up the mitochondrial leak. In contrast, metabolically active tissues in cold-blooded creatures (ectotherms) contain far fewer mitochondria,
and they are proportionately smaller than those in gas-guzzling endotherms. As a result, it has been suggested that mitochondrial proton leak
could be a key factor in the evolution of a warm-blooded lifestyle. But what about species that seem to straddle both warm and cold camps; have
their mitochondria become specialised so that they too benefit from warming proton leak? Kathryn Dickson, Jeff Graham and their colleagues in
southern California explain that some shark species are endothermic, while the rest are ectotherms. Could the mitochondria of these endothermic
fish contribute to their warmth? To find out, Dickson and her colleagues measured proton leak rates from the tissues of warm shortfin makos and
two ectothermic species (p.·2678). But before the team could go fishing, Dickson set off for a summer in England, to join Martin Brand’s
Cambridge lab and master the technically challenging assays used to measure mitochondrial proton leak. Having returned to California, Dickson
explains that proton leak rates can only be measured on freshly caught animals, so the team could only work on days when Chugey Sepulveda
returned from fishing trips in the Pacific Ocean with a catch of endothermic shortfin makos and ectothermic blue sharks and leopard sharks.
Knowing that makos maintain their liver and red muscle temperatures well above ambient temperatures, and that both tissues are metabolically
active, the team isolated mitochondria from both tissues before measuring the organelle’s respiration rates and membrane potential, and
calculating the proton leak rates. Surprisingly, the mitochondrial proton leak rates at the same membrane potential were essentially identical in all
three sharks; that is that all three species pumped the same number of protons per milligram of protein at the same electric driving force. Dickson
says ‘this suggests that mitochondria from endothermic tissues of the mako shark are not specialised for thermogenesis’. However, the team
noticed that the mako shark’s red muscle oxygen consumption rates were much higher than their ectothermic cousins, suggesting that even
though the mitochondria are not adapted for heat production, the increased respiration rate could increase mitochondrial proton leak sufficiently to
contribute to the fish’s endothermy. And when the team measured the mitochondrial density in all three fishes’ livers and calculated the proton
leak per gram of tissue, they realised that the endothermic shark’s was almost twice that of the ectothermic sharks. Having found that both red
muscle and liver could contribute to mako’s endothermy, despite their lack of specialised mitochondria, Dickson and Graham are curious to know
whether the mitochondria of other endothermic fish contribute to the challenge of keeping them warm. 10.1242/jeb.02390 Duong, C. A.,
Sepulveda, C. A., Graham, J. B. and Dickson, K. A. (2006). Mitochondrial proton leak rates in the slow, oxidative myotomal muscle and liver of
the endothermic shortfin mako shark (Isurus oxyrinchus) and the ectothermic blue shark (Prionace glauca) and leopard shark (Triakis
semifasciata). J. Exp. Biol. 209, 2678-2685).
Proc Natl Acad Sci U S A. 2006 Dec 26;
Parasitic inhibition of cell death facilitates symbiosis.
Pannebakker BA, Loppin B, Elemans CP, Humblot L, Vavre F. Laboratoire de Biometrie et Biologie Evolutive, Unite Mixte de Recherche 5558,
and Centre de Genetique Moleculaire et Cellulaire, Unite Mixte de Recherche 5534, Centre National de la Recherche Scientifique, Universite
Claude Bernard Lyon 1, IFR 41, 69622 Villeurbanne Cedex, France; Institute of Evolutionary Biology, School of Biological Sciences, University of
Edinburgh, Ashworth Laboratories, King's Buildings, West Mains Road, Edinburgh EH9 3JT, Scotland, United Kingdom.
Symbiotic microorganisms have had a large impact on eukaryotic evolution, with effects ranging from parasitic to mutualistic.
Mitochondria and chloroplasts are prime examples of symbiotic microorganisms that have become obligate for their hosts, allowing for a dramatic
extension of suitable habitats for life. Out of the extraordinary diversity of bacterial endosymbionts in insects, most are facultative for their hosts,
such as the ubiquitous Wolbachia, which manipulates host reproduction. Some endosymbionts, however, have become obligatory for host
reproduction and/or survival. In the parasitoid wasp Asobara tabida the presence of Wolbachia is necessary for host oogenesis, but the
mechanism involved is yet unknown. We show that Wolbachia influences programmed cell death processes (a host regulatory feature typically
targeted by pathogens) in A. tabida, making its presence essential for the wasps' oocytes to mature. This suggests that parasite strategies, such
as bacterial regulation of host apoptosis, can drive the evolution of host dependence, allowing for a swift transition from parasitism to mutualism.
Proc. Nati. Acad. Sci. USA Vol. 85, pp. 7288-7292, October 1988 Genetics
Plasmids can stably transform yeast mitochondria lacking endogenous mtDNA (Saccharomyces cerevisiae/oxil/rhol-/high-velocity microprojectile
bombardment)
THOMAS D. FOX*t, JOHN C. SANFORD*, AND THOMAS W. MCMULLIN* *Section of Genetics and Development, Cornell University, Ithaca, NY
14853; and tDepartment of Horticultural Sciences, New York State Agricultural Experiment Station, Cornell University, Geneva, NY 14456
Communicated by Gerald R. Fink, June 10, 1988
ABSTRACT
The mitochondrial gene oxil, carried on a bacterial plasmid, has been used to transform the mitochondria of a yeast strain lacking
mtDNA (rhoo). The plasmid DNA behaved in a manner entirely consistent with the known properties of normal yeast rho- mtDNA after its
introduction by high-velocity microprojectile bombardment. Like the mtDNA sequences retained in natural rho- strains, the plasmid DNA in the
transformants was reiterated into concatemers whose size was indistinguishable from that of wild-type mtDNA. The oxil sequences in the
transformants were surrounded by restriction sites derived from the plasmid that were not present in wild-type mtDNA. oxil genetic information in
these "synthetic rho"- strains could be expressed in diploids either after "marker rescue" by recombination with rho+ mtDNA carrying an
appropriate oxil point mutation or in trans during the growth of diploids heteroplasmic for both the plasmid-derived oxil sequences and rho' mtDNA
with oxil deleted. The ability to generate such "synthetic rho-" strains by transformation will allow transfer of mutations generated in vitro to wildtype rho' mtDNA as well as examination of the function of altered genes in trans.
l. jegyzetek, hivatkozások: 13
Idézet:
Mitochondria: More than
Mitochondrial DNA in Cancer
Bora Baysal
In their PLoS Medicine article, entitled “A critical reassessment
of the role of mitochondria in tumorigenesis,” Salas et al. [1]
reviewed reports describing identifi cation of mitochondrial
DNA (mtDNA) mutations in several tumors. They identifi ed
many instances where the purported mutations in tumors
corresponded to certain populational haplotypes, suggesting
that contamination or sample mix-up could be a better
explanation for these mtDNA variations found in tumors.
This manuscript has important implications for this research
fi eld by questioning the validity of conclusions drawn in
several high-profi le publications that laid foundations for the
role of mtDNA in cancer. While it is essential to investigate
the origin of mtDNA variations found in certain tumors, the
conclusion in the abstract that “the role of mitochondria in
tumorigenesis remains unclarifi ed” is simply incorrect.
March 2006 | Volume 3 | Issue 3 | e167 | e156
PLoS Medicine | www.plosmedicine.org 0414
The causal link between mitochondrial abnormalities and
tumorigenesis was provided by the positional cloning of the
hereditary paraganglioma gene at chromosome band 11q23
as the SDHD subunit gene of mitochondrial complex II
(succinate dehydrogenase) in the year 2000 [2]. Since then,
the role of mitochondria in cancer is further highlighted
through identifi cation of over 100 mutations in the SDHB,
SDHC, and SDHD subunit genes in hundreds of index cases
and families with hereditary and sporadic paragangliomas
and pheochromocytomas [3]. Furthermore, fumarase
gene mutations in a distinct hereditary tumor syndrome
characterized by multiple skin and uterine leiomyomatosis
and renal cell cancer—hereditary leiomyomatosis renal
cancer (HLRCC)—further strengthened the role of
mitochondria in cancer [4].
Although it is clear that Salas et al. question specifi cally the
mutations in mtDNA of tumors, they did not acknowledge
the causal link between mitochondria and cancer provided
by the discovery of nuclear-encoded mitochondrial gene
mutations. This is especially important because, in their
unfortunate title and in their conclusion, the authors seem to
make a sweeping statement against the role of mitochondria
in cancer. It is essential to emphasize to readers that it is the
mtDNA, but not mitochondria, which has a questionable role
in tumorigenesis.
Bora Baysal
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania, United States of America
E-mail: [email protected]
References
1. Salas A, Yao YG, Macaulay V, Vega A, Carracedo A, et al. (2005) A
critical
reassessment of the role of mitochondria in tumorigenesis. PLoS Med
2:
e296. DOI: 10.1371/journal.pmed.0020296
2. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek
D, et al.
(2000) Mutations in SDHD, a mitochondrial complex II gene, in
hereditary
paraganglioma. Science 287: 848–851.
3. Bayley JP, Devilee P, Taschner PE (2005) The SDH mutation
database: An
online resource for succinate dehydrogenase sequence variants
involved
in pheochromocytoma, paraganglioma and mitochondrial complex II
defi ciency. BMC Med Genet 6: 39.
4. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, et al.
(2002)
Germline mutations in FH predispose to dominantly inherited uterine
fi broids, skin leiomyomata and papillary renal cell cancer. Nat Genet
30:
406–410.
Citation: Baysal B (2006) Mitochondria: More than mitochondrial DNA
in cancer. PLoS Med 3(3): e156.
Copyright: © 2006 Bora Baysal. This is an open-access article
distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction
in any medium, provided the original author and source are credited.
Competing Interests: The author has declared that no competing
interests exist.
DOI: 10.1371/journal.pmed.0030156
Authors’ Reply
We gratefully acknowledge the letter by Bora Baysal [1],
which emphasizes that there is some interesting evidence
for the role of mitochondria in tumorigenesis mediated by
nuclear DNA factors—an issue that was outside the scope of
our article [2]. We, however, do not entirely agree with him
that the title of our contribution [2] is “simply incorrect”;
it could probably be described as somewhat imprecise or
ambiguous. In fact, the originally submitted, more precise,
title of our contribution was “A pitcher of cold water on
mutational hotspots in mitochondrial DNA and the hot
debate about the role of mitochondria in tumorigenesis.” In
any case, the Oxford English Dictionary, for example, states that
“reassess” is “to assess again, especially differently (derivatives:
reassessment [noun])”; synonyms of assess would be “evaluate
or estimate.” Certainly, the role of the mitochondria has to be
reassessed since the role of their most essential element, the
mitochondrial genome, remains obscure in view of dozens
of studies on the potential association of tumorigenesis
with mitochondrial DNA (mtDNA) that are based on
obviously fl awed data. Since those inadvertent circumstances
(contamination and sample mix-up) are not mitochondriaspecifi
c but lab-specifi c, there would also be good reason to
reassess other spectacular DNA fi ndings in regard to potential
laboratory errors.
We would like to stress that mtDNA somatic mutations
are by no means uncommon either in normal tissues or in
tumors, but the natural pattern of these somatic mutations
(most commonly involving the polycytosine stretches and
other well-known hotspot mutations) is quite different
from those that were published in the papers criticized in
our article [2]. Consistent with the title of our article [2]
would be the possibility that the nuclear-mediated effect
on the mitochondrial function could perhaps be mtDNA
haplogroup–specifi c—but certainly not in the form of
the artefactual instabilities, as claimed in those dubious
publications (which, however, in one case, have now been
explicitly defended [3], but unfortunately, without carrying
out the necessary “forensic-type” analysis looking into
potential sample mixture of the previously analyzed samples
[4] and without determining whether the patient received
blood transfusion before the onset of the disease [5]). Rather,
some complex susceptibility background for tumorigenesis
might be anticipated—in analogy to some mtDNA diseases
such as Leber’s hereditary optic neuropathy (LHON) [6].
2. Salas A, Yao YG, Macaulay V, Vega A, Carracedo Á, et al. (2005) A
critical
reassessment of the role of mitochondria in tumorigenesis. PLoS Med
2:
e296. DOI: 10.1371/journal.pmed.0020296
3. Zanssen S, Schon EA (2005) Mitochondrial DNA mutations in
cancer. PLoS
Med 2: e401. DOI: 10.1371/journal.pmed.0020401
4. Vecchiotti C, Spaltro G, Bloise D, Brunetti E, Sciacchitano S (2004)
Demonstration of a gastric bioptic specimen mix-up by laser capture
microdissection (LCM) and DNA fi ngerprinting. Am J Forensic Med
Pathol
25: 113–116.
5. Meierhofer D, Ebner S, Mayr JA, Jones ND, Kofl er B, et al. (2006)
Platelet
transfusion can mimic somatic mtDNA mutations. Leukemia 20: 362–
363.
6. Carelli V, Achilli A, Valentino ML, Rengo C, Semino O, et al. (2006)
Haplogroup effects and recombination of mitochondrial DNA: Novel
clues
from the analysis of Leber hereditary optic neuropathy pedigrees. Am J
Hum Genet. In press.
Antonio Salas ([email protected])
Instituto de Medicina Legal
Universidad de Santiago de Compostela
Galicia, Spain
Yong-Gang Yao
Kunming Institute of Zoology
Kunming, Yunnan, China
Hans-Jürgen Bandelt
University of Hamburg
Hamburg, Germany
Citation: Salas A, Yao YG, Bandelt HJ (2006) Authors’ reply. PLoS
Med 3(3): e166.
Copyright: © 2006 Salas et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction
in any medium, provided the original author
March 2006 | Volume 3 | Issue 3 | e156 | e166
PLoS Medicine | www.plosmedicine.org 0415
and source are credited.
Competing Interests: The authors have declared that no competing
interests exist.
DOI: 10.1371/journal.pmed.0030166
References
Idézet vége.
1. Baysal B (2006) Mitochondria: More than mitochondrial DNA in
cancer.
PLoS Med 3: e156. DOI: 10.1371/journal.pmed.0030156
Ökológia
A Wikipédiából, a szabad lexikonból
Az ökológia a tudományoknak azon ága, amely az élettereket, az élőlények és a környezet kapcsolatait vizsgálja. A kifejezést 1866-ban
alkotta meg Ernst Häckel német darwinista biológus az "öko" (görögül oikosz="lakás, "ház", "háztartás") és a lógia (görögül logosz="tudomány")
szavakból. Az ökológia a biológiához, s azon belül az egyed feletti szünbiológiához tartozó, tehát élőlényközpontú tudományág;
környezetbiológiának is szokták közhasználatban nevezni. Környezetbiológiai jelenségeket előidéző okokat, kényszerfeltételeket, a jelenségek
mechanizmusát és hátterét kutatja. Az ökológia az élőlény populációk és élőlény-együttesek tér-időbeli eloszlásával és az azt előidéző okokkal
foglalkozó tudomány. Más vélemények szerint az ökológia az ökoszisztémák működésével foglalkozó tudomány. Az ökológiai vizsgálódások a
környezet (hatótényező) és a tolerancia (a fogadóképes tényező; tehát maga az élőlény, pontosabban populáció vagy populációkollektívum)
komplementaritásain alapszanak. Az ökológia tehát nem egyenlő a környezettel. Az ökológia nem környezet- vagy természetvédelmet jelöl. A
környezet- és természetvédelem csupán felhasználja az ökológiai vizsgálódások egyes eredményeit (természetvédelmi biológia). Az ökológia
nem a nagy mindent áthálozó folyamatok ismerője. Egyrészt a valóban "nagy" folyamatok megértéséhez még sok idő kell, másrészt lehet
beszélni pl. ökofiziológiáról (résztudomány), amely az élettani jelenségek (melyek másodpercek alatt lejátszódhatnak) ökológiai hátterét kutatja.
Ez a háttér "piciben" lehet jelen, pl. hogy most süt e a Nap s milyen mértékben egy árnyas erdő mélyén. A biológia tudomány fiatal hajtása
(tulajdonképpen keresi még a helyét). Mint ilyent igen nehéz jól definiálni. Juhász-Nagy Pál értelmezésében az ökológia azzal foglalkozik, hogy
miért nem élhetnek az élőlények bárhol, bármikor, bármekkora számban a Földön. (Ez a Juhász-Nagy Pál-féle metametodológiai quadruplet.). Az
ökológiai ismeretekre számos más alap és alkalmazott tudomány támaszkodik és magának az ökológiának is számos alkalmazott részterülete
ismert pl. mezőgazdasági ökológia, vízügyi ökológia, környezet- és természetvédelmi ökológia, közegészségugyi és állategészségügyi ökológia,
igazságügyi ökológia stb.
Az ökológia fogalma
Az ökológia, mint tudomány elnevezését Haeckel használta először 1866-ban az élőlények és környezetük kapcsolatát vizsgáló
fiziológiai szakterület megjelölésére, tehát a maitól nagyon eltérő módon (forrás: Majer, 1993). Igaz nem sokkal később már Ő maga is árnyaltabb
véleményt alkotott:
„By ecology we mean the body of knowledge concerning the economy of nature – the investigation of the total relations of the animal both to its
inorganic and to its organic environment; including, above all, its friendly and inimical relations with those animals and plants with which it comes
directly or indirectly into contact – in a word, ecology is the study of all those complex interrelations referred to by Darwin as the conditions of the
struggle for existence” (Ernst Haeckel 1870 , forrás: Allee 1949).
A mai szóhasználatban ecology-ként felfogott szünbiológia alapjai Clements (1916, 1928), Volterra (1926, 1931), Lotka (1925), Elton (1927),
Gause (1934), Lindeman (1941, 1942) és Allee (1911, 1932, 1949) munkásságával a XX. század első felétől kezdtek kirajzolódni. A korai
művekben a különböző módszertani lehetőségek eredményei még egymást kiegészítve, egymással egységben jelentek meg, később azonban
éppen az eltérő módszertan és eltérő fogalomhasználat vezetett az ökológia tárgyával kapcsolatos napjainkig észlelhető bizonytalanságokhoz.
Az MTA Ökológiai Bizottságának testületi állásfoglalása szerint az ökológia „feladata azoknak a limitálással irányított (…) jelenségeknek és
folyamatoknak (…) a kutatása, amelyek a populációk és közösségeik tér- és időbeni mennyiségi eloszlását és viselkedését (…) ténylegesen
okozzák”. (Anonim, 1987)
A testületi állásfoglalás a módszertani problémákat nyitva hagyja. Mára a módszertani specializálódás olyan méreteket öltött, hogy a különböző
ökológiai iskolák képviselői egymás munkáit gyakran appercipiálni sem képesek, ezért más tudományos szervezetekbe tömörülnek, más
szakfolyóiratokba publikálnak és alapvetően különböző fogalmakat használnak.
Az ökológiai gondolkodás alapjai
Az ökológia sohasem egyes kiragadott élőlényegyedekkel, hanem azok populációival, azaz halmazszintű attribútumokkal foglalkozik
(ezt nevezzük az "ökológia populációcentrikus posztulátumának"). Ha egy élőlényféleség egyedei (rendszertani vagy másféle csoport tagjai)
bárhol, bármikor, bármilyen mennyiségben előfordulhatnak a vizsgálati területünkön (és vizsgált időintervallumon), akkor kellően nagy
egyedszámok esetén az adott féleség egyedeinek tér és időbeli eloszlása véletlenszerű. A véletlenszerű eloszlást tehát kiindulási alapesetnek
kell tekintenünk, amely mint előfordulási mintázat, további magyarázatra nem szorul. Ezt a kindulási elgondolást az ökológia Juhász-Nagy Pálféle centrális nullhipotézisének nevezzük. Ha tehát egy vizsgált élőhelyfolton belül, valamely élőlény előfordulási mintázatát vizsgálataink során
véletlenszerűnek találjuk, akkor ezzel kapcsolatban ökológiai kérdést már nem kell feltennünk. A megfigyelt előfordulási mintázatok azonban
általában nem véletlenszerűek szoktak lenni. Ilyen esetben meg kell határoznunk a megfigyelt mintázat véletlenszerű esettől való eltérésének
mértékét, mert ez lesz az a jelenség amelyre az ökológiai vizsgálat során magyarázatot kell találnunk. Elsőként meg kell vizsgálnunk, hogy az
eltérés nem a mintavételi eljárásunk valamelyik sajátosságának következménye-e. Ha már igazoltuk, hogy valódi eltérésről van szó és annak
mértékét is megmértük , megkezdhetjük az okok felderítését. A mintázatot létrehozó okok ökológiai vagy történeti jellegűek lehetnek. Ökológiai
okokról akkor beszélünk, ha a mintázatot létrehozó hatótényezők a jelenben (tehát a vizsgálatunk idején) fejtik ki hatásukat. Az élőlényekre
számtalan külső tényező fejthet ki közvetlen vagy közvetett hatást. A külvilág azon hatótényezőit amelyek az élőlényegyedek tér-időbeli
mintázatait közvetlenül befolyásolni képesek, az adott élőlénycsoport miliőspektrumának nevezzük. A ténylegesen megfigyelt mintázatot azonban
nem a miliőspektrum egésze, hanem annak csak az adott szituációban konkrétan ható néhány komponense hozza létre. Ezen (ebből a
szempontból és ebben a szituációban) ténylegesen ható tényezők összességét az adott élőlényféleség ökológiai környezetének nevezzük. A
miliőspektrum minden egyes tényezője egy változóként fogható fel amelynek csupán bizonyos értékei mellett biztosított az élőlény
fennmaradása, ezt a tartományt az élőlény toleranciájának nevezzük. A különböző hatótényezők azonban egymás hatását is befolyásolhatják. A
miliőspektrum egyes hatótényezőinek azon értékkombinációit amelyek az élőlény toleranciatartományába esnek, az adott élőlény potenciális
niche-nek nevezzük. Amely értékkombinációk a valós tér-idő egyes pontjaiban ténylegesen előfordulnak összeségükben a realizálható niche-t
alkotják, ebből azok az értékkombinációk amelyeket az élőlény valóban ki is használ a realizált niche-t jelentik. A valós tér azon pontjai
amelyekben a niche-t alkotó értékkombinációk előfordulnak, az adott élőlény realizálható vagy realizált élőhelyét (vagyis a niche révén
definiálható élőhelytípusát a biotópot) jelentik. A realizálható és realizált niche illetve az ezeknek megfelelő realizálható és realizált élőhely közötti
eltérések ökológiai okokkal már nem magyarázhatók, ilyenkor szükséges a történeti okok (vagyis a múlt ökológiai okai és a terjedési korlátok)
vizsgálata. Ezekkel részben a biogeográfia (életföldrajz), részben a cönológia (társulástan) is foglalkozik. Azon tényezők közül, amelyek az
élőlényre hatóképesek, csupán azok alkotják az élőlény ökológiai környezetét amelyek aktuális értéke éppen a toleranciatartomány határán van.
Ezt nevezzük az ökológiai limitáció elvének. A élőlényegyedek potenciális előfordulási mintázata jelzi a hatótényezők limitáló értékeinek
előfordulási mintázatát. Ez az ökológiai indikáció elve. A limitáló külső tényezők általában nem az élőlény összes fiziológiai funkcióját és
alrendszerét egyszerre, hanem közvetlenül csak az adott tényezőre legérzékenyebb belső tényezőt limitálják. Így a limitáló értékek és a limitált
belső tényezők, csak szorosan egymáshoz rendelve értelmezhetők, egymás nélkül értelmetlenek, tehát egymást kiegészítik. Ezt az ökológiai
komplementáció elvének nevezzük. Egy adott földrajzi terület (környék) számtalan élőlényféleségnek adhat otthont, az egyes előlények
környezete azonban saját toleranciájuktól függően más és más lehet (és definiálni is csak azok ismeretében lehet). Hatóképesnek idáig csak
azokat a tényezőket tekintettük, amelyek az előfordulási mintázatokat befolyásolhatták és ökológiai szempontból ez így is helyes. Számos olyan
tényező van ami az előfordulási viszonyokat nem befolyásolja, de az élőlény fiziológiai állapotát, viselkedését vagy a populáció genetikai
összetételét annál inkább, ezek szempontjából bevezethető lenne a fiziológiai-, etológiai-, evolúcióbiológiai- stb. környezet fogalma is, amit a
multiplurális környezetek elvének szoktak nevezni. Ez azonban egyes vélemények szerint teljesen felesleges, mivel a populáció megfelelő
definiálásával ezek is előállíthatók ökológiai környezetként. (Ha például a csoportba csak az azonos fiziológiai állapotú, viselkedésű vagy
genotípusú egyedeket soroljuk.) Az ökológia alapvető fogalmai és elvei közül nem volt még szó az ökoszisztéma fogalmáról. Ökoszisztéma alatt
a kutatók nagyon sokféle valós vagy elképzelt rendszert érteni szoktak, azonban összhangban az MTA Ökológiai Bizottságának állásfoglalásával
célszerűbb, ha ökoszisztéma alatt inkább csak a természet ökológiai tanulmányozása céljából létrehozott rendszermodelleket értjük.
Az ökológia módszertani irányzatai
A Bioszférát alkotó élőlényegyüttesek állapotának vizsgálata, az állapotváltozások nyomonkövetése (monitorozása), az adatstruktúrák
értékelése és a mintázatok mögött megbúvó hatótényezők kutatása az emberi társadalom hosszútávú érdekei szempontjából a legfontosabb
feladatok közé sorolható (Lovelock 1987).
Az ökológiai kutatások módszertani (metodikai és metodológiai) irányvonalait tekintve, három fő megközelítési mód rajzolódik ki:
- A valós természeti folyamatok megfigyeléséből kiinduló terepi ökológusok arra törekszenek, hogy vizsgálataik a megfigyelendő
folyamatokba való minél kevesebb beavatkozással járjanak (Spellerberg 1991). Céljuk a szünbiológiai mintázatok előítéletmentes leírása, majd
ezen precíz leírások (adatsorok, adattáblázatok) birtokában próbálják meg a mintázatokat generáló hatótényezőket (pontosabban azok háttérmintázatát) feltárni. Ehhez általában a többváltozós adatstruktúra-feltáró módszereket és a mintázat-elemzés egyéb – gyakran kanonikus –
módszereit alkalmazzák. Ezen módszertan legtisztább elméleti megalapozását Juhász-Nagy Pál és tanítványainak munkássága (Juhász-Nagy
1984, 1986, 1993) teremtette meg, nemzetközi összehasonlításban is egyedülálló módon.
- Az ökológiai kutatások másik iskolája (a kísérletezők) nem a megfigyelt természeti folyamat komplex leírását, hanem egy kiragadott
részjelenséggel kapcsolatos hipotézist, vagy néhány alternatív hipotézisből álló hipotézis-rendszert állít vizsgálódásának középpontjába. Ezen
kutatások lényege a hipotézisek differenciáló predikcióinak tesztelése, gyakran erősen kontrollált, manipulatív kísérletekben. A kísérletek
értékelésében zömmel a próbastatisztikák és a variancia-analízis hagyományos lehetőségeit aknázzák ki. Az „angolszász ecology” sokatidézett
klasszikusai nemegyszer ezt az utat követték (Précsényi 1995).
- A harmadik fő csapásirányt a modellező ökológusok jelentik, akik jól ismert biológiai alapjelenségek birtokában és a szükségesnek
látszó legvalószínűbb hipotézisek felhasználásával, a vizsgált jelenséggel kapcsolatos legegyszerűbb elmélet nagyon pontos (tehát matematikai)
leírását (modelljét) készítik el. A módszertan lényege egy logikai ciklussal írható le, amely a modell teszteléséből (esettanulmányokkal való
ütköztetéséből) és a modell fejlesztéséből (javításából és újraillesztéséből) áll. Ezen módszertani irányzat alkalmazásával a vizsgált jelenség
egyre realisztikusabb elméletéhez jutunk, de a munka kezdeti szakaszaiban a rendelkezésre álló ismereteknek csak a töredékét használjuk fel.
Az egzakt elméleti ökológia vezető tan- és kézikönyvei ökológiai modellrendszereket használnak vezérfonalul, a másik két iskola
eredményeit inkább csak illusztrációként használják. Az eddig rendelkezésre álló modellek azonban általában még nagyon messze állnak a
terepi ökológusok megfigyelési eredményeitől.
Mindhárom fenti megközelítésnek megvannak a nyilvánvaló előnyei és hátrányai. Megbízható, körültekintően ellenőrzött és igazolt
ismeretekhez legkönnyebben kísérleti szituációk elemzésével juthatunk. A körültekintő ellenőrzöttség kritériuma azonban gyakran vagy az állítás
érvényességi körét szűkíti le túlságosan, vagy az ily módon vizsgálható jelenségek komplexitását korlátozza. Ezen módszertan segítségével
tehát viszonylag könnyen érhetünk el szakszerűen és színvonalasan igazolt, ámde szűk heurisztikus erejű és a gyakorlati alkalmazhatóságtól is
nagyon messze álló eredményeket. Ha valóban komplex és így gyakorlati szempontból is potenciálisan fontos jelenségeket akarunk vizsgálni,
akkor a folyamat korrekt megfigyelésétől és részletes leírásától nem tekinthetünk el, hiszen megbízható alapadatok nélkül nem lehetséges
realisztikus hipotéziseket felállítani. A természetközeli életközösségeket komplex megközelítésben tekintő terepi ökológiai kutatások azonban
általában kénytelenek az alapadatközlésnél vagy egyszerűbb korrelációk kimutatásánál megállni, mert az oknyomozás során olyan bonyolult
hipotéziseket kellene felállítani, amelynek tesztelése reménytelen vállalkozás volna. Komplex jelenségek oki vizsgálatához elengedhetetlen a
hipotézisek szimulációs modellekben való megfogalmazása, mert az alternatív jelenség-magyarázatok között ennek hiányában gyakran nem is
lehet prediktív különbséget tenni. A szimulációs technika másik előnye, hogy világosan rámutathat azokra az interpretációs tévedésekre, amelyek
a kísérletesen igazolt részállítások egyesítésekor ugyanúgy elsikkadhatnak, mint a megfigyelési adatok statisztikai elemzése során.
A terepen dolgozó specialista kutatók között gyakori az a vélemény, hogy a természetközeli élőlényközösségek (de még az
agroökoszisztémák és egyéb monokultúrák) taxonómiai-faunisztikai „feltártsága” olyan alacsony fokú, hogy működési jellegű hipotézisek vagy
modellek megfogalmazása teljesen komolytalan próbálkozás. Álláspontjuk szerint még hosszú évtizedekig csak az adatgyűjtésnek és a leíró
kutatásoknak lesz létjogosultsága. A kísérletes módszertan hívei közül viszont sokan úgy vélik, hogy komoly tudományos kutatás csak úgy
képzelhető el, ha már a munka megkezdése előtt világos „szakmai hipotézist” állítunk fel. Ha másképp nem megy, inkább vizsgáljunk nagyon
leegyszerűsített kísérleti szituációkat, de ott törekedjünk körültekintően igazolt ismeretek megszerzésére. A modellező ökológusok egy része
(„stratégiai modellezők” vagy „elméleti ökológusok”) az alapvető jelenségek megragadására, az elvi lehetőségek számbavételére törekszik és
magának az ökológiai modellezésnek a módszertani fejlesztését tartja legfontosabbnak. A „taktikai modellezők” vagy „alkalmazott ökológusok”
munkáiban pedig még a modell áttekinthetősége (a matematikai műveletek biológiai értelmezhetősége) sem cél, hanem kizárólag a modell
prognosztikai használhatóságára koncentrálnak.
Ökológiai alapfogalmak
Bioszféra
Földünk életközössége, a földi élővilágot alkotó egyedek összessége. A Bioszféra egyúttal egy térrészletet is kijelöl, amelyen belül a
földi élet létezik. Ez a térrészlet lényegében a litoszféra (szilárd földfelszín), hidroszféra (óceánok, tengerek, folyó és állóvizek), valamint az
atmoszféra (légkör) érintkezési felületén található, de ezen megjelölt szféráktól nem határolható el. A Bioszféra a földi élővilág funkcionális és
származási (ontológiai) egysége is. Funkcionális egység, mert a Bioszférát alkotó különböző populációk csak egymással kölcsönhatásban
életképesek és származási egység, mert valamennyi populációja evolúciós rokonságban (leszármazási kapcsolatban) áll egymással. A Bioszféra
együttes működésének eredménye többek között a klímaszabályozás, a légkör kémiai összetételének szabályozása, és az ún. biogeokémiai
ciklusok működtetése.
Ökoszisztéma
Ökológiai rendszerek tanulmányozása céljából biomatematikai és bioinformatikai eszközök segítségével létrehozott rendszermodell,
amely az élőlényegyüttes és környezete kapcsolatrendszerét írja le. Az ilyen rendszermodelleket gyakran ökológiai információs rendszerek
részeként alkalmazzák.
Biotóp (élőhely)
megfigyeléseken alapuló tapasztalati kategória, hasonló megjelenésű természetföldrajzi egységeknek egy olyan típusa, ill. annak egy
olyan meghatározott és többnyire küllemileg is jól elkülönülő része, ahol adott élőlények populációkat, ill. populációkollektívumokat alkotva
tartósan és rendszeresen előfordulnak, mivel néhány kivételes esettől (pl. vándorló halak, költöző madarak) eltekintve valamennyi fejlődési
alakjuk megtalálja az élete fenntartásához, ill. szaporodásához szükséges körülményeket. (A szakirodalom speciális esetekre más kifejezéseketpl. habitat- is használ.)
Környék
ökológiai értelemben az a tényleges, többé-kevésbé jól körülhatárolható, a valós térben elhelyezkedő, rendszerint eltérő közegekből
álló topográfiai egység, amely a vizsgálat tárgyát képező populációk vagy populációkollektívumok előfordulási helyeként megjelölhető.
Populáció
A populáció az ökológia egyik legfontosabb alapfogalma. Ennek ellenére két egymástól részben eltérő módon is használják. Egyik
jelentése szerint: egy adott fajba tartozó élőlények tényleges szaporodási közössége. Másik – ezzel részben átfedő – jelentése: egy ökológiai
vizsgálat céljából esszenciálisan azonosnak tekintett (az adott vizsgálatban meg nem különböztetett) élőlényegyedek összessége. A populáció
feletti szerveződési szinteken – az adott szint sajátosságai szerint összerendezendő populációkat összefoglaló néven populációkollektívumként
lehet értelmezni.
Populáció-dinamika
A populációk egyedszámának vagy egyedsűrűségének tér és időbeli változásaival foglalkozó tudomány, a szünbiológia
résztudománya. Alkalmazott szakterületei a demográfia, járványtan és a gradológia.
Szünbiológia
Az élőlény-együttesek tér-időbeli előfordulási viszonyainak tanulmányozásával és a szupraindividuális szerveződési szint
életjelenségeivel foglalkozó tudomány, amely magában foglalja az ökológiát és a szünfenobiológiát is.
Társulás azaz biocönózis
Egy biotópon belül és egy időben élő élőlények összessége.
Cönológia
A szupraindividuális (szün-) biológiához tartozó tudományág, amely az élőlény együttesek koegzisztenciális állapotának leírásával
foglalkozik. (Ezen tudományág oknyomozó irányzatait gyakran közösségi ökológiának nevezik.)
Közösségszerkezeti (v. cönológiai) állapot
A vizsgált objektum (élőhely, gyűjtőhely, mintavételi egység stb.) egy adott cönológiai állapotát úgy adhatjuk meg, ha a vizsgálatba
bevont (tehát aktuálisan változóként definiált) élőlényféleségek (rögzített vizsgálati módszerrel észlelhető) jelenlétét (tömegességi mutatószámát)
vagy hiányát megadjuk. A cönológiai állapot megadása tehát egy nagyon szigorú szabályok szerint megadott fajlistát és/vagy mennyiségi fajlistát
(esetleg gyakorisági eloszlást) jelent.
Cönológiai állapotváltozás
Cönológiai állapotváltozás minden olyan tér vagy időbeli folyamat, amely a fentiekben leírt cönológiai állapot bármely változójának,
vagy változóinak eltérésével jár, függetlenül annak okától vagy statisztikai jellegétől.
Cönológiai viselkedés
Tér vagy időbeli állapotváltozási mintázat, amely az együttes egészére, vagy annak tetszőleges részére is vonatkozhat.
Ökológiai monitoring vagy monitorozás
Meghatározott céllal és a célhoz adekvát módszerrel végzett többlépéses terepi vizsgálatsorozat, amely rögzített skálán és rögzített
időintervallumban, időbeli állapotváltozásokat követ nyomon.
Monitoring rendszer
Monitorozás csak monitoring rendszer keretében képzelhető el. A monitoring rendszer akkor tekinthető definiáltnak, ha meghatároztuk
a vizsgálandó objektumot (v. objektumok körét), a vizsgálandó állapotváltozókat (esetünkben élőlényféleségeket), a vizsgálat időszakát és a
megfigyelési (mintavételi) egységek frekvenciáját (vagy más módon rögzített egymásrakövetkezési rendjét), az adatfelvételezés módszereit,
továbbá az adatbázis feltöltésének módját és az elsődleges adatfeldolgozás módszereit.
Ajánlott irodalom
1. Anonim: Az MTA ökológiai bizottságának állásfoglalása az ökológia néhány fogalmának definíciójáról, Természet Világa 1987/9. szám
2. Balogh János 1953. A zoocönológia alapjai Akadémiai Kiadó Budapest.
3. Demeter András- Kovács György 1991. Állatpopulációk nagyságának és sűrűségének becslése, Akadémiai Kiadó, Budapest
4. Fábián Gyula 1986. Ökológai rendezőelvek a környezet- és természetvédelemben In: Jegyzetek a környezetvédelmi szakmérnökképzéshez,
OKTH, Budapest
5. Fekete Gábor (szerk.) 1998. A közösségi ökológia frontvonalai. Sciencia Kiadó, Budapest
6. Gallé László 1973. Az állatökológia alapjai (egyetem jegyzet), Szeged
7. Hortobágyi Tibor, Simon Tibor (szerk.) 1981. Növényföldrajz, társulástan és ökológia, Tankönyvkiadó Budapest.
8. Hufnagel Levente 2000 Bevezetés a folyóvíz-ökológiába In: Dukay I (szerk.) Kézikönyv a kisvízfolyások komplex vizsgálatához, Göncöl
Alapítvány és Szövetség, Vác
9. Juhász-Nagy Pál 1984 Beszélgetések az ökológiáról, Mezőgazdasági Kiadó, Budapest
10. Juhász-Nagy Pál 1986. Egy operatív ökológia hiánya, szükséglete és feladatai. , Akadémiai Kiadó, Budapest, pp 251.
11. Juhász-Nagy Pál, Vida Gábor 1978. Szupraindividuális organizáció In.: Csaba György (szerk.) A biológiai szabályozás, Medicina Kiadó,
Budapest.
12. Kozár Ferenc, Samu Ferenc, Jermy Tibor 1992 Az állatok populációdinamikája, Akadémiai Kiadó Budapest
13. Ladányi M 1995 Növénytermesztési modellek, In "Agro-21" Füzetek, Az agrárgazdaság jövőképe, "Agro-21" Kutatási Programiroda, Budapest
14. Lovelock J.E 1987. Gaia , Göncöl Kiadó, Budapest.
15. Majer József 1993. Az ökológia alapjai, Szaktudás Kiadó, Budapest.
16. Margóczi Katalin 1998. Természetvédelmi biológia, JATE Press, Szeged
17. Mátyás Csaba és munkatársai 1996. Erdészeti ökológia, Mezőgazda Kiadó, Budapest
18. Nánási Irén 1992. A humánökológia mint transzdiszciplína, In: Humánökológia, ELTE TTK Budapest
19. Nováky Erzsébet (szerk) 1990. Prognosztizálás, tervezés, modellezés a környezetvédelemben, KVM, Budapest.
20. Pásztor Erzsébet, Oborny Beáta (szerk.) 2007. Ökológia, Nemzeti Tankönyvkiadó, Budapest
21. Regős János 1989 Bevezetés a trópusi ökológiába (Introduction a la Ecologia Tropical, Un libro de estudio,) ECORENA/UCA Managua,
Nicaragua
22. Rózsa L 2005. Élősködés: az állati és emberi fejlődés motorja. Medicina, Budapest. p. 318.
23. Sasvári Lajos 1986 Madárökológia I-II, Akadémiai Kiadó, Budapest
24. Southwood, T.R.E. 1984 Ökológai módszerek -különös tekintettel rovarpopulációk tanulmányozására- Mezőgazdasági Kiadó, Budapest
25. Sváb János (1981) Biometriai módszerek a kutatásban, Mezőgazdasági Kiadó, Budapest
26. Szentesi Árpád, Török János (1997) Állatökológia, ELTE TTK egyetemi jegyzet, Kovásznai Kiadó, Budapest
27. Udvardy Miklós 1983. Dinamikus Állatföldrajz Tankönyvkiadó, Budapest.
28. Vida Gábor (szerk.) Evolúció I-IV. kötetek 1981–1984. Natura Kiadó, Budapest
29. Wilson, Edward O.- William H. Bossert 1981. Bevezetés a populációbiológiába, Gondolat, Budapest.
Elektronikus információforrások
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Alkalmazott ökológia és környezeti kutatások
BiologyBrowser
CABI
Cambridge Scientific Abstracts
BIOSIS
MBT Ökológiai Szakosztály
A lap eredeti címe "http://hu.wikipedia.org/wiki/%C3%96kol%C3%B3gia"
Kategória: Ökológia
jegyzetek, hivatkozások:15
Parasitism
from Wikipedia:
This article is about a relationship between organisms. For other uses, see Parasite (disambiguation).
Low Temperature Scanning Electron Microscope (LTSEM) image of Varroa destructor on a honey bee host
Mites parasitising a harvestman
Parasitism is one version of symbiosis ("living together"), a phenomenon in which two organisms which are phylogenetically unrelated
co-exist over a prolonged period of time, usually the lifetime of one of the individuals. The requirement for a prolonged interaction precludes
predatory or episodic interactions (such as a mosquito feeding on a host), which are usually not seen as symbiotic relationships. Symbiosis
encompasses commensalism ("eating at the same table", wherein two organisms co-exist in the same space, and one organism benefits while
the other is not affected to much extent), though mutualism (wherein both species benefit from the interaction) to parasitism, wherein one
organism, usually physically smaller of the two (the parasite) benefits and the other (the host) is harmed. (Various forms of "social parasitism",
kleptoparasitism, and "cheating parasbetween a parasite and a host, however.) Especially in the field of medical parasitology, the term "parasite"
has come to mean a eukaryotic, pathogenic organism. Thus, protozoan and metazoan infectious agents are classified as parasites while bacteria
and viruses are not. Fungi are not discussed in textbooks of medical parasitology even though they are eukaryotic. They are saprophytes.
Flea bites on a human.
Classification
Parasites that live inside the live body of the host are called endoparasites (e.g., hookworms that live in the host's gut) and those that
live on the outside are called ectoparasites (e.g., some mites). An epiparasite is a parasite that feeds on another parasite. This relationship is also
sometimes referred to as "hyperparasitoidism", especially in the insect world. For example a wasp or fly larva may be an endoparasite of an
Ichneumon wasp larva, which is in turn an endoparasite of a wood-boring beetle larva. Therefore the ovipositing adult female hyperparasitoid
must find the host of her host, namely the beetle larva, and oviposit into that beetle larva, after which her egg hatches within the beetle larva and
seeks out the Ichneumon larva, ultimately burrowing into it and becoming an endoparasite. It is most likely that in this case, the ovipositing female
adult hyperparasite locates the beetle larva by chemical cues it emits as a result of being parasitized itself by the Ichneumon wasp larva.
Many endoparasites acquire hosts by gaining entrance to their tissue; others enter the host when it consumes certain raw foods, as in
the case of the nematode Ascaris lumbricoides, an endoparasite of the human intestine. A. lumbricoides produces large numbers of eggs which
are passed from the host's digestive tract and pancreas into the external environment, relying on other humans to inadvertently ingest them in
places without good sanitation. Ectoparasites, on the other hand, often have elaborate mechanisms and strategies for finding hosts. Some
aquatic leeches, for example, locate hosts by sensing movement and then confirm their identity through skin temperature and chemical cues
before attaching.
Parasitoids are parasites that use another organism's tissue for their own nutritional benefit until the host dies from loss of needed
tissues or nutrients. Parasitoids are also known as necrotroph.
In contrast, biotrophic parasites cannot survive in a dead host and therefore keep their hosts alive. Many viruses, for example, are
biotrophic because they use the host's genetic and cellular processes to multiply.
Some parasites are social parasites, taking advantage of interactions between members of a social host species such as ants or
termites to their detriment.
Kleptoparasitism involves the parasite stealing food that the host has caught or otherwise prepared. A specialized type of
kleptoparasitism is brood parasitism, such as that engaged in by many species of cuckoo. Many cuckoos use other birds as "babysitters"; cuckoo
young are raised and fed by adults of the host species, but adult cuckoos fend for themselves.
Cheating or exploitation types of parasitism are often found in situations where there are generalized non-specific mutualisms between
broad classes of organisms, such as mycorrhizal relationships between plants and many types of fungi. Some myco-heterotrophic plants behave
as "mycorrhizal cheaters", establishing mycorrhiza-like interactions with a fungal symbiont, but taking carbon from the fungus (which the fungus,
in turn, gets from other plants) rather than donating carbon.
Evolutionary aspects
A female Catolaccus grandis wasp homes in on a boll weevil larva.
Biotrophic parasitism is an extremely successful mode of life. [citation needed] Depending on the definition used, as many as half of all
animals have at least one parasitic phase in their life cycles, and it is also frequent in plants and fungi. Moreover, almost all free-living animals are
host to one or more parasite taxa. [citation needed]
The hosts of parasites often evolve elaborate defensive mechanisms as well. Plants often produce toxins, for example, which deter
both parasitic fungi and bacteria as well as herbivores. Vertebrate immune systems can target most parasites through contact with bodily fluids.
On a behavioral level, the itching sensation, and resulting scratching behavior is used to fend off parasites. Many parasites, particularly
microorganisms, evolve adaptations to a particular host species; in such specific interactions the two species generally coevolve into a relatively
stable relationship that does not kill the host quickly or at all (since this would be detrimental for the parasite as well).
Sometimes, the study of parasite taxonomy can elucidate how their hosts are similar or related. For instance, there has been a dispute
about whether Phoenicopteriformes (flamingos) are more closely related to Ciconiiformes (storks and related groups) or to Anseriformes
(waterfowl and allies). Flamingos share parasites with ducks and geese, so these groups are thought to be more closely related to one another
than either is to storks. Modern DNA methods, however, have shown that flamingos are not closely related to Anseriformes either.
It is important to note that "benefit" and "harm" in the definition of parasitism apply to lineages, not individuals. Thus, if an organism
becomes physically stronger as a result of infection but loses reproductive capabilities (as results from some flatworm infections of snails), that
organism is harmed in an evolutionary sense and is thus parasitized. The harm caused to a host by a parasite can take many forms, from direct
pathology, including various specialized types of tissue damage, such as castration, to more subtle effects such as modification of host behaviour.
See also
List of parasitic organisms
Intestinal parasite
Macroparasite
Plasmodium
Myco-heterotrophy
Parasitic plant
Parasitic wasp
Pinworm
Superparasitism
Teratology
Toxoplasmosis
The Extended Phenotype
Symbiosis
Further reading
•Zimmer, Carl 2001. Parasite Rex. Free Press. ISBN 0-7432-0011-X
External links
Toxoplasmosis
Parasitology Parasites Zoonoses - (Polish/English) over 50 movies (Filmoteka) and over 250 photos (Fotogaleria/Photogallery) with
human and animal parasites.
Aberystwyth University: Parasitology – class outline with links to full text articles on parasitism and parasitology.
KSU: Parasitology Research - parasitology articles and links.
Medical Parasitology – online textbook.
Division of Parasitic Diseases, Centers for Disease Control and Prevention
VCU Virtual Parasite Project - Virtual Parasite Project at Virginia Commonwealth University's Center for the Study of Biologicial
Complexity
l. jegyzetek, hivatkozások: 16 Forrás: wikipedia
Növénybetegségek
Plant pathology
Plant pathology (also called phytopathology) is the scientific study of plant diseases caused by pathogens (infectious diseases) and
environmental conditions (physiological factors). Organisms that cause infectious disease include fungi, oomycetes, bacteria, viruses, viroids,
virus-like organisms, phytoplasmas, protozoa, nematodes and parasitic plants. Not included are insects, mites, vertebrate or other pests that
affect plant health by consumption of plant tissues. Plant pathology also involves the study of the identification, etiology, disease cycle, economic
impact, epidemiology, how plant diseases affect humans and animals, pathosystem genetics and management of plant diseases.
Plant pathogensThe "Disease triangle" is a central concept of plant pathology for infectious diseases[1] . It is based on the principle that
disease is the result of an interaction between a host, a pathogen, and environment condition.
Fungi
The fungi reproduce both sexually and asexually via the production of spores. These spores may be spread long distances by air or
water, or they may be soil bourne. Many soil bourne spores, normally zoospores and capable of living saprotrophically, carrying out the first part
of their lifecycle in the soil.
Fungal diseases can be controlled through the use of fungicides in agriculture, however new races of fungi often evolve that are
resistant to various fungicides.
Significant fungal plant pathogens
Ascomycetes
Fusarium spp.
Thielaviopsis spp. (Causal agents of: canker rot, black root rot, Thielaviopsis root rot)
Verticillium spp.
Magnaporthe grisea (T.T. Hebert) M.E. Barr; causes blast of rice and gray leaf spot in turfgrasses
Basidiomycetes
Rhizoctonia spp.
Phakospora pachyrhizi Sydow; causes Soybean rust
Puccinia spp.; causal agents of severe rusts of virtually all cereal grains and cultivated grasses
Oomycetes
The oomycetes are fungal-like organisms that until recently used to be mistaken for fungi. They include some of the most destructive plant
pathogens including the genus Phytophthora which includes the casual agents of potato late blight and sudden oak death.
Despite not being closely related to the fungi, the oomycetes have developed very similar infection strategies and so many plant pathologists
group them with fungal pathogens.
Significant oomycete plant pathogens
Pythium spp.
Phytophthora spp.; including the causal agent of the Great Irish Famine (1845-1849)
Rice blast is hemibiotrophic
Bacteria
Crown gall disease caused by AgrobacteriumMost bacteria that are associated with plants are actually saprotrophic, and do no harm to
the plant itself. However, a small number, around 100 species, are able to cause disease. Bacterial diseases are much more prevalent in subtropical and tropical regions of the world.
Most plant pathogenic bacteria are rod shaped (bacilli). In order to be able to colonise the plant they have specific pathogenicity factors.
There are 4 main bacterial pathogenicity factors:
1. Cell wall degrading enzymes - used to break down the plant cell wall in order to release the nutrients inside. Used by pathogens such
as Erwinia to cause soft rot.
2. Toxins These can be non-host specific, and damage all plants, or host specific and only cause damage on a host plant.
3. Phytohormones - for example Agrobacterium changes the level of Auxin to cause tumours.
4. Exopolysaccharides - these are produced by bacteria and block xylem vessels, often leading to the death of the plant.
Significant bacterial plant pathogens
Proteobacteria
Xanthomonas spp.
Pseudomonas spp.
Phytoplasmas ('Mycoplasma-like organisms') and spiroplasmas
Vitis vinifera with "Ca. Phytoplasma vitis" infection
Vitis vinifera with "Ca. Phytoplasma vitis" infectionPhytoplasma and Spiroplasma are a genre of bacteria that lack cell walls, and are
related to the mycoplasmas which are human pathogens. Together they are referred to as the mollicutes. They also tend to have smaller
genomes than true bacteria. They are normally transmitted by sap-sucking insects, being transferred into the plants phloem where it reproduces.
Viruses, viroids and virus-like organisms
Pepper mild mottle virusThere are many types of plant virus, and some are even asymptomatic. Normally plant viruses only cause a
loss of yield. Therefore it is not economically viable to try to control them, the exception being when they infect perennial species, such as fruit
trees.
Most plant viruses have small, single stranded RNA genomes. These genomes may only encode 3 or 4 proteins: a replicase, a coat
protein, a movement protein to allow cell to cell movement and sometimes a protein that allows transmission by a vector.
Plant viruses must be transmitted from plant to plant by a vector. This is normally an insect, but some fungi, nematodes and protozoa
have been shown to be viral vectors.
Nematodes
Root-knot nematode gallsNematodes are small, multicelluar wormlike creatures. Many live freely in the soil, but there are some species
which parasitize plant roots. They are mostly a problem in tropical and subtropical regions of the world, where they may infect crops. Root knot
nematodes have quite a large host range, whereas cyst nematodes tend to only be able to infect a few species. Nematodes are able to cause
radical changes in root cells in order to facilitate their lifestyle.
Protozoa
There are a few examples of plant diseases caused by protozoa. They are transmitted as zoospores which are very durable, and may
be able to survive in a resting state in the soil for many years. They have also been shown to transmit plant viruses.
When the motile zoospores come into contact with a root hair they produce a plasmodium and invade the roots.
Parasitic plants
Parasitic plants such as mistletoe and dodder are included in the study of phytopathology. Dodder, for example, is used as a conduit for
the transmission of virues or virus-like agents from a host plant to either a plant that is not typically a host or for an agent that is not grafttransmissible.
Physiological plant disorders
Significant abiotic disorders can be caused by:
Natural
Drought
Frost damage, and breakage by snow and hail
Flooding and poor drainage
Nutrient deficiency
Salt deposition and other soluble mineral excesses (e.g. gypsum)
Wind (windburn, and breakage by hurricanes and tornadoes)
Lightning and wildfire (also often man-made)
Man-made (arguably not abiotic, but usually regarded as such)
Soil compaction
Pollution of air and/or soil
Salt from winter road salt application
Herbicide over-application
Poor education and training of people working with plants (e.g. lawnmower damage to trees)
Vandalism
See also
American Phytopathological Society
Biological Control
British Society for Plant Pathology
burl
Common names of plant diseases
Fungicides
Gene-for-gene relationship
Global Plant Clinic
Herbivory
List of phytopathology journals
Mycology
Pesticide
Plant disease forecasting
QoI
Phytoplasma
Plant virus
Strobilurins
Stunt
References
^ George N. Agrios (1997) Plant Pathology fourth edition, Academic Press. New York.
Further reading
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Customs
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Plant protection
Phytopathology • Pesticide • Weed control
External links
American Phytopathological Society
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Plant Health Progress, Online journal of applied plant pathology
Pacific Northwest Fungi, online mycology journal with papers on fungal plant pathogens
Rothamsted Plant Pathogen Interactions Department
Grape Virology
Retrieved from "http://en.wikipedia.org/wiki/Plant_pathology"
A rákbetegség
A Wikipédiából, a szabad lexikonból.
Amikor a normális sejtek helyreállíthatatlanul károsodnak, apoptózis útján eltávolítják őket. A rákos sejtek elkerülik az apoptózist és folytatják
ellenőrizetlen szaporodásukat.
A rákbetegségek közös jellemzője a szabályozatlan sejtszaporulat, a biológiai szövetekbe való betörési képesség. Ez utóbbi
tulajdonságuk történhet invázióval és áttétképzéssel is. Ezt a kontrollálatlan növekedést olyan DNS-hibák, genetikai mutációk okozzák, melyek a
sejtciklus szabályozásában vesznek részt.
Általában több ilyen mutációra van szükség a daganat kialakulásához. Néhány ilyen hibát kemikáliák, fizikai hatások okoznak, mások
öröklődnek vagy éppen spontán jelennek meg. Azaz genetikus és környezeti tényezők együttesen vezethetnek eltorzult növekedési
szabályozáshoz.
A rák számos tünetet okozhat, melyek attól függően alakulnak ki, hogy a daganat hol helyezkedik el, milyen a karaktere és van-e
áttétképzés. Akár fájdalmatlan is lehet. A diagnózishoz általában szükség van a patológus szövettani vizsgálatára, a laboratóriumi eredményekre
és a klinikai megfigyelésekre egyaránt. A patológus a mintát biopsziával vagy műtét során veszi le. A diagnózis után a rákos betegségeket
leggyakrabban kemoterápiával, sugárkezeléssel vagy sebészeti beavatkozással kezelik. Az orvostudománynak a rákos daganatokkal foglalkozó
ágát onkológiának nevezzük.
Kezelés nélkül a rák gyakran halálhoz vezet. A rák igazából a legutóbbi időszak betegsége, a fejlett országok egyik vezető haláloka. A
legtöbb rák kezelhető, sok közülük teljesen gyógyítható, amennyiben kezelése időben megkezdődik. A rák több formája olyan környezeti
tényezőkkel van összefüggésben, mint a dohányzás, az alkohol hatása a szervezetre vagy egyes vírusok. Ezek egy része könnyedén
elkerülhető, ezért a világ közegészségügyi és oltási programjai igen fontosak.
Történelem
Hippokratész több rákfajta leírását is elkészítette. A jóindulatú tumorokat onkosz-nak nevezte, ami duzzanatot jelent görögül, míg a
rosszindulatú tumorokat karcinosz-nak hívta, ami a rák görög elnevezése. A különös névválasztás oka valószínűleg a rosszindulatú daganat
távoli hasonlósága egy rákhoz, a jól körülhatárolható, kör alakú középrésszel és az innen szerteágazó, vékony nyúlványokkal.
Később a szó végéhez csatolta az -oma toldalékot, ami görögül daganatot jelent, így alakult ki a karcinóma elnevezés. A mai szóhasználatban a
karcinóma az epiteliális sejtekből kiinduló rosszindulatú daganat orvosi elnevezése. Celsus volt az az orvos, aki a karcinosz kifejezést latinra
fordítva bevezette a cancer elnevezést, amely magyarra fordítva lett rák. Galenus az „onkosz” kifejezéssel írta le általában a tumorokat, innen
ered a mai onkológia elnevezés.
Nomenklatúra és osztályozás
Az alábbi rokonértelmű kifejezések használatosak abnormális daganatok említése során:
-Neoplasia vagy neoplazma a pontos, tudományos meghatározása az első paragrafusban említett megbetegedéseknek. A csoportba
sok különböző betegség tartozik, a szokásos osztályozásuk alább olvasható. A neoplazma lehet jóindulatú vagy rosszindulatú.
-A rák a betegség széles körben elterjedt elnevezése, általában a rosszindulatú neoplazma értendő alatta. Néha az ilyen rosszindulatú
daganatok egyik alcsoportja, a karcinóma említésére alkalmazzák. Tekintettel a szó ismertségére, gyakran még orvosok és tudósok is ezt a
kifejezést alkalmazzák, amikor neoplazmikus betegségekről, mint csoportról beszélgetnek.
Az orvosi nyelvezetben a tumor egyszerűen daganatot vagy csomót jelent, legyen az neoplazmikus, gyulladásos vagy egyéb. A
köznyelvben azonban ez a kifejezés is gyakorlatilag azonos a jó- vagy a rosszindulatú neoplazmával. Ez a használat azonban nem pontos,
hiszen egyes neoplazmák, például a leukémia vagy az in situ carcinoma, soha nem formálnak tumort.
Ráktípusok
Az egyes rák típusokat osztályozhatjuk aszerint, hogy honnan erednek, azaz milyen fejlődéstani sejtcsoportból származnak; hol
helyezkednek el stb.
Benignus (jóindulatú) tumorok osztályozása
-adenoma: mirigyes szerkezetű vagy mirigyes eredetű
-papilloma: hámfedte terület ujjszerű kiemelkedése
-polyp: nyálkahártya terület makroszkóposan is látható szövetszaporulata
-cystadenoma: üreges szerkezetű szövetproliferáció.
A kiindulási sejt elhelyezkedése alapján a karcinóma epiteliális sejtből indul. Ebbe a csoportba tartoznak a leggyakoribb megbetegedések, pl.: a
mell, a prosztata, a tüdő, a vastagbél, a bőr, az emésztőrendszer vagy a mirigyek rákjai.
a leukémia a csontvelői őssejtekből indul,
a limfóma a nyirokcsomó betegsége,
a melanóma a melanocitákból,
a szarkóma a kötőszövetekből,
a teratóma a magzati sejtekből,
a glióma az agy sejtjeiből indul ki,
a szeminóma a here daganata.
A rosszindulatú daganatokat általában úgy nevezik el, hogy az érintett testrész latin vagy görög neve után csatolják a fenti kategóriák
egyikét. Például, a rosszindulatú májdaganat elnevezése hepatokarcinóma; a zsírsejtek rosszindulatú daganata pedig liposzarkóma.
A jóindulatú daganatok általában az -oma toldalékkal kerülnek elnevezésre. Például az anyaméh simaizmának jóindulatú daganata a
leiomyoma. Ez a névszabály azonban nem tökéletes, mivel több rosszindulatú tumor elnevezése is tartalmazza ezt a toldalékot: pl.
neuroblasztóma, limfóma vagy melanóma.
Kialakulásának okai és patofiziológia
A rák alapjai
A sejtosztódás vagy sejtburjánzás egy fiziológiai folyamat, amely szinte minden szövetben és számos körülmény hatására beindulhat.
Normális esetben a sejtburjánzás és a sejtek elhalásának egyensúlya szigorúan szabályozottan megy végbe, hogy a szervek és szövetek
integritása megmaradjon. A rák kialakulásához vezető DNS mutációk megszakítják ezt a rendezett folyamatot.
A szabályozatlan és gyakran igen gyors sejtburjánzás jóindulatú vagy rosszindulatú daganat (rák) kialakulásához vezethet. A jóindulatú
daganat nem terjed át a test más szerveire vagy támad meg más szöveteket, ritkán jelent életveszélyt, hacsak fizikailag nem nyom össze
létfontosságú szerveket vagy okoz ektópiás hormontermelést. A rosszindulatú daganat megtámadhat más szöveteket is, a test távoli részeiben
alakíthat ki áttéteket (metasztázis), és veszélyeztetheti az egyén életét.
Sejtszintű megközelítés
A rák kialakulása
A rák kialakulása (karcinogenezis) olyan folyamat, ahol felborul a sejtosztódás normális szabályozása. Általában komoly mutációk
sorozata vezet a rák kialakulásához. A folyamatban részt vesznek onkogének és tumorszupresszor gének. Az onkogén elősegíti a rák
kialakulását, ha egy mutáció során bekapcsolódik, míg a tumorszupresszor gének a rák kialakulását akadályozzák meg, amíg egy mutáció során
ki nem kapcsolódnak.
A proto-onkogének változatos módon segítik elő a sejtnövekedést. Hormonokat termelhetnek, a sejtek közötti „kémiai
üzenetközvetítőket”, amelyek elősegítik a mitózist, amelynek eredményessége a fogadó szövet vagy sejt jeltovábbítóin múlik. Mások az
ingertovábbítási rendszerért és a sejtek, szövetek receptoraiért felelősek, így magukra a hormonokra való fogékonyságot irányítják. Mitogéneket
termelnek, vagy a fehérje szintézishez nyújtanak segítséget a DNS transzkripció irányításával.
A proto-onkogének mutációja megváltoztathatja funkciójukat, megnövelve a termelt fehérjék mennyiségét vagy aktivitását. Ha ez
bekövetkezik, onkogének alakulnak ki, így a sejtek nagyobb valószínűséggel kezdhetnek ellenőrizetlen szaporodásba, burjánzásba. A rák
kialakulásának valószínűsége nem csökkenthető a proto-onkogének génkészletből való eltávolításával, hiszen szerepük kritikus a test
növekedésében, „karbantartásában” és homeosztázisában. Csak a mutálódott gének adnak le kontrollálhatatlan növekedési jelzéseket.
A tumorszupresszor gének kódjai jelzéseket adnak a fehérjéknek, amelyek elnyomják a mitózist és a sejtnövekedést. A
tumorszupresszorok általában transzkripciós faktorok, amelyeket a sejtszintű stressz, vagy a DNS valamilyen károsodása aktivál. A DNS
károsodása beindít bizonyos enzimeket, amelyek végül aktiválják a tumorszupresszor géneket. E gének feladata, hogy felfüggesszék a sejtciklus
előrehaladását, amíg a DNS kijavításra nem kerül, és így megakadályozzák a mutációk továbbadását a létrejövő új sejteknek. A legfontosabb
tumorszupresszorok közé tartozik a p53 gén, amely egy transzkripciós faktor és számos sejtszintű hatás képes aktiválni, úgy mint a hypoxia vagy
az UV-sugárzás által okozott károsodás.
Sajnos, magát a tumorszupresszor gént, vagy az őt aktiváló ingercsatornát is károsíthatja mutáció, „kikapcsolva” ezzel a gént. Ennek
állandó folyománya, hogy a DNS kijavítására vagy egyáltalán nem kerülhet sor, vagy a javítás jelentősen lelassul, ez az állapot pedig
elkerülhetetlenül rák kialakulásához vezet.
Ahhoz, hogy a rák kialakulhasson, általában mindkét géntípusban szükség van mutációs folyamatra. A csak egyetlen onkogénre korlátozódó
mutációt elnyomná a normális mitózis-kontroll és a tumorszupresszor gének, amint azt a Knudson-hipotézis először megjósolta.
Hivatkozás:
http://hu.wikipedia.org/w/index.php?title=Knudson-hipot%C3%A9zis&action=edit
Knudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by
Carl O. Nordling in 1953,[1][2] and later formulated by Alfred G. Knudson in 1971.[3] Knudson's work led indirectly to the identification of cancerrelated genes. Knudson won the 1998 Albert Lasker Medical Research Award for this work.
The multi-mutation theory on cancer was proposed by Nordling in the British Journal of Cancer in 1953. He noted that in industrialized nations the
frequency of cancer seems to increase according to the sixth power of age. This correlation could be explained by assuming that the outbreak of
cancer requires the accumulations of six consecutive mutations.
Later, Knudson performed a statistical analysis on cases of retinoblastoma, a tumour of the retina which occurs both as an inherited disease and
sporadically. He noted that inherited retinoblastoma occurs at a younger age than the sporadic disease. In addition, the children with inherited
retinoblastoma often developed the tumour in both eyes, suggesting an underlying predisposition.
Knudson suggested that multiple "hits" to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was
inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two "hits" had to take place before a
tumour could develop, explaining the age difference.
It was later found that carcinogenesis (the development of malignancy) depended both on the activation of oncogenes (genes that stimulate cell
proliferation) and deactivation of tumor suppressor genes (genes that keep proliferation in check). A first "hit" in an oncogene would not
necessarily lead to cancer, as normally functioning tumor suppressor genes (TSGs) would still counterbalance this impetus; only damage to
TSGs would lead to unchecked proliferation. Conversely, a damaged TSG (such as the Rb1 gene in retinoblastoma) would not lead to cancer
unless there is a growth impetus from an activated oncogene.
Field cancerisation may be an extended form of the Knudson hypothesis. This is the phenomenon of various primary tumours developing in one
particular area of the body, suggesting that an earlier "hit" predisposed the whole area for malignancy.
References
^ Nordling C (1953). "A new theory on cancer-inducing mechanism". Br J Cancer 7 (1): 68-72. PMID 13051507.
^ Marte B (2006-04-01). Milestone 9: (1953) Two-hit hypothesis - It takes (at least) two to tango. Nature Milestones Cancer. Retrieved on
2007-01-22.
^ Knudson A (1971). "Mutation and cancer: statistical study of retinoblastoma". Proc Natl Acad Sci U S A 68 (4): 820-3. PMID 5279523.
External Links
Knudson’s two-hit hypothesis for tumourigenesis involving a tumour suppressor gene (TSG)
Retrieved from "http://en.wikipedia.org/wiki/Knudson_hypothesis"
A többi között vizsgálták a mitokondriális örökítő anyag hibáit is a carcinogenesis folyamatában.
Idézet a Molecular Cancerből:
Mitochondrial defects in cancer
Jennifer S Carew1,2 and Peng Huang*1,2
Address: 1Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston,
Texas
77030, USA and 2The Graduate School of Biomedical Sciences, University of Texas Health Sciences Center, 1515 Holcombe Boulevard,
Houston, Texas 77030, USA
E-mail: Jennifer S Carew - [email protected]; Peng Huang* - [email protected]
*Corresponding author
Keywords: mitochondria, cancer, mutation, respiration, free radical
Abstract
Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial
function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief
summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer,
and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic
implications.
Idézet vége.
Idézet az Expert Reviews in Molecular Medicine: http://www.expertreviews.org/-ból:
Accession information: (02)00445-3h.htm (shortcode: txt001ksb); 11 April 2002
Mitochondria as targets for detection and treatment of cancer
Josephine S. Modica-Napolitano and Keshav K. Singh
Mitochondria are dynamic intracellular organelles that play a central role in oxidative metabolism and apoptosis. The recent resurgence
of interest in the study of mitochondria has been fuelled in large part by the recognition that genetic and/or metabolic alterations in this organelle
are causative or contributing factors in a variety of human diseases including cancer. Several distinct differences between the mitochondria of
normal cells and cancer cells have already been observed at the genetic, molecular and biochemical levels. As reviewed in this article, certain of
these alterations in mitochondrial structure and function might prove clinically useful either as markers for the early detection of cancer or as
unique molecular sites against which novel and selective chemotherapeutic agents might be targeted.
Expert Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994
Idézet vége.
Egy tumor szupresszor gén mutációja nem okoz rákos elváltozást, hiszen a gén párja még be tudja tölteni funkcióját. Viszont ha több
protoonkogén onkogénné alakul, és több tumorszupresszor génben is mutáció keletkezik, akkor sokkal nagyobb esély van rá, hogy a sejtciklus
kicsússzon a szabályozás alól és a sejt kontrollálatlan osztódásba kezdjen. Mivel ezen gének szerepet játszanak a DNS hibák kijavításában, az
ilyen jellegű mutációk számának növekedésével a génhibák mennyisége is nő.
Az onkogének általában domináns helyzetbe kerülnek, mivel mutálódva új funkcióhoz jutnak, míg a tumor szupresszorok általában
recesszívek, mivel mutációik általában funkcióvesztéssel járnak. Minden sejt minden génből két példányt tartalmaz, mindkét szülőjétől egyetegyet, és általában elég, ha a proto-onkogénnek csak az egyik génjében jön létre a funkciónyerő mutáció, a sejt már valódi onkogénné válik, míg
a funkcióvesztő mutációnak mindkét génben meg kell ahhoz jelennie, hogy a tumor szupresszort teljesen kiiktassa. Vannak azonban olyan
esetek is, amikor egy tumor szupresszor funkcióvesztő génje a másik példányt is kiiktatja, ezt hívjuk domináns negatív hatásnak. Több p53
mutációban is megfigyelhető ez a folyamat.
Apoptózis
Apoptózisnak (aktív sejtelhalásnak) (Görögül: απόπτωσις: apo – tól, től, ptosis – esés) a biológia területén a programozott sejthalál
egyik változatát nevezzük. Az apoptózis normális fiziológiás válaszreakció specifikus „öngyilkos” szignálokra vagy a „túlélő” szignálok hiányára.
Tartalomjegyzék
1 Kutatása
2 Az apoptózis feladata
2.1 A sejtek elpusztítása
2.2 A homeosztázis biztosítása
2.3 Sejdifferenciáció, fejlődés
2.4 Immunreakció
3 Az apoptózis folyamata
3.1 Az intrinszik, mitokondriális útvonal
3.2 Extrinszik, halál ligandok indukálta útvonal
3.3 Jellegzetességei
4 Funkcióvesztés
4.1 p53 degeneráció
4.2 Virális fertőzés, tumorképződés
Kutatása
Egy egér májsejtjének apoptózisa. Az elhaló sejt nyíllal jelölve
Az elmúlt évtizedek fontos kutatási területévé vált a programozott sejthalál és főleg ennek egyik formája, az apoptózis
mechanizmusának tanulmányozása. A programozott sejthalál fontos szerepet játszik a soksejtű élőlények fejlődésében és az immunrendszer
működésében. A fiziológiás sejtelhalás nagy része apoptózissal zajlik, de az aktív sejthalálnak, illetve ennek zavarainak a patológiás folyamatok
lefolyásában is jelentős szerepe van, pl. neurodegeneratív kórképek, autoimmun betegségek, AIDS, daganatos megbetegedések esetében.
A folyamat első definíciója és az apoptózis elnevezés két patológus, Kerr és Wyllie nevéhez fűződik, akik in vivo megfigyelték, hogy az
elhalt sejtek jellegzetes és egységes morfológiát mutatnak. A természetes sejthalál eme folyamatát egy görög hasonlattal jellemezték, mint
"ahogyan a levelek hullanak le a fáról". Ezzel párhuzamosan fejlődésbiológusok (Horvitz és Brenner, 2002 Nobel-díj) megfigyelték, hogy egy
fonálféreg-faj, Caenorhabditis elegans bizonyos sejtcsoportja „programozottan” elpusztul a fejlődés egy kijelölt időpontjában, és az ennek
szabályozásásban résztvevő specifikus géneket is azonosították.
Az apoptózis feladata
Egy egérből származó máj festett metszete. Jól látszódik az elhaló sejt
A sejtek elpusztítása
Az apoptózis bekövetkezhet, ha a sejtet olyan károsodás ér, amit nem lehet kijavítani, vagy ha vírussal fertőzött, illetve ha különböző,
végzetes stressznek, mint például éhezésnek van kitéve. A DNS-t károsító ionizáló sugárzások, kemikáliák, toxinok is előidézhetik a folyamatot,
kiváltva a p53 gén expresszióját. A sejthalál utasítása származhat magától az érintett sejttől, jöhet a sejt környezetéből, illetve az immunrendszer
sejtjeitől. Az utóbbi esetben a folyamat célja a fertőzött sejt elpusztítása, s így a kórokozó terjedésének meggátolása.
A sejthalál fontos feladatot lát el a rákos folyamatok megakadályozásában. Ha a sejt nem képes az apoptózisra, köszönhetően
mutációknak, vagy egyéb biológiai gátlásnak, akkor korlátlan szaporodásnak indul, tumort képezhet.
A homeosztázis biztosítása
A felnőtt szervezetben a sejtek száma gyakorlatilag állandó szinten van. Ezt az osztódó és az elpusztuló sejtek azonos aránya szabja meg. Ha
egy sejt elpuszzúl pótolni kell, a szervezet igyekszik fenntartani a belső egyensúlyt, a homeosztázist. Az egyensúly azonban felborulhat:
-A sejtek gyorsabban szaporodnak, mint ahogy elpusztulnak. Így kóros sejtburjánzás, daganat képződik.
-A sejtek lassabban osztódnak, mint ahogyan pusztulnak.
Az egyensúlyt a szervezet többlépcsős, bonyolult, jelmolekulákban gazdag folyamatokkal tartja irányítása alatt. A rendszer meghibásodása
súlyos problémák forrása lehet.
Sejdifferenciáció, fejlődés
Az apoptózis jelentős sejtdiferenciációs tényező. Hiányában kisebb-nagyobb rendellenességek jelentkezhetnek
Az apoptózis mind a növényi, mid az állati szövetek differenciálódásának alapvető részét képezi. Régóta sejtették, hogy bizonyos
alacsonyabbrendű, gerinctelen állatokban a programozott sejthalál fontos szerepet játszik az egyedfejlődés során (mint pl. a lepkehernyók teljes
átalakulása vagy egyéb metamorfikus kifejlési modellek lezajlása esetén). Később egyértelművé vált, hogy a magasabbrendű szervezet fejlődése
során a sejtelhalás különböző szervek, szervrendszerek, testrészek kialakulásához vezet, ezen kívül a fejlődés bizonyos szakaszában
funkcionáló azon struktúrák eltüntetésében vesz részt, melyekre a továbbiakban már nincs szükség. A kifejlett szervezetben is tovább folytatódik
bizonyos sejttípusok folyamatos elhalása. Például az emberi szervezetben is percenként sejtek milliói halnak el, illetve újonnan születő sejtekre
cserélődnek le. Különösen élénk ez a sejtcsere a bélnyálkahártyában és a csontvelőben.
Immunreakció
Az immunsejt Granzyme-B enzime képes a membránt kilyukasztani, így beindítja a kaszpáz rendszert
Az immunrendszer kialakulásában és működésében is vitathatatlan az apoptózis fontossága.
A T és B limfociták fejlődése az emberi szervezetben komplex folyamat. Az állandóan megújuló limfocita készlet folyamatos kialakulása
során létrejönnek funkcióképtelen vagy autoagresszív klónok is, melyeknek eltávolítása a funkcionális repertoár hatékony működése
szempontjából alapvető fontosságú. Ezen klónok elpusztulása szintén az apoptózis mechanizmusával megy végbe, így a szervezet
megakadályozza a saját sejtjei ellen fellépő autoimmun reakciókat.
A citotoxikus T-sejtek képesek a sejtek apoptózisának a beindítására. Először pórust nyitnak a sejmembránon, majd jelmolekulák
szekréciójával beindítják a sejthalál lépéseit.
Az apoptózis folyamata
Az apoptózist sejtszignálok indítják be és vezérlik. Ezen szignálok lehetnek extracelluláris, és intracelluláris molekulák. Az utóbbiak
lehetnek: hormonok, növekedési faktorok, cytokinek, illetve nitrogén-monoxid is.
A belső folyamat a sejtben felszabadult vegyületek hatására indul be. Ezt előidézheti: sugárzás, magas hőmérséklet, vírusfertőzés. A
halálutak lejátszódásának feltétele, hogy a jelmolekula kötődjön receptorához. Összegezve elmondható, hogy létezik:
-Intrinszik, azaz belső, mitokondriális útvonal
-Extrinszik, azaz külső, a halál szignálok, ligandok bekötődése a sejtmembrán receptoraira indukálta útvonal
Az intrinszik, mitokondriális útvonal
A mitokondriális útvonal
A mitokondrium létfontosságú sejtalkotó a többsejtes élőényekben, hiszen a biológiai oxidáció több lépése zajlik itt. Apoptózist kiváltó
fehérjék különböző módon hathatnak a mitokondriumra. Előidézhetik a csatornáik nyílását, illetve a membrán permeabilitásának a
megváltoztatásával elérhetik, hogy a sejthalálban résztvevő, a kaszpázokat aktiváló molekulák (pl. citokróm-c, SMAC-ok) kifollyanak a
sejtorganellumból. Az utóbbi időben több bizonyíték is alátámasztja, hogy a nitrogén-monoxid (NO) a membránpotenciál módosításával
megváltoztatja a mitokondrium membránjának a permeabilitását.
Egyes mitokondriális fehérjék, amiket SMAC gyűjtőnéven is ismerünk a cytoplazmába ürítődnek. A SMAC-ok kötődnek az apoptózist
gátló proteinekkel (IAP-okkal, inhibitor of apoptosis proteins), gátolják őket a működésükben, így az apoptózis tovább folytatódhat. A sejthalált
gátló és a membránpermeabilitást szabályozó fehérjecsaládba tartoznak a Bcl-2 típusú fehérjék. Ezen proteinek nem csak az apoptózis
beindulását gátolják, de néhányuk a már elindult folyamatot is leállíthatja.
Alapállapotban a Bcl2 és Bcl-xL fehérjék a mitokondriumok külső falában gátolják a citokróm c kiáramlást egy ioncsatornára hatva. Sejtkárosodás
hatására azonban a pro-apoptotikus Bax fehérje gátolja a Bcl-2, és a Bcl-xL fehérjéket, így felszabadul a Citokróm-C, ami az Apof-1 (apoptotic
protease activating factor-1) fehérjével kapcsolódva apoptoszómákat képez. Az apoptoszómák aktiválják a Kaszpáz-9 nevű fehérjét, ami viszont
aktiválja a Kaszpáz-7-et, és 3-at. A kaszpáz 7 és 3 úgynevezett kivégző kaszpázok: képesek a sejt fehérjéinek a hasítására, proteolízisre.
A Citokróm-C és a SMAC-ok végső soron a kaszpázokat aktiválják.
Extrinszik, halál ligandok indukálta útvonal
A külső útvonal sematikus ábrája. A Fas ligand bekötődik a Fas-receptorba és elindítja a sejthalált
Az extrinszik útvonal legfontosabb összetevői az emlősökből izolált TNF (Tumor Nekrózis Faktor) és Fas receptórba bekötődnek a
receptorhoz hasonló nevű, a sejthalált elindító jelmolekulák. Mindkét receptor a TNFR receptorcsaládba tartozik.
A TNF ligandot (a receptorba bekötő fehérjét) a makrofágok termelik. A humán sejtek kettő TNF receptorral rendelkeznek: TNF-R1-el, és TNFTheMitochondrial Theory of Cancer © Copyright 2008. Czimbalmos-Kozma, Ferenc, MD., GP., DCH., Dr. Papp, Erika MD.,
R2-vel. A Fas receptor (amit CD95-ként is ismerünk) köti a Fas ligandot (FasL). A Fas-ligand akárcsak a TNF, aktiválja a Kaszpáz-8 nevű fehérjét,
ami aktiválja a kivégző Kaszpáz-3-at és a mitokondriális útvonalat is.
Jellegzetességei
Habár a két folyamat különböző, egyben közös: a végső feladat a kaszpázoké. Az apoptózist jellegzetes változások kísérik, amelyek
nyomonkövethetőek a sejteken:
-A kromatin kondenzálódik és a sejtmaghártyához tapad
-A citoplazma sejtmembrán hasadás nélkül zsugorodik
-Sejtmembrán és sejtmaghártya „blebbing”
-A sejt membránnal határolt csomagokba kerül, majd fagocitálódik (A foszfatidilszerin a sejthártya belsejéből kívülre kerül és ligandként
szolgál a fagocitózist végző sejteknek)
-A sejt nem ömlik ki, nincs gyulladás (A fagocitózist végző sejtek gyulladást gátló citokineket szekretálnak, mint pl. az IL-10-et és a
TGF-B-t.)
Funkcióvesztés
A p53 fehérje szerkezete
Mint ahogy látható, az apoptózis bonyolut, többlépcsős folyamat, így valamelyik rész meghibásodása az apoptózis hajlamának
elvesztését eredményezheti.
p53 degeneráció
A p53, akárcsak a retinoblasztóma (Rb) tumor-szupresszor protein. A sejtciklus G1/S1 fázisát ellenőrzi. Ha a DNS hibás, a p53 fehérje
leválik az MDM-2-ről (foszforilálódik), kötődik a p21 gén promóteréhez, és így beindítja annak transzripcióját. A p21 mRNS-ről leíródó p21 fehérje
hozzákötődik a sejtciklus egyik szabályozó proteinjéhez, a ciklinből és ciklin-dependens kinázból álló komplexhez, így meggátolja azok
működését, azaz leállítja a sejtciklust.
A p53 gén mindkét kópiájának a mutációja a fehérje funkcióvesztéséhez, és így korlátlan osztódáshoz, tumorok képződéséhez vezet.
Az emberi daganatok több mint a felében nincs funkcionáló p53 protein.
Érdekesség, hogy egy genetikailag módosított adenovírus csak p53-at nem tartalmazó sejtekben képes replikálódni, tehát hatékony
eszköz lehet rákos sejtek szelektív elpusztítására.
Virális fertőzés, tumorképződés
Egyes vírusok igen hatékony módszereket fejlesztettek ki, hogy meggátolják az általuk megfertőzött sejt apoptózisát.
A humán papilloma vírus bizonyos típusai méhnyakrákot okoznak. A vírus kódol egy fehérjét (E6), ami megköti és inaktiválja az
apoptózist indukáló p53 fehérjét. Az adenovírus eredetű E1B-55K, és a hepatitis-B vírusból származó HBx protein is a p53 fehérjét veszi célba:
hozzákötődik, így az nem képes a funkcióját betölteni. Az Epstein-Barr Virus a mononucleosis infectiosa és bizonyos limfómák okozója egy Bcl-2höz hasonló anti-apoptótikus fehérjét kódol, míg egy másik fehérjéje serkenti a fertőzött sejt saját Bcl-2 termelését, gátolva a sejt öngyilkosságát.
Bizonyos B-sejtes leukémiák és limfómák is a Bcl-2 termelését fokozzák, akárcsak a myxoma vírus M-T2 fehérjéje. A melanóma (a
legveszélyesebb bőrrák) sejtek az Apaf-1 expreszióját (kifejeződését) gátolják. Egyes tüdő és vastagbél daganatok sejtjei egy FasL-hez kötődő
és azt inaktiváló fehérjét választanak ki, ezért a citotoxikus T sejtek (CTL) nem képesek bennük apoptózist indukálni. Más rákos sejtek FasL-t
termelnek, amely a citotoxikus T sejtek Fas receptorához kapcsolódik, és apoptózist indukál a citotoxikus T sejtekben.
A lap eredeti címe
"http://hu.wikipedia.org/wiki/Apopt%C3%B3zis"
Kategória: Sejtbiológia
Idézet:
MOLEKULÁRIS SEJTBIOLÓGIA
LÕW PÉTER
A sejt őrző-védő szolgálata a rák ellen
Az egyik fő, sejtosztódást és daganatképződést gátló, úgynevezett tumorszupresszor gén a p53. Normális mûködésekor, a sejtet ért
stressz és DNS-károsodás hatására a róla átírt fehérje felszaporodik a sejtmagban és leállítja a sejtosztódást, valamint beindítja a sejt
programozott pusztulását. Ezzel megakadályozza, hogy a sérült DNS tovább másolódjon, és így megőrzi a genom épségét. Az elváltozott, rákos
sejtek p53 által irányított „eltüntetése" igen fontos a daganatfejlődés elleni védekezésünkben, a p53-válasz elvesztése pedig rosszindulatú
sejtburjánzáshoz vezet. Ma már sok biztató kísérlet mutatja, hogy mesterségesen helyreállíthatók kiesett funkciói. Retrovírus segítségével
sikerült már ép p53-gént bevinni beteg sejtekbe a mutáns gén helyére. A genetikailag megváltoztatott adenovírus pedig célzottan elpusztítja a
hibás molekulát hordozó, vagy éppen p53 hiányos rákos sejteket, míg a normál sejtekben képtelen szaporodni. Lehetőség van a sérült, inaktív
fehérje újraaktiválására is egy rövid peptiddel, ami a tumorban apoptózist indíthat el és így eltüntetheti a daganatot. A p53-ról kiderült: a
mikrotubuláris rendszert használja ahhoz, hogy a sejtmagba kerülhessen. Ez a felfedezés érdekes kérdéseket vet fel a mikrotubulus-hálózatot
szétromboló kemoterápiás szerek hatásával kapcsolatban.
A többsejtû szervezet sejtjeinek osztódása, differenciálódása és fennmaradása finom szabályozás alatt áll. A rákos sejtekbenez a
reguláció omlik össze, így ezek a sejtek ellenőrizetlenül növekednek és osztódnak, míg végül ellepik az egész szervezetet és összezavarják a
még ép szövetek és szervek mûködését. Mivel a rák az alapvető sejtszabályozó folyamatok sérülésével alakul ki, teljes megértése csak
molekuláris szinten lehetséges. Rák a szervezet bármely sejtjének szabályozatlan osztódásával kialakulhat, így több mint százféle különböző
típusa van, melyek lényegesen eltérnek viselkedésükben és a kezelésekre adott válaszukban. A daganatok egyik jellemző tulajdonsága, hogy
egyetlen abnormálisan osztódó sejtből fejlődnek ki. Mindez persze nem jelenti azt, hogy az eredeti sejt már kezdettől a tumorsejt minden
jellegzetességével rendelkezik. A rák kifejlődése többlépcsős folyamat, mely az évek során felhalmozott rendellenességekből alakul ki, ezért
találunk időskorúak között sokkal több rákos megbetegedést.
Rákkeltő anyagok
A rákot előidéző vegyületeket karcinogén (rákkeltő) anyagoknak nevezzük. Mivel a daganat kifejlődése összetett folyamat, sok tényező
csak a rák kialakulásának valószínûségét fokozza. A legtöbb daganatos sejtburjánzásnál túlzott leegyszerûsítés volna egyetlen kiváltó okról
beszélni. A sugárzás (például a napsugárzás ultraibolya tartománya) és több kémiai karcinogén anyag, mint a dohányfüst-összetevők: benzpirén,
dimetilnitrózamin, nikkelkarbonil a DNS roncsolásávalhatnak. Ezeket iniciáló anyagoknakhívjuk, mert a rák kialakulásában a kezdeti lépés a
mutációk indukálása a kulcsfontosságú génekben. Más karcinogének (forbolészter, ösztrogén) a sejtosztódás serkentéséveljárulnak hozzá a rák
kifejlődéséhez. Ezeket tumor promóterekneknevezzük. A korai tumorfejlődésben a mutáns sejtek nem tudnának nélkülük osztódni és növekedni.
Ezek mellett egyes vírusok is elindíthatnak rákos folyamatokat. Így például a májrákot a hepatitisz-B, a méhnyakrákot az emberi papillomavírus
(HPV) okozza. A tumorvírusokfontos szerepet játszottak a rákképződésért felelős molekuláris mechanizmusok feltárásában.
Az állati vírusok hat különböző családjának tagjai képesek rákot előidézni. Ezek közül ötnek DNS-genomja van, ezek a DNS
tumorvírusok. A hatodik családnak, a retrovírusoknak RNS-genomjuk van, melyek a fertőzött sejtben először DNS provírust hoznak létre. A
tumorvírusok kis genomja alkalmassá teszi őket a molekuláris elemzésre, ami a rák kialakításáért felelős vírusgének azonosításához vezetett és
a rák jelenlegi molekuláris szintû megértését lehetővé tette. Molekuláris biológiai szempontból a két legjobban tanulmányozott DNS tumorvírus
az úgynevezett majomvírus( simian virus 40, SV40) és a polyomavírus (ez utóbbinak egér a gazdaszervezete). Ezek egyike sem okoz emberben
rákot, mégis kulcsfontosságúak voltak a sejttranszformáció (rákos átalakulás) molekuláris alapjainak megértésében.
Vannak olyan sejtek, ezek az úgynevezett permisszív(„megengedő") gazdasejtek, melyekben a fertőzés a vírus szaporodásához
(replikálódásához), a sejt széteséséhez (líziséhez) és az új vírusrészecskék kiszabadulásához vezet. Mivel ezek a sejtek elpusztulnak a vírus
replikációja következtében, nem lehet rákossá tenni (transzformálni) őket. Egy másik sejttípusban, a non-permisszív(, nem megengedő')
sejtekben azonban a vírus nem képes szaporodni, itt jól érvényesül a tumorvírusok transzformáló képessége. Ilyenkor a vírusgenom beépül a
gazdasejt DNS-ébe, majd a megfelelő vírusgének kifejeződésével a sejt rákos átalakulását okozza.
A vírusgenom átíródása korai és késői szakaszra osztható. A „korai" gén azonnal a fertőzés után kifejeződik (ez a vírus-RNS
szintéziséhez kell), a „késői" gén azonban csak a DNS-replikációjának megkezdése után, és ez a vírusrészecske szerkezeti elemeit kódolja. Az
SV40 korai régiója két fehérjét kódol, melyeket kis és nagy T-antigénnek hívnak. mRNS-eik ugyanazon elsődleges átírási termékből keletkeznek
az eltérő érési folyamat során (alternatív splicing). A nagy T-antigén egymaga is elégséges a tumor kialakításához.
A tumorvírusok azon génjeit, melyek nem vesznek részt a vírus replikációjában és képesek a gazdasejt rákos transzformációjára,
onkogéneknek nevezzük. Később felfedezték, hogy a virális onkogének mellett vannak az egészséges sejtekben is onkogének. Ezek
aktiválódása rendellenes sejtosztódáshoz vezet túlzott expressziójuk vagy az általuk kódolt fehérje ellenőrizetlen aktivitása miatt. A rák
kialakulásának másik genetikai útja a tumorszupresszor gének inaktiválódása. Ezek a gének az egészséges szervezetben gátolják a
sejtosztódást és a daganatképződést, sok tumorban azonban hiányoznak vagy nem mûködnek.
A p53-at az SV40 nagy T-antigénjével (SV40LT) szorosan kapcsolódó sejtfehérjeként írták le, először 1979-ben. Azóta a p53 kutatása
több izgalmas, néha meglepő fordulatot vett. Ma a p53-at hatékony tumorszupresszor génként ismerjük, mely az emberi rák sok fajtájában
(leukémia, limfoma, szarkoma, agytumor és több szöveti karcinoma, például mell-, vastagbél- és tüdőrák) inaktiválódik. Míg az egészséges
sejtek vad típusú p53 fehérjét (wild-type p53, wtp53) termelnek, a rákos sejtekben gyakran a fehérje mutáns formáját találhatjuk. A p53 gén
transzkripciós faktortkódol, mely a sejtet érő stresszre vagy az örökítő anyagot károsító hatásokra egy sereg gén kifejeződését szabályozza.
Ezek a gének a sejt osztódási ciklusának leállításában vagy a programozott sejthalál beindításában játszanak szerepet.
Négy p53 molekula összekapcsolódva tud specifikusan a DNS-hez kötődni. Maga a fehérje több, különböző feladatot ellátó egységre
(doménre) osztható (1. ábra). Az N-terminális végen egy transzkripciót aktiváló domén található, mely az egész molekula DNS-hez kötődésekor
az átírásban részt vevő többi fehérjéhez kapcsolódik. A középső (mag) résza megfelelő bázissorrendû DNS-szakasz kiválasztásáért és a fehérje
kötődéséért felelős. A p53 molekula C-terminális végén egy szabályozó domén helyezkedik el, mely a mag domén specifikus kötődését
befolyásolja. Közvetlenül mellette a tetramerizációért felelős domén húzódik, ez kapcsol össze négy p53 fehérjét a DNS-hez illeszkedéskor.
A sejt a normális növekedés és fejlődés fenntartásához a p53 sejtciklust megállító és apoptózist indító szerepét nagyon szigorúan
szabályozza és csak akkor aktivizálja, ha szükséges. Az egészséges sejtekben a p53 jellemzően látens, lappangó formában van csak jelen, s mi
több, e látens forma egyensúlyi koncentrációja is igen alacsony a gyors lebontás következtében. Stressz hatására (DNS-károsodás, alacsony
oxigénszint, a mitotikus orsó sérülése, onkogén aktiválódás) a p53 biokémiailag megváltozik és ez a stabilizálódott fehérje nagy mennyiségben
felhalmozódik a sejtben.
A DNS-károsodás a p53 gyors indukcióját váltja ki, mely többek között a ciklin dependens kinázt (Cdk) gátló p21 fehérje átíródását
serkenti. A p21 G1- fázisban gátolja a sejtciklust, azaz még a DNS megkettőződése (S-fázis) előtt. A sejtciklus megtorpanása nyilvánvalóan időt
ad arra, hogy a roncsolt DNS-szakaszt kijavítsa a sejt, még mielőtt replikálódna. A p53 elvesztése nem teszi lehetővé a sejtciklus megállítását,
ami megemelkedett mutációs gyakorisághoz és a sejt genomjának instabilitásához vezet. Ez a genetikai instabilitás a ráksejtek általános
jellemzője, emiatt az onkogének és tumorszupresszorok további mutációkat szenvednek a tumorfejlődés során.
A sejtciklus megállításán kívül a p53 DNS-sérülés hatására apoptózist, sejtpusztulást is képes indukálni. (A p53 többek között a Baxgént is szabályozza, melynek génterméke a Bcl-2-vel összkapcsolódva elősegíti a sejtpusztulást.) Ez a válasz érthetően előnyös a szervezet
egésze számára, mert eltávolítja a hiányos DNS-û sejteket, vagyis azokat, amelyek esetleg rákos sejtekké válhatnak. Azok a sejtek, melyekből a
p53 hiányzik, nem képesek apoptózisra a DNS-károsodás hatására. Sok tumor kezeléssel szembeni rezisztenciáját éppen az okozza, hogy a
besugárzás vagy a kemoterápiás szerek által okozott DNS-sérülés nem vált ki bennük sejtpusztulást. A p53 elvesztése, úgy tûnik, a más
hatásokra (növekedésifaktor- megvonás, oxigénhiány) beinduló apoptózist is gátolja.
A p53 mûködésének egyik fő szabályozója az MDM2(murine double minute 2) fehérje, mely közvetlenül annak N-terminálisához
kötődik. A két fehérjemolekula összekapcsolódása nemcsak a p53 transzaktivációs doménjét fedi el, ezzel megakadályozva, hogy transzkripciós
faktorként mûködjön, hanem ubiquitin-függő lebontási útra is irányítja őket (lásd folyóiratunk 1999. decemberi számát). Az MDM2 ezt annál is
inkább megteheti, mivel E3-ubiquitin ligáz enzimként is mûködik és így maga ubiquitinálhatja a p53-at közvetlenül a proteaszómába irányítva azt
(lásd folyóiratunk 2000. novemberi számát). Mivel az MDM2 fehérje egy p53 irányítása alatt álló gén terméke, a p53 a saját lebontási
folyamatának egyik résztvevőjét aktiválja. Így negatív visszacsatolási kör jön létre, mely egészséges sejtekben normál körülmények között a p53
alacsony szintjét biztosítja, illetve lezárja a p53 által indított folyamatokat, ha a kiváltó jel már megszûnt.
Az emberi daganatos megbetegedéseket több, mint 50 százalékban a p53 gén inaktiválódása (deléciója, mutációja vagy más
fehérjékkel történő összekapcsolódása) okozza, így a p53 fontos célpontja a rákellenes beavatkozásoknak. A p53 gén mutációi általában
egyetlen aminosav megváltozásával járnak a fehérje DNS-kötő részében és ez részben, vagy teljesen megakadályozza a molekula DNS-hez
kapcsolódását. A p53- fehérje mûködését az is gátolhatja, ha tumorvírusok által kódolt onkogén fehérjék kötődnek hozzá. Az emberi
papillomavírus (HPV) E6 fehérjéje komplexet alkot a p53- mal, az adenovírus E1B fehérjéje, illetve az SV40 nagy T-antigénje ugyancsak hozzá
kötődik.
Génterápia
Több, p53-ra alapozott kezelési stratégián is dolgoznak jelenleg. Az egyik rendszerben sérült p53-at tartalmazó tumorsejtekbe
retrovírussal visznek be vad típusú gént. Így sikerült gátolni a daganat növekedését tüdőrákos betegekben. A módszer egyik hátránya, hogy az
ép génnek az öszszes tumorsejtet el kellene érnie és elpusztítania, máskülönben a fennmaradó sejtek újabb daganatot hoznak létre. A
gyakorlatban ilyen nagy hatékonyságú génbevitel lehetetlen. Egy másik korlát, hogy a retrovírusok bejuttatása csak helyileg lehetséges, a tumor
visszahúzódása is csak itt figyelhető meg, azaz távolabbra eljutott áttétek ezzel a módszerrel nem kezelhetők.
Egy másik, teljesen eltérő gyógymód azon alapszik, hogy az adenovírusok blokkolják a vírusfertőzés hatására a p53 által beindított
apoptózist a vírus replikációja és az új vírusrészecskék keletkezése érdekében. Az E1B vírusfehérje megakadályozza, hogy a p53 más gének
transzkripcióját aktiválja. A kezelést egy mutáns adenovírussal (ONYX- 015) végzik, melyben pont az E1B gén a hibás. Mint ez várható, a
mutáns adenovírus nem képes a vad típusú p53-at tartalmazó sejtekben (normál vagy tumorsejtek) szaporodni. Hibás p53-at hordozó
tumorsejtekben (méh- és vastagbélrák) azonban replikálódik, a sejtek pusztulását okozva. Az intravénásan beadott adenovírus eléri a daganatot,
szaporodik benne és ez a daganat visszahúzódását eredményezi. Ez a kezelési módszer remélhetőleg a tumortól távoleső áttétekre is
alkalmazható, de egyelőre még klinikai kipróbálás alatt áll.
Egy harmadik eljárás abból indul ki, hogy a központi domén DNS-kötő képességét a C-terminális szabályozó régiója befolyásolja (1
.ábra). Találtak olyan mutáns p53-at tartalmazó vastagbélráksejteket, melyekhez izolált C-terminális peptidetadva a p53 transzkripciós faktor
funkciója helyreállt. A mutáns gént hordozó tumorsejtekben a p53 újra aktiválódása erős apoptotikus választ váltott ki, míg a normál sejtek
viszonylag érzéketlenek voltak a kezelésre. A peptidek nem ideális gyógyszerek, de ezek az eredmények talán lehetővé teszik a C-terminális
peptidhatását utánzó molekulák tervezését.
A p53 fehérjecsalád
Bár sokáig azt gondolták, hogy a p53 fehérje egyedülálló a maga nemében, nemrégen felfedezték két közeli rokonát, a p63 és a p73
fehérjét. E két fehérje aminosav-sorrendje a kritikus funkcionális szakaszokon megegyezik a p53-éval, ami azt sugallja, hogy ezek is a sejtciklus
és a sejthalál szabályozásában vesznek részt. A legújabb kutatások azonban világosan bizonyítják, hogy az evolúciósan megőrzött szerkezeti
hasonlóság ellenére a p53 család tagjai más, sőt ellentétes biológiai feladatokat látnak el. A p53-tól eltérően a p63 és p73 kifejeződése
megdöbbentően bonyolult, így a p63-nak 14, a p73-nak pedig 6 változata (izoforma) jön létre.
A fehérjék aktivitásának szabályozása meglehetősen összetett folyamat. Sok fehérje csak egy meghatározott sejtkompartmentumban
fejti ki hatását, így mûködése igen hatékonyan szabályozható sejten belüli helyének változtatásával. Különösen jó példák erre a transzkripciós
faktorok: e fehérjék mûködését a sejt nagyszerûen szabályozhatja azzal, hogy ide-oda mozgatja őket a sejtmag és a citoplazma között. Ma már
meglehetősen jól ismerjük, hogyan lépnek be a sejtmagba a fehérjék, illetve hogyan hagyják el azt import-, vagy exportreceptorok segítségével.
Ez utóbbiak felismerik a mozgatandó fehérjén a maglokalizációs, illetve magexport jeleket. De hogyan kerülnek a fehérjék a sejtmag megfelelő
közelségébe, hogy az importáló receptorokkal kapcsolódhassanak? Bár nem kizárt, hogy mindez csak diffúzió útján zajlik, egyre inkább az a kép
rajzolódik ki, hogy a fehérjék utazása a citoplazmában igen finoman szabályozott folyamat, mely a mikrotubuláris hálózatothasználja a hozzá
kapcsolódó motorfehérjékkel együtt. A mikrotubulushálózat irányított; a mikrotubulusok dinamikusan változó '+ vége' általában a sejt perifériáján
helyezkedik el, a viszonylag stabil '- végük' a sejtközpontnál, rendszerint a sejtmag közelében. Számos motorfehérje képes a mikrotubulusokon
egyik, vagy másik irányba mozogni és közben a hozzájuk kapcsolódó molekulákat a sejt központja vagy széle felé szállítani.
A p53 fehérje is, mint transzkripciós faktor, a sejtmagban fejti ki hatását. A legújabb kutatási eredmények szerint a p53- nak
kapcsolódnia kell a mikrotubulárishálózathoz és a dyneinhez*, hogy a mag közelébe kerülhessen (3. ábra). Itt transzportreceptorokra kerül, hogy
azok a magpórusokon keresztül végül a magba juttassák őket. Ez a szállítás a mikrotubulárishálózaton csak a sejtet ért stressz hatására
következik be. A hálózat szétesése esetén a p53 nem tud a sejtmagba kerülni és így hatását sem fejtheti ki. Érdekes, hogy a p53 N-terminális
régiója felelős a mikrotubulus kapcsolatért, a C-terminális vége pedig a maglokalizációs jelet hordozza (1. ábra). Tehát a két folyamat, vagyis a
p53 sejtmaghoz szállítása és a magpóruson át a magba jutása egymástól független.
Míg a p53-nak a sejtmagba kell jutnia ahhoz, hogy aktivitását kifejtse, normálisan osztódó sejtekben mûködésének gátlása érdekében
nagyon fontos, hogy kikerüljön a magból. Ehhez az szükséges, hogy az MDM2 molekula segítségével a p53 ubiquitinálódjon, a magexport jel
elérhetővé váljon a C-terminálisán és így a p53-MDM2 komplex kikerül a magból. Stressz hiányában a p53 aktivitását úgy szabályozza a sejt,
hogy gátolja a sejtmaghoz szállítását és serkenti exportját a magból. Megfelelő jelek hatására aktiválódik a p53 importja a sejtmagba, miközben
exportja gátlódik, így a molekula felhalmozódik a magban és kifejtheti hatását.
A p53 aktiválása tehát hatékony rákellenes kezelésnek bizonyul azokban a tumorokban, melyekben még van vad típusú fehérje. Ez a
módszer nem mûködik olyan daganatokban, ahol a p53 nem tud a magba kerülni a mikrotubuláris rendszer sérülése miatt. Így a vad típusú p53at megtartó rákok esetén a mikrotubuláris mérgek kemoterápiás alkalmazása pontosan a p53 aktivitása ellen hat. Más kemoterápiás szerekkel,
illetve sugárkezeléssel együtt alkalmazva azonban kivédheti a normál sejteken tapasztalható káros mellékhatásokat.
* A dynein a mikrotubulusokon, azok negatív, sejtközpont felőli vége irányába mozgó motorfehérje.
IRODALOM
1. M. A. E. Lohrum és K.H. Vousden (2000) Regulation and function of the p53-related proteins: same family, different rules. Trends in Cell
Biology 10:197-202.
2. K. G. Wiman (1998) New p53-based anti-cancer therapeutic strategies. Medical Oncology15:222-228.
3. P. Giannakakou és mtsi (2000) p53 is associated with cellular microtubules and is transported to the nucleus by dynein. Nature Cell Biology
2:709-717.
Idézet vége
jegyzetek, hivatkozások 19:
DCA - diklóracetát
DRUG NAME: Dichloroacetate (DCA)
MANUFACTURER: Various
DRUG CLASS (MOA)
Bioenergetics- The pyruvate dehydrogenase complex (PDC) catalyzes
the ratedetermining
step in the aerobic metabolism of glucose, pyruvate, and lactate, the
latter of which is in equilibrium with pyruvate (i.e., lactate converted to
pyruvate)
(1). DCA activates the PDC indirectly by inhibiting the activity of
pyruvate
dehydrogenase kinase. As a consequence of stimulating PDC, DCA
increases
irreversible oxidation of lactate via pyruvate. Pyruvate then enters the
Krebs
cycle as acetylCoA, which ultimately generates NADH and ultimately
ATP.
Overall, DCA, through inhibition of PDC, is believed to reduce the
intracellular
and systemic accumulation of lactate and enhance energy production
through
oxidative phosphorylation.
SCIENTIFIC RATIONALE
Lactate is elevated in the cortex of patients with HD; and mitochondrial
dysfunction and ATP depletion are believed to play a role in the
pathogenesis of
the disease(2, 3). In addition, excitoxicity and oxidative stress have
been
implicated in the progression of HD. DCA, by helping restore energy
balance,
decreasing brain lactate, and indirectly helping to clear glutamate may
have a
disease modifying effect.
DCA’s actions may help clear CNS lactate, increase cell energy, and
increase
clearance of glutamate, thereby reducing excitotoxicty (4). In neurons
and
astroglia, pyruvate and lactate are partitioned. Astroglia are the primary
storage
site for brain glycogen and catabolize glucose and glycogen to lactate,
which is
for the most part transported to neurons to be oxidized in the
production of ATP.
It has been shown that astroglial cells have a limited ability to oxidize
glucose
and lactate, whereas neurons have a greater potential to do so.
However,
neurons are less efficient at oxidizing intracellularly accumulated
lactate and
prefer lactate obtained from extracellular sources. In the case of both
cell types,
clearance of lactate can be superseded in excitotoxicity. It is known that
glutamate stimulates astroglial cell glycolysis and that there is a 1:1
ratio
between glucose utilization and the uptake of glutamate and its
conversion to
glutamine in astroglial cells (clearance of glutamate from the
extracellular
environment). This process generates lactate. Logically, if there is
sufficient
accumulation of glutamate, the astroglial and neuronal cells’ ability to
clear
lactate is overcome. DCA by stimulating PDC activity helps clear
lactate from the
CNS. Likewise, because lactate is converted to pyruvate, which
ultimately is
converted to NADH/ATP through the Kreb’s cycle, the brain’s energy
balance is
increased.
In cell culture, DCA (100 µM) has been shown to increase glucose
(astroglia
34%, p<0.05; neurons 5%, p<0.05) and lactate (astroglia 36%, p<0.01;
neurons
11%, NS) oxidation in both cell types with a more pronounced effect in
astroglia
(4). Lactate release is also reduced in both (astroglia 20%, neurons
11%),
however this is not statistically significant. When DCA is given to rats
(50 mg/kg
IV x1), baseline local cerebral glucose utilization increases throughout
the brain
(5/6 rats and in 16/18 structures). In functionally activated (stimulation
of the
whisker-to-barrel cortical pathway) rats given DCA, local glucose
utilization
increased to a lesser extent in the activated brain regions (p<0.05).
This may be
in part due to increased utilization of lactate through DCA’s actions.
ANIMAL MODEL DATA
RODENT:
DCA’s disease modifying effects were examined in two transgenic
models (R6/2
and N171-82Q) (5). DCA (500 mg/L) was added to the mice’s drinking
water to
give an estimated daily dose of 100 mg/kg (assuming 5 mL water
consumed/day), with treatment initiated at 4 weeks of age (R6/2 pre- to
early
symptomatic; N171-82Q-presymptomatic. Treatment groups were as
follows:
R6/2, 20DCA-treated mice/17 control; N171-82Q, 17DCA/36 control.
Survival
was assessed as a criteria for euthanasia (point in time in which an
animal was
unable to initiate movement after prodding for 2 minutes). Additional
outcome
measures included, for R6/2 mice: Motor (rotarod test), blood glucose,
histological assessments for aggregation analysis, and brain PDC
activity
(acetylCoA formation); and for N171-82Q mice: survival, motor activity,
and
weight loss. No pharmacokinetic or pharmacodynamic data were
reported.
R6/2 Results:
Survival: DCA increased survival in R6/2 mice compared to control
transgenic
mice by 6.4% (p<0.001).
Motor Performance: DCA-treated transgenic mice showed improved
rotarod
performance over that observed in controls from 90 days onward (last
assessment time point for both groups was 98 days, however
significance was
only noted at 90 and 95 days of life (p<0.05). It is also important to note
that this
positive trend in rotarod performance was only noted late in the
symptomatic
phase of the disease (mean survival was 97.2 days in untreated
transgenic mice
vs. 103.9 days in DCA-treated mice).
Histology: In DCA-treated transgenic mice, there was no significant
atrophy in the
striatum at the 70-day time point assessment when compared to
healthy
littermates (striatal neuron area measurements18% less in R/6 mice
treated with
DCA compared to wild-type, NS). DCA helped to prevent striatal
atrophy in
transgenic mice when compared to untreated transgenic mice (40%
less striatal
atrophy in R6/2 –DCA-treated mice vs. transgenic control mice,
p<0.001). At 10
weeks there was no difference in the degree of protein aggregation in
transgenic
mice groups (DCA treated or control). It is unclear if there would have
been a
significant difference observed at later time points. However, it is likely
that DCA
has no effect of protein aggregation because of its proposed
mechanism of
action. At 12 weeks, the quantity of brain PDC was normal in R6/2
mice,
however the percentage in the active form was significantly reduced
(42%
compared to normal littermates.) DCA reversed this reduction in active
PDC; in
fact, the active/total PDC ratio was slightly greater in transgenic mice
than in
wild-type littermates (5%).
Glucose: At 12 weeks, untreated transgenic mice experienced a 3-fold
increase
in blood glucose concentrations (p<0.01). DCA reduced glucose
concentrations
in both wild-type mice and in transgenic mice. In DCA-treated mice, no
increase
was noted when compared to wild-type littermate controls [Mean
(SEM) glucose
concentration (mg/dL): DCA transgenic, 113.8±17.1 vs. wild type
controls,
98.5±7.3].
N171-82Q Results:
Survival: Survival was prolonged in DCA-treated transgenic mice
(9.8%, p
<0.05).
Motor Performance: DCA significantly improved performance on
rotarod testing
between 107 and 127 days of age (p <0.05). No difference in rotarod
performance was noted in the last time point assessed (Day 135).
Weight Loss: DCA-treatment also significantly attenuated weight loss in
transgenic mice from 115 days of age on. This was significant (p<0.01)
for all but
the last time point assessed. It is unclear if the difference in weight loss
between
the DCA-treated and control transgenic mice affected rotarod
performance given
that the difference in the two parameters occurred at a similar time
period.
PHARMACOKINETICS (INCLUDING BBB PENETRATION)
DCA’s pharmacokinetics are complex and nonlinear, and its
hypolactatemic
effect is not clearly linked with plasma concentrations (6, 7). In single
dose
pharmacokinetic studies, DCA’s plasma concentration increases
linearly up to 30
mg/kg IV; however, given in doses greater than 20-30 mg/kg, the Cmax
and
clearance are greater (6). DCA’s half-life during the linear portion of its
pharmacokinetics is 0.5-4 hours, with clearance of 0.047-0.13 L/kg/hr
(8, 9).
Another study showed that DCA’s pharmacokinetics fit a onecompartment
model with concentrations less than 80 mg/L; however concentrations
greater
than 80 mg/L resulted in zero-order elimination (9). Measurement of
systemic
lactate concentrations suggests that the DCA decreases lactate within
minutes of
administration, however the duration is dependent upon the dose
administered
(30 mg/kg reduces lactate for 4.5 hrs, 100 mg/kg reduces serum
lactate > 8 hrs.).
However, this dose-effect phenomenon is not observed across all
studies (7).
BBB Permeability
DCA is presumed to be capable of penetrating the BBB, although most
of the
available literature fails to examine DCA concentrations directly,
instead
measuring lactate concentrations or PDC. Data from patients with head
trauma
show that doses of 100 mg/kg x 1 followed by 50 mg/kg every 12 hours
for 5
doses reduced CSF lactate concentrations to approximately one third.
Increasing
the dose to 150 mg/kg x1 followed by 75 mg/kg x 5 doses did not
significantly
further decrease CSF lactate concentrations, even though DCA plasma
concentrations increase by 60% (10). The rationale for nonlinearity is
that DCA’s
transport across the BBB is via the monocarboxylate transport system,
which
may be saturable; or that the number of PDC binding sites is limited
and increase
plasma concentrations do not translate into a direct clinical effect. One
case
report in a child with congenital lactic acidosis showed a DCA
blood:CSF ratio of
2, however the patient did not show a reduction in CSF lactate
concentrations
(11).
In fasted rats, the average activity of PDC is 0.4±0.04 µmol/min/g of
brain tissue,
which represents 21% of the total activity of the complex (12). Upon
administration of DCA, 125 mg/kg i.p., the relative percentage of active
PDC
increases to 107%. This increase in PDC activation corresponds to a
significant
decrease in brain lactate concentrations (13). DCA in doses of 100 mg/
kg given
to pre-ischemic rats results in significant reduction of brain volume loss.
Taken
together with human pharmacokinetic data cited above (7,10) suggests
that
doses of 100-125 mg/kg may have disease-modifying effects in both
humans and
rodents, but more data in transgenic HD mice ,including DCA’s effects
on lactate
or PDC activity needs to be obtained. Alternatively, imaging data using
lactate
as a surrogate marker could be obtained in HD patients given DCA in a
doseresponse
type of design.
SAFETY/TOLERABILTY IN HUMANS
DCA is used extensively for the treatment of metabolic/mitochondrial
disorders
and the treatment of lactic acidosis in sepsis, malaria, and many other
conditions.
Doses have ranged from 25 mg/kg-200 mg/day and are similar to those
used in
preclinical testing (14). Doses are usually given as a divided dose twice
daily.
Many of the studies have been short term, and overall DCA has been
well
tolerated without significant side effects (10). Sedation may occur and
long-term
use has been associated with neuropathies. It is recommended that
thiamine be
administered to help prevent this side effect. Toxicology studies
suggest the
DCA plasma concentrations should be maintained below 600 mg/L to
minimize
adverse effects. In mice, DCA (0.1 to 2 g/L in the drinking waterestimated mg/kg
within the range found to be protective in HD models described above)
has been
linked to hepatic cancer, the exact risk to humans is unknown (15).
DRUG INTERACTION POTENTIAL
No formal drug interaction studies have been performed.
CLINICAL TRIAL EVIDENCE IN HUMAN HD
None
AVAILABILE DOSAGE FORMS
Various dosage forms, not approved in U.S.
RECOMMENDED RESEARCH PHASE IN HD
1) The data from preclinical experiments suggest that DCA has
therapeutic
potential in HD, particularly when administered early in the course of
the
disease. However, there are concerns about the definition of survival
used in these studies. In addition, DCA has no effects on protein
aggregation and therefore, with time, DCA will most likely lose clinical
benefits.
2) More information on dose-response is needed in preclinical HD
models to
make certain a suboptimal dose will not be used in clinical studies.
Alternatively, a phase II design linking imaging data (lactate
concentrations), clinical symptoms, and dose would help in the design
of
larger studies. This may help also avoid the difficulties in understanding
DCA pharmacokinetics and pharmacodynamic relationships in HD.
3) DCA is a fairly old drug and unfortunately, the data in adults with
long-term
use are limited. In addition, data from preclinical sources suggesting
tumor
promoting potential are of concern. Likewise, the potential of
neuropathy
is of concern and the relative risk of this side effect in patients receiving
DCA is unknown.
REFERENCES:
1. J Clin Pharmacol. 2003;43:683-91.
2. Trends in Neurosci 2000;23:298-304.
3. Neurology 1993;43:2689-95.
4. PNAS 2003;100:4879-84.
5. Ann Neurol. 2001;50:112-117.
6. Diabetologia 1980;19:109-13.
7. J Clin Pharmacol. 2003;43:683-91.
8. Br J Clin Pharmacol 1996;41:29-34.
9. J Pharmacol Exp Ther. 1996;279:686-93.
10. J Clin Pharmacol 2001;41:259-67.
11. J Inherit Metab Dis. 1986;9:244-52.
12. Pediatr Res. 1984;18:936-8.
13. J Cereb Blood Flow Metab. 1992;12:1030-8.
14. Metabolism. 1989;38:1124-44.
15. Toxicology. 2004;199:169-83.
A family practitioner and epidemiologist are prescribing
dichloracetate (DCA) in Canada
Category: Bioethics • Cancer • Clinical trials • Medicine
Posted on: May 29, 2007 9:23 AM, by Orac
It never seems to end, does it?
I'm talking about the hype and questionable practices revolving around
dichloroacetate
(DCA), the small molecule chemotherapeutic agent that targets the
Warburg effect, in
essence normalizing the metabolism of tumor cells and thereby
inhibiting their growth.
(See here and here for more details.) A report by Evangelos Michelakis
at the University of Alberta in Cancer Cell in January reported strong
antitumor activity against a wide variety of tumors in rat tumor models
resulted in a phenomenon ballooning out of control in a way that he
could never have imagined. Even though DCA has never been tested
in humans against cancer (although it has been tested against specific
metabolic diseases),
desperate cancer patients are seeking DCA from bootleg sources. This
hysteria, even
though there had not yet been any evidence that DCA had any
antitumor activity in
humans, was fueled mainly by the mystique applied to DCA because
(1) it's a small
molecule, orally available drug; (2) a novel and interesting mechanism
of activity; and, in
my mind most importantly, (3) big pharma was not very interested in
funding clinical trials
to test it against cancer because the drug itself was not patented,
leading to a lot of
Internet and blogospheric hype about the "cure for cancer" being
"suppressed" or
"ignored' by big pharma. I've written about this extensively since
January, most recently
about a week ago, and I had hoped to leave the topic alone for a while.
Then on Friday there was a new development. I managed to restrain
myself from writing
about it for the entire Memorial Day weekend, but that's about all I can
manage.
This time around, believe it or not, I won't be primarily writing about The
DCA Site, the
website run by a pesticide dealer named Jim Tassano, who hired a
chemist to make up
some home brew DCA and sell it from his other website BuyDCA.com
to dying cancer
patients. Many of these patients populate forums of TheDCASite.com
and tell stories that
are either wishful thinking, tell tales of side effects, or border on
downright quackery in
which patients are told that they must "alkalinize their blood" to make
DCA work.
Unfortunately, I will be discussing a couple of other "entrepreneurs"
who've decided to
enter the DCA fray:
EDMONTON - A private cancer centre in Toronto is selling itself as the
first in
Canada to prescribe a possibly poisonous chemical to patients, even
though
the compound hasn't been tested on humans and hasn't been
approved by
Health Canada.
In February, wife-and-husband team Drs. Humaira and Akbar Khan
heard how
a University of Alberta researcher used dichloroacetate (DCA) to
successfully
shrink tumours in rats without damaging healthy cells. Last month, they
offered
the water-soluble powder to cancer patients in Ontario who have
exhausted all
other treatments.
They did so despite dire warnings from Edmonton's Dr. Evangelos
Michelakis
that the chemical can be toxic and can cause imbalance, finger
numbness and
nerve damage.
"I agree with the warnings," said Humaira Khan, a public health
epidemiologist
who focuses on research in Toronto's Medicor Cancer Centres. The
clinic
opened one year ago and charges patients about $150 for one week's
supply
of DCA.
"But at the end of the day, it comes down to patients' rights. It comes to
the
patient's choice. That was the philosophy and the motivation because
patients
come to us and say, 'We know the risks. We understand it hasn't been
studied.
I don't have much to lose.' "
Khan said it's better for her clinic to supervise patients instead of
having them
self-medicate, as hundreds around the world are doing after hearing
about
Michelakis's research, published in the prestigious academic journal
Cancer Cell.
And why do Drs. Khan and Khan want to do this? Why, they're
humanitarians, of course:
The paper sparked worldwide frenzy, with patients buying questionable
DCA
from unproven sources and reporting their outcomes in Internet chat
rooms.
"We felt we needed to do it," Khan said.
Her husband, a family physician with 13 years experience in palliative
and
cancer care, is the clinic's medical director. "It didn't seem ethically right
to say
no," he said. "At the end of the day, even if we've saved one life, it's
worth it."
"Didn't seem ethically right to say no?" How about more like "didn't
seem financially right
to say no"? And, of course, the Khans have, as all alternative medical
practitioners do,
testimonials:
One woman in her 70s, who almost died from chemotherapy, had a
fourcentimetre
tumour on her shoulder that has disappeared.
One man could walk again after taking a strong dose of DCA. His
nausea and
severe pain also disappeared, even after he had to go off the treatment
when
he suffered side-effects. Some patients reported memory loss,
stomach upset
or tremors in their arms.
"Most of our patients have benefited from it," Humaira Khan said.
"It's hard to say how much of a benefit, but they are palliative patients
and
pretty much had nothing else to go on, so DCA has prolonged their life
and
given them a better quality of life. That gives us a lot of confidence."
I'd be very interested in knowing exactly on what evidence they base
this claim that DCA
has prolonged the lives of patients. For one thing, it's only been four
months since DCA hit the blogosphere, and that's not long enough to
determine whether DCA actually extends patient survival, even in a
well-designed clinical trial. In the unsupervised experimentation that's
going on right now, determining if DCA has actually prolonged the life
of a cancer patient is virtually impossible in such a short period of time.
It may even be close to impossible in any amount of time, because
determination of survival requires comparison of patients taking DCA to
a control group, plus enough time for differences in survival due to the
drug to manifest themselves. Unless DCA is truly a miracle drug,
which, alas, it is not (as I've documented below), such differences will
not manifest themselves in the two or three months since Jim Tassano,
for instance, started selling his home brew DCA. In any event, neither
of the Drs. Khan are oncologists. Dr. Akbar Khan is a family practitioner
who is clearly lacks the training to be prescribing chemotherapy and
monitoring the progress of cancer patients. Yes, he does have
experience in the palliative care of terminally ill cancer patients, but he
doesn't appear to have any experience in administering
chemotherapeutics. His wife, Dr. Humaira Khan, is a physician with an
MPH who's primarily an epidemiologist. The clinic also employs a
naturopath, a physiotherapist,
a counselor, a massage therapist, a dietitian, and a pharmacist, among
others, but
apparently not a single oncologist.
Despite the lack of oncologists, this clinic, Medicor, this clinic actually
offers the
antiangiogenic drug Avastin™. They also offer a whole lot of woo, such
as high dose
vitamin C therapy, among others. They also offer a test called
ChemoFit, which
supposedly tests the tumor cells of cancer patients and informs them
which chemotherapy
will and won't work. Using in vitro measurements of tumor cell
response to chemotherapy
is a line of research that has been fraught with problems and is far less
useful than
Medicor would have you believe. Indeed, I find it telling that, on the
ChemFit website,
several peer-reviewed papers supposedly supporting the efficacy of
using in vitro tumor
assay-guided therapy, but none that I could find in a search of PubMed
supporting the use
of the ChemoFit test itself. I have to say, I'd want some strong, specific
evidence about the
ChemoFit test itself and its ability to predict the chemosensitivity or
chemoresistance of a
patient's tumor before I would consider actually using it to guide
therapy, especially since
the test is not cheap, costing $2,500, and, contrary to claims by the
Khans, it is not
"standard practice south of the border."
But maybe Medicor really is being reasonable about DCA therapy. Let's
see what it has to
say about DCA:
Medicor believes that is essential for clinical trials to be conducted with
DCA as
a cancer treatment. However, we are aware of many patients who are
currently
self-medicating with DCA, or are being treated with DCA under
naturopathic
care alone. Medicor is committed to helping cancer patients who
request DCA
treatment to receive it in the safest possible way.
We respect the patient's right to choose their treatment once they know
all the
potential risks and benefits. All of our DCA patients understand that
DCA is not
yet scientifically proven as a cancer treatment.
There it is, not unexpectedly, the old "health freedom" gambit, beloved
of purveyors of
dubious "alternative therapies" and, apparently, just as useful to
doctors selling an
unproven drug outside the confines of a clinical trial. Of course, if they
really are collecting
hard data on patients taking an experimental anticancer
chemotherapeutic, it could be
argued that they are doing clinical research. If that's the case, then, i
wonder, are they
getting valid informed consent from these patients? Do they have a
valid protocol that
could produce actual useful information about whether DCA has an
anticancer effect
against specific cancers? If they do, then why should they be able to do
this sort of
research without oversight by an IRB, or whatever Canada's equivalent
is? None of the
employees of Medicor appears to have any relevant experience in
running cancer clinical
trials; given that, their supervision is probably only marginally better
than the lack of
supervision going on at The DCA Site.
Perhaps it's just the nasty advocate in evidence-based medicine in me,
but am I so off
base to suspect that this is nothing more than a case of some
alternative medicine
"entrepreneurs" seeing an opportunity to make a buck and going after
it? After all, when
Medicor opened a year ago, it was custom-designed to provide
"personalized care" (a.k.a.
woo) to cancer patients who can pay for it:
A clinic set to open today is offering what its operators call a privatemedicine
first in Canada -- intensive care, counseling and portable electronic
health
records specifically for fee-paying cancer patients.
The physician couple behind Medicor Cancer say they will provide the
kind of
comprehensive aid in dealing with the disease and the health care
system that
many cancer patients cannot get now.
Clients will have to pay at least $2,500, but the physicians say any
medically
necessary services will be charged to the medicare system, as legally
required.
It is the latest twist in the growing field of private health care, and the
Ontario
government says it will watch the clinic closely to ensure it abides by
the law.
The doctors opening Medicor say they would be happy to see the
province pay
for the sort of services they will offer. In the meantime, patients have a
right to
pay for them, they argue.
"If I'm sick and I want something, I don't want the government to tell me
what I
can spend my money on," said Dr. Humaira Kahn, a public-health
physician
and Medicor president. "If it's my life or the life of someone I love, I
want to be
able to control what treatment I want, where I want it, whether I pay for
it or
not."
"Is it fair that the system forces mediocrity on every citizen?" asked her
husband, Dr. Akbar Kahn, the clinic's medical director and a family
physician.
Medicor will not provide actual cancer treatment such as
chemotherapy,
radiation or surgery.
More "health freedom" blather. You know, whenever you hear someone
providing nonevidencebased treatments start invoking "health freedom," it's a pretty good
indication
that you should run, not walk out of their office, because almost
invariably what they really
want is freedom from accountability and the freedom from oversight. In
any case, it
appears that the Khans have changed their minds about actually
treating cancer or
providing chemotherapy. After all, Avastin is a chemotherapeutic agent.
DCA is a
chemotherapeutic agent, and an experimental one at that. In fact, one
has to wonder, if
the Khans aren't providing any real anticancer therapy to patients, what
exactly are they
doing that's worth $2,500 up front and a $1,200 monthly fee. Certainly
a visit with a family
practitioner, naturopath, and various other CAM practitioners, plus a
PDA on which they
can carry their personal medical record seems a bit thin gruel to be
charging this sort of
money for. True, they claim that patients can see them through the
Canadian medicare
system, but state in their brochure that their fee-based services are
intimately related to
their medicare-covered services to the point that "doctors can't
separate them."
I have to wonder if perhaps the alternative medicine business isn't
working out quite as
well as hoped, given how little service Medicor appears to provide for a
rather significant
fee. Maybe the Khans needed a new angle to attract patients. Thanks
to DCA, apparently
they've found it. Dr. Khan could do more for his patients going back to
the palliative care
that he used to provide before he thought of Medicore and especially
before he decided to
jump on the DCA bandwagon.
All Orac posts on DCA:
1. In which my words will be misinterpreted as "proof" that I am a
"pharma shill"
2. W ill donations fund dichloroacetate (DCA) clinical trials?
3. T oo fast to label others as "conspiracy-mongers"?
4. D ichloroacetate: One more time...
5. L aying the cluestick on DaveScot over dichloroacetate (DCA) and
cancer
6. A couple of more cluesticks on dichloroacetate (DCA) and cancer
7. W here to buy dichloroacetate (DCA)? Dichloroacetate suppliers,
even?
8. A n uninformative "experiment" on dichloroacetate
9. S lumming around The DCA Site (TheDCASite.com), appalled at
what I'm finding
10. S lumming around The DCA Site (TheDCASite.com), the finale (for
now)
11. I t's nice to be noticed
12. T he deadly deviousness of the cancer cell, or how dichloroacetate
(DCA) might fail
13. T he dichloroacetate (DCA) self-medication phenomenon hits the
mainstream
media
14. D ichloroacetate (DCA) and cancer: Magical thinking versus Tumor
Biology 101
15. C hecking in with The DCA Site
16. D ichloroacetate and The DCA Site: A low bar for "success"
17. D ichloroacetate (DCA): A scientist's worst nightmare?
18. D ichloroacetate and The DCA Site: A low bar for "success" (part 2)
19. " Clinical research" on dichloroacetate by TheDCASite.com: A
travesty of science
20. A family practitioner and epidemiologist are prescribing
dichloracetate (DCA) in
Canada
21. A n "arrogant medico" makes one last comment on dichloroacetate
(DCA)
Posts by fellow ScienceBlogger Abel Pharmboy:
1. T he dichloroacetate (DCA) cancer kerfuffle
2. W here to buy dichloroacetate...
3. L ocal look at dichloroacetate (DCA) hysteria
4. E dmonton pharmacist asked to stop selling dichloroacetate (DCA)
5. F our days, four dichloroacetate (DCA) newspaper articles
6. P erversion of good science
7. C BC's 'The Current' on dichloroacetate (DCA)
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Comments
I have a suggestion for the Khans, place your Medicor clinic at the
Creation Museum!
Posted by: S. Rivlin | May 29, 2007 10:24 AM
Here's an article by Professor Pedersen who is in the biochemistry
department at Johns
Hopkins - he's one of the people working on 3-bromopyruvate. You will
have to pay for the
whole article. This is an introductory article for an issue of Journal of
Bioenergetics and
Biomembranes discussing mitochondria-focused cancer treatments.
He mentions
dichloroacetate along with some others. I think it would make an
interesting topic for your
blog. From the tenor of the article, it seems to me that Pedersen is
frustrated with the
focus on signal transduction at the expense of cancer
energetics/metabolism.
I understand the need for clinical trials, but if someone points to a
deeper understanding
of what is going on inside the cancer cell, and they have a treatment
based on that
understanding, I for one would not expect to have to make do with
whatever is on offer
while we wait for years for clinical trials (obviously they're needed, but I
would expect trials
for drugs based on new understandings of cancer to be expedited).
http://www.ncbi.nlm.nih.gov/sites/entrez?
Db=pubmed&Cmd=ShowDetailView&TermToSe
arch=17404823
Posted by: Willis | May 29, 2007 12:09 PM
I wonder if all this DCA woo is having some kind of negative effect on
the research of Dr.
Evangelos Michelakis and others.
I know nothing about the researcher, but it sounds like he's alarmed at
all the weird woo
attention generated by his research. I doubt he welcomes this
attention. His motivations
for getting into cancer research are presumably some mix of scientific
curiosity and
medical altruism (plus, of course, a dash of happy egoism at the
prospect of becoming a
significant pioneer in an important field). I don't think the actions of a
few woos will
dissuade him or other serious researchers from continuing to look for
and test therapies
for illnesses.
But, I wonder if there are any graduate student researchers out there,
who have seen the
stupidity of the media frenzy and might divert their efforts to less
populist causes? I know I
don't want my publications associated with such stupidity; I'd rather be
completely ignored
by the foolish fringe than either lauded or condemned by them.
Posted by: TheBrummell | May 29, 2007 2:02 PM
Dear Orac
Looks like it's my turn to be embarrassed by an alleged professional
colleague.
How can complete a masters degree in public health epidemiology and
then think that
anecdotes are perfectly acceptable evidence?
The shame. The shame.
Posted by: Nat | May 29, 2007 7:27 PM
Excellent investigation of the Khans and their practices. I was
particularly taken by your
comment (emphasis mine):
You know, whenever you hear someone providing non-evidence-based
treatments start invoking "health freedom," it's a pretty good indication
that you
should run, not walk out of their office, because almost invariably what
they
really want is freedom from accountability and the freedom from
oversight.
Posted by: Abel Pharmboy | May 29, 2007 7:58 PM
This is your regular poster 'khan' assuring you that I be not them.
Posted by: khan | May 29, 2007 8:11 PM
The oncologists and drug companies want us to wait 15 years for a
treatment like
dibromopyruvate or dichloroacetate, fact is, they stop glycolysis in
some cancers, and a
half a million Americans are sent home to die, they are walking dead
from the time they
get their 30 day death sentence after being butchered and poisoned
and the damn
radiation, which one study says may actually kick start the cancer stem
cells. Stop being
cowards, when there is no hope for your patients, use the research,
use multiple
compounds to kill the cancer stem cells and the daughter cells. Shame
on you doctor.
Physician, heal thyself, and forget about the mansion payment and the
liability
insurance,and the yacht payment, and the Proche, and the mistress,
and the 3 x wives
alimony and
Posted by: Dale Biden | May 30, 2007 6:22 AM
Willis said: "I would expect trials for drugs based on new
understandings of cancer to be
expedited."
I'm a layperson, so I don't have answers, but I do have questions: Is
the way that DCA's
supposed to work in fact based on a "new" understanding of cancer? Is
this understanding
"newer" than the research behind other drugs currently in trial? And
why should trials
based on new information be expedited? Shouldn't it be trials of drugs
that are judged, on
the basis of available information, to have the best chance of success?
If not, why not?
Posted by: Jud | May 30, 2007 6:57 AM
This clinic sounds like it may be operating in contravention of the
Canada Health Act. Of
course, that doesn't mean a hill of beans if Do-Nothing Dalton
McGuinty's government
doesn't get off its collective asses and actually, oh, say, enforce the
Act... *mutter grump*
The "private clinic" is not the issue here; there are tons of private clinics
here. The
intimation of "private, for-profit clinic" bothers me, and if they've so
much as stuck one toe
over that line, I want them shut down with extreme prejudice and media
fanfare. I've had
about damn enough with the laissez-faire right-wing governments here
looking the other
way while con artists undermine the Canada Health Act, one minor
violation at a time.
Eventually, we're going to wind up with a de facto two-tier system, and
that contravenes
the Act, as well as rubbing my fur seriously the wrong way... It's too
dangerous a
precedent for my liking.
Posted by: Interrobang | May 31, 2007 3:48 AM
I have a question to all of you who think DCA should not be
administered without a trail. If
you were a terminal patient and your conventional doctor tells you that
you have anywhere
between 4 weeks to 12 weeks before the tumour in your throat chokes
you to death, and
another less known doctor tells you that there is some hope. What
would you do?
Now, assuming that you quite humanely took up the hopeful option and
outlived those
conventional life spans statistics. Who would be the biggest gainer. I
suppose it is only
You.
For heaven's sake stop talking about implementing outdated and
absurd laws and rules. If
you cannot help a cancer patient, atleast don't hurt. If DCA does not
work the way its
expected, bad for all of us. However, if it does - I think we will all see
some major firing in
the pharma black hole.
Posted by: Ken Anderson | July 23, 2007 7:30 AM
I read your report with interest. The being castle effect of the aneroben
fermentation is
well-known and understandable me. I read also all reports over dosage
and side effects.
Only one problem I have, as get I DCA.
Yours sincerely
Manfred Wendt
Posted by: Manfred wendt | August 6, 2007 2:05 PM
In which my words will be misinterpreted as "proof"
that I am a "pharma shill"
Category: Cancer • Clinical trials • Medicine • Politics
Posted on: January 22, 2007 10:01 AM, by Orac
I would have written about this one on Friday, except that Your Friday
Dose of Woo had to
be served up. (You did read last week's YFDoW, didn't you? It was a
particularly loopy bit
of woo, with a bad computer interface grafted on to it, to boot!) The
reason I wanted to
write about it is because the responses to this particular bit of news in
the blogosphere
grated on me, for reasons that will become apparent soon.
It's about a new cancer drug that I learned about from both fellow
ScienceBlogger Jonah
and readers who forwarded articles about it to me. If you believe some
other bloggers
(one of whom, Ezra Klein, who really should know better, even gave his
article the utterly
ridiculous title Objectively Pro-cancer), it sounds a lot like a "miracle
cure" that "they" don't
want you to know about, if you know what I mean. Yes, if you believe
blogs like Daily Kos
(especially the comments, many of which sound as though they come
from Kevin Trudeau
wannabes), it's one more bit of evidence of big pharma supposedly
"suppressing" yet
another cheap near-miraculous cure for cancer. Here's the story:
It sounds almost too good to be true: a cheap and simple drug that kills
almost
all cancers by switching off their "immortality". The drug,
dichloroacetate (DCA),
has already been used for years to treat rare metabolic disorders and
so is
known to be relatively safe.
It also has no patent, meaning it could be manufactured for a fraction of
the
cost of newly developed drugs.
Evangelos Michelakis of the University of Alberta in Edmonton,
Canada, and
his colleagues tested DCA on human cells cultured outside the body
and found
that it killed lung, breast and brain cancer cells, but not healthy cells.
Tumours
in rats deliberately infected with human cancer also shrank drastically
when
they were fed DCA-laced water for several weeks.
DCA attacks a unique feature of cancer cells: the fact that they make
their
energy throughout the main body of the cell, rather than in distinct
organelles
called mitochondria. This process, called glycolysis, is inefficient and
uses up
vast amounts of sugar.
Until now it had been assumed that cancer cells used glycolysis
because their
mitochondria were irreparably damaged. However, Michelakis's
experiments
prove this is not the case, because DCA reawakened the mitochondria
in
cancer cells. The cells then withered and died (Cancer Cell, DOI:
10.1016/j.ccr.2006.10.020).
Michelakis suggests that the switch to glycolysis as an energy source
occurs
when cells in the middle of an abnormal but benign lump don't get
enough
oxygen for their mitochondria to work properly (see diagram). In order
to
survive, they switch off their mitochondria and start producing energy
through
glycolysis.
I looked up the paper and read it, although not yet in as much depth as
I would like to. I
also have to point out that my memory of the finer points of glycolysis
and mitochondrial
aerobic energy production is a little shaky. Even so, whether it is the
cause of cancer (less
likely) or a consequence of the genetic derangements in cancer cells
(more likely), I have
to admit, targeting the Warburg effect is a way cool idea, and the
experiments are pretty
convincing in cell culture and in rats. Basically, this is an idea that goes
back 75 years or
more, namely that tumor cells are metabolically different than normal
cells in that they can
survive on the less efficient process of glycolysis, rather than having to
use aerobic
metabolism. It's been well known that many, if not most, tumors are
metabolically more
active than the normal tissues from which they arise. Indeed, increased
glucose
metabolism resulting in increased avidity in taking up glucose is the
entire basis of
positron emission tomography (PET scans). What's different is that
many cancer cells
continue to use glycolysis even when there is sufficient oxygen present
to switch on the
aerobic process of oxidative phosphorylation in noncancer cells, a
process that takes
place in tiny structures called mitochondria. The concept behind this
drug was to target
this difference, as the article explains:
Crucially, though, mitochondria do another job in cells: they activate
apoptosis,
the process by which abnormal cells self-destruct. When cells switch
mitochondria off, they become "immortal", outliving other cells in the
tumour
and so becoming dominant. Once reawakened by DCA, mitochondria
reactivate
apoptosis and order the abnormal cells to die.
"The results are intriguing because they point to a critical role that
mitochondria
play: they impart a unique trait to cancer cells that can be exploited for
cancer
therapy," says Dario Altieri, director of the University of Massachusetts
Cancer
Center in Worcester.
Indeed they appear to. In rats, tumor weights in the treated animals
were approximatel
60% lower than the tumors in the untreated control groups (my reading
of the data in the
paper, figure 8). The drug increase apoptosis, decreases proliferation,
and inhibits tumor
growth by acting on a critical enzyme that controls the switch between
aerobic and
anaerobic metabolism. The results of this study are likely to result in
new targeted
therapies aimed at mitochondria and, even better from an intellectual
and scientific
standpoint, rekindle the old argument about the metabolic changes in
cancer cells,
specifically: Which comes first, the metabolic or genetic derangements
in tumor cells?
So where do I put on my pharma shill hat? Patience, dear readers.
First, you must read
this from the investigators in a different news story:
It is expected there would be no problems securing funding to explore
a drug
that could shrink cancerous tumors and has no side-effects in humans,
but
University of Alberta researcher Evangelos Michelakis has hit a
stalemate with
the private sector who would normally fund such a venture. Michelakis'
drug is
none other than dichloroacetate (DCA), a drug which cannot be
patented and
costs pennies to make.
It's no wonder he can't secure the $400-600 million needed to conduct
human
trials with the medicine - the drug doesn't have the potential to make
enough
money.
Michelakis told reporters they will be applying to public agencies for
funding, as
pharmaceuticals are reluctant to pick up the drug.
At roughly $2 a dose, there isn't much chance to make a billion on the
cancer
treatment over the long term.
And now the responses from bloggers that irritated me. First, Daily
Kos:
It seems to good to be true. A cheap, effective cancer cure that
BigPharma
doesn't own. If further research proves effective in humans, it could be
the
answer to many peoples prayers. I've always thought something
simple, rather
than the current convoluted regimen of surgery, radiation and
chemicals would
be the cure for cancer.
Again, if proven effective, will we ever see it in use in this country? Will
patients
have to take 'DCA tours' to Canada for treatment?
Yes, you spotted some real ignorance right there when this Randular
character claimed
DCA is likely a "cure" for cancer and that the cure for cancer would
likely be "simple" (as if
cancer were one disease!), but what I'm more interested in is the spin
being put on this
story. Spin like this, from Digby:
And here I thought the pharmaceutical companies had to charge such
high
prices because of all the research they were doing. Seems without the
possibility of future revenue they can't be bothered. Of course, a cheap
cure for
cancer would cut into profits in so many ways, wouldn't it?
Yet another claim that this might be a "cure" for cancer and that
pharmaceutical
companies are being downright evil for not being immediately
interested in it. And here's a
guy blogging under the 'nym akaoni opining:
Big Pharma won't put up the dough to fund human research and
enable this
drug to come to market, there's no money in it. In fact, it wouldn't
surprise me to
discover that they had an interest in actively preventing the research so
as to
maintain demand for more expensive less effective drugs. This drug
looks to be
extremely promising, and I can't imagine that it won't get government
funding
for human trials, but that said, it doesn't pay to underestimate the
power of Big
Pharma...
Time for a reality check, and to lay down some Respectful Insolence™
on these guys,
who sound disturbingly like alties in many ways, so much so that
perhaps I should get
them Kevin Trudeau's contact information:
1. This drug has only been tested in cell culture and rats. Yes, the
results were promising
there, but that does not--I repeat, does not-- mean the results will
translate to humans. In
fact, most likely, they will not. Those of us who've been in the cancer
field a while know
that all too common are drugs that kill tumors in the Petrie dish and in
mice or rats but fail
to be nearly as impressive when tested in humans. In the 1980's it was
immunotherapy.
Man, some immunotherapies totally melted tumors away but, sadly,
didn't do nearly as
well in human trials. The same is true of antiangiogenic therapy,
pioneered by my surgical
and scientific hero Judah Folkman. In 1998, it was all over the media
(see pictures below)
that antiangiogenic therapy would be the "cure" (or at least would turn
cancer into a
manageable chronic disease). These drugs dramatically shrank tumors
in mice in two
major studies published in Cell and even induced tumor dormancy, as
described in
Nature. Guess what? They didn't do the same thing in humans. Don't
get me wrong,
antiangiogenic drugs have proven to be a useful addition to our
anticancer
armamentarium (not to mention an area of research interest for me).
However, remember
the saying: "If it sounds too good to be true, it probably is." Well, it
probably is in the case
of DCA.
2. Cancer is not a single disease. It is many diseases, and requires
many different
approaches. This drug showed activity against several cancers in vitro,
but there are
conventional chemotherapeutic drugs that also show activity against
lots of cancers. In
fact, the comparison to antiangiogenics becomes even more relevant
here, because
antiangiogenic drugs theoretically could act against any cancer. That's
because they
target normal cells lining blood vessels, which are needed to grow new
blood vessels to
supply tumors with blood and oxygen. These cells are very stable, and
much less prone to
the mutations that cancer cells undergo with such frequency that can
lead to resistance. In
contrast. DCA targets the tumor cells themselves, which are far more
likely to develop
resistance. Bloggers ranting against big pharma are showing magical
thinking in assuming
that this drug will work against nearly all tumors, given that at best only
60-90% of cancers
even demonstrate the Warburg effect. Indeed, remember how I
mentioned that in this
study DCA inhibited tumor growth by 60% or more in rats? Pretty
impressive, yes?
Compare this result to that obtained by angiostatin and endostatin,
both of which melted
experimental mouse tumors away to a few dormant cells. Neither were
anywhere as
impressive against human tumors. That doesn't mean antiangiogenics
aren't useful cancer
drugs (Bevicuzimab, in particular is quite effective at potentiating the
effect of
chemotherapy in colorectal cancer, for example), but they are useful in
the same way that
a number of chemotherapeutic agents are usefu: as an additional
weapon. They are not
miracle cures, and I'd be willing to bet that DCA isn't, either.
3. Here's where the worst misinformation is being spread about this
story. It will not cost
$600-800 million to do clinical trials to test this drug, yet certain
bloggers are acting as if
that much money will be needed to to see if this drug works in humans.
That's just a load
of crap. That figure refers to the total cost of bringing a new drug to
market, from idea to
research and development, to synthesis, to cell culture and animal
studies, to patent
applications, to all the clinical trials needed, to filing the regulatory
documentation, all of
which together can sometimes approach $1 billion. It does not refer to
the amount of
money required to do a clinical trial to see if there is efficacy in
humans, the logical next
step after what has been published thus far. In contrast to what's being
spewed into the
blogosphere, to run a preliminary trial to determine if there is evidence
of efficacy in
humans could be done for costs that are well within the means of an
investigator, if he's
willing to apply for grants. All he would require is a few hundred
thousand dollars for a
small preliminary trial (less ideal) or probably between $1 and $5
million for an
intermediate-sized Phase II study against one tumor (it's the Phase III
trials, with
thousands of patients, that cost tens of millions of dollars). Most NIH
R01 grants are
funded for between $1 and $2 million (mine's for a little more than $1.3
million over 5
years), and clinical R01 grants can be funded for up to a few million
dollars. Thus, this is
not by any means an unreasonable amount of money to be trying raise
to do the trial to
confirm in humans the preclinical data and, if the effect is as great in
humans as it is in
animals, should be adequate to detect the drug's promise. If that turns
out not to be a big
enough sample, then that would imply either that (1) this drug isn't
effective at all in
humans or (2) isn't any more effective than many other conventional
chemotherapeutics
that we already have. True, the funding climate sucks these days, but
Michelakis is funded
by grants from the Canadian Institutes for Health Research (CIHR),
Alberta Heritage
Foundation for Medical Research (AHFMR), and Canadian Foundation
for Innovation.
He's perfectly free to apply to the NIH and other organizations for
funding. Given such
compelling preclinical data, hewould stand a very good chance of being
funded.
4. Lastly, there was nothing stopping the investigator from patenting the
idea of using DCA
to treat cancer. I know someone who is doing just that for a use of a
drug that's FDAapproved
for treating something totally unrelated to cancer. indeed, I sincerely
hope that
Michelakis has, in fact, done this, because now that his results have
published it's too late;
the cat's out of the bag. If he had done that, he could then have
licensed his idea to
whatever pharmaceutical company was interested, and that
pharmaceutical company
would then have had a patent on the use of this drug to treat cancer. If
Michelakis hasn't
done that, well, I applaud his idealism (or curse his naďveté); he shot
himself in the foot
and made his idea less appealing to industry.
I'm not in any way saying that it isn't a problem that drug companies
show little or no
interest in potentially promising new compounds that they can't patent.
It can be a
problem, just as "orphan" drugs often don't make it to market because
there aren't enough
patients who could benefit from the them to make it profitable for drug
companies to invest
in developing and marketing them. In those cases, there are
government programs to
encourage the manufacture of these drugs. Perhaps a similar sort of
program should be in
place for situations like this or perhaps tax incentives to encourage
pharmaceutical
companies to manufacture drugs like this. Also, if this drug were truly
the miracle cure that
it's being represented as, believe me, pharmaceutical companies would
find a way to
make money off of it, either by trying to modify it to make it more
effective or adding a
molecule to target it more closely to the cancer cell.
What irritates me about the hysteria some bloggers are whipping up
over this is that it is at
its heart basically paranoid conspiracy mongering, and the reason this
story has any legs
at all is because people are inherently distrustful of big pharma. There
are some good
reasons for this and many reasons that boil down to little more than an
inherent distrust of
big corporations. Even now, for example, our old "friend" Dean Esmay
is likening big
pharma's disinterest in DCA to its disinterest in the use of high dose
vitamin C against
cancer. Never mind that Dean doesn't know what he is talking about
when it comes to the
alleged efficacy of vitamin C against cancer. Never mind that vitamin C
never in even
Linus Pauling's hands showed anywhere near the efficacy against
cacncer cells in vitro
and in animal models that DCA has. Never mind that even high dose
vitamin C has shown
in essence no evidence of efficacy against cancer in humans. Given
those facts, it's not
surprising that pharmaceutical companies aren't interested in vitamin C
as a treatment for
cancer, regardless of its cost or patentability.
What is most pernicious about the conspiracy-mongering stories being
spread about DCA
is that it builds false hope. People with cancer hear about this drug,
and they think there's
an amazing cure out there that's being withheld from them because of
the greed of big
pharma. Big pharma may show a lot of greed at various times, but
that's nonetheless a
very distorted version of the true situation. I agree with a a blogger
going under the 'nym of
Walnut (the only blogger I've yet found thus far who knows enough to
refrain from the
usual pharma bashing over this):
But this all plays into people's yen for conspiracy theories. Big Pharma
hates
us. And yes, I've indulged in this on my blog, I know, I know. Big
Pharma is bad.
But they also make money off of healing people.
You know what the worst part of this DCA flap is? It builds false hope.
And
when it comes to cancer, I think there are fewer things crueler than
building
false hope. It's sadism, as far as I'm concerned.
Yes, it's very easy and satisfying to take this promising preliminary
study and build from it
a conspiracy theory of evil big pharma "keeping cures from the people."
It's just not very
accurate and it adds too much heat and noise to the debate over the
real shortcomings in
our system of developing new drugs that make drug companies
reluctant to pursue
research on drugs that show promise but little profit potential. There
are real, systemic
problems with the financing of drug development and how drugs are
marketed, but
hyperbole and conspiracy theories don't address these problems; they
obscure them.
Look for DCA to be featured as yet another cure "they" don't want you
to know about in
Kevin Trudeau's next book.
ADDENDUM: Walnut has posted his critique on Daily Kos as well.
"pharma shill"
2. W ill donations fund dichloroacetate (DCA) clinical trials?
cancer
even?
what I'm finding
now)
(DCA) might fail
mainstream
media
Biology 101
travesty of science
Canada
(DCA)
5. Four days, four dichloroacetate (DCA) newspaper articles
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Comments
Hey, the Geiers are trying to patent their Lupron protocol for the bogus
treatment of
autism. Why can't the DCA protocol for cancer be patented? Hell, it
doesn't even have to
be proven to work - it just has to be novel.
Posted by: anonimouse | January 22, 2007 10:29 AM
Off topic, but congrats on hitting 1,000,000 served!
I might also add that a PubMed search for "efficacy xenograft" reveals
over 2,000
publications, a great many with experimental agents showing efficacy
similar to or better
than DCA.
The truth is that there are hundreds, if not thousands, of compounds
competing for
investment dollars of pockets big enough to develop these agents.
Hence, many agents,
inexpensive and not so, fall by the wayside because of cost barriers
and competition with
other worthy drug candidates.
Targeting the Warburg effect in cancer is a pretty cool idea that I'd like
to see tested
comprehensively, but there is just a hell of a lot of competition out
there, with most
decisions made by business/marketing folks, not always the docs and
scientists.
Posted by: Abel Pharmboy | January 22, 2007 10:51 AM
4. Lastly, there was nothing stopping the investigator from patenting the
idea of using
DCA to treat cancer. I know someone who is doing just that for a use of
a drug that's FDAapproved
for treating something totally unrelated to cancer.
Exactly. Just because the compound can be synthesized cheaply
doesn't mean the drug
has to be sold or dispensed for next to nothing. The use in human
patent will make it
attractive to drug companies just like several other antineoplastic
agents that are dirt
cheap to make.
Nitrogen mustard is still used to treat certain cancers and it's pretty
simple and cheap to
make.
Posted by: notmercury | January 22, 2007 11:47 AM
When you see a ridiculous title from some who should know better, you
should consider
that it might just be a joke...
Posted by: Ezra | January 22, 2007 11:58 AM
At this point, whenever I hear anyone use the phrase 'Big X', I mentally
substitute "the
devil". There is never a loss of meaning.
Posted by: dzd | January 22, 2007 12:01 PM
Anti-stroke drugs are another example of drugs that have shown
promise in in vitro
experiments and in animal models yet, were unsuccessful in human
clinical trials. In
regard to the involvement of energy metabolism in a disastrous disease
such as cancer,
your readers might be interested to know that there is evidence that the
mecahnism of
other diseases, notwithstanding their genetic basis, involves altered
energy metabolism
(Alzheimer's disease and Parkinsonism, to name two).
Posted by: S. Rivlin | January 22, 2007 12:33 PM
Orac,
When I read this newspaper story, I immediately wondered what was
stopping physicians
from prescribing this med off-label to their cancer patients. Since the
safety is already
known, is there anything stopping them? Besides the fact that they
would only obtain
anecdotal evidence on way or another, I guess.
Posted by: Jennifer | January 22, 2007 12:37 PM
Orac -- you, of course, are familiar with CRISP, the online search
application for
information on NIH-funded research, but it may be new to some of your
readers. I note
that NCI is funding 171 studies related to mitochondria and cancer; this
is hardly an
overlooked area! Interestingly, the only specific mentions of
dichloroacetate in all of NIH
are environmental health studies looking into the mechanisms of its
toxicity. No; it is not
"harmless" in the broadest sense.
Bottom line: NCI is very interested in studies of mitochondrial activity in
cancer, and it
looks like dichloroacetate is wide open -- so PIs, start your engines!
Posted by: jre | January 22, 2007 1:16 PM
If DCA anti-cancer action is mainly via its ability to activate a dormant
mitochondrial K+
channel, then, there are other compounds more specific and less toxic
than DCA that can
do the same. It would be interesting and probably important to compare
DCA anti-cancer
activity to one or more of these compounds to find out about their
efficacy and toxicity.
Posted by: S. Rivlin | January 22, 2007 1:55 PM
I was wondering why he was going private sector for funding when
there are public funds
available for these tests. At least, I thought there were. I'm at the
University of Calgary and
we hear all the time about our cancer research centre, but never really
in the context of a
private donor.
Maybe I just don't understand how medical testing works re: funding,
but if something is
promising and has press, the Alberta government will be all over it to
fund as it makes
them look rather good.
And this might be urban university legend only, but I was under the
impression that certain
sections of the university could not have corporate sponsorship, so that
might also
contribute to it.
I guess my mind just doesn't jump to "conspiracy!" fast enough.
Posted by: Jess | January 22, 2007 3:49 PM
ORAC:
thx for doing such an extensive review of the claims being made for
DCA. Hopefully it'll get
some play over there.
Posted by: boojieboy | January 22, 2007 4:23 PM
All this cost/profit talk has me thinking about the whole process again.
I've seen quotes of
hundreds of millions of dollars to get a new drug to market and I don't
doubt them. My
question is, is there anything we can do to make this better? We talk
endlessly about the
patent process and the number of patients and whether we're providing
enough profit
incentive to get the research done. What can we do on the other side,
though? If we could
lower the cost in the first place, we wouldn't have to do worry nearly
about generating
huge potential revenues through patents or large numbers of patients.
The revenue bar to
jump over and into the black would just be a lot lower. I want to make it
profitable to find a
cure for a rare but terrible disease, and it would be really nice if that
profitability could
come from a less expensive R&D cycle than from insanely high prices
for an already
unlucky few.
I'm really not familiar with the drug R&D industry at all, so I can't make
any suggestions. Is
there a way to (safely) change regulations? Can we do more to
subsidize research? We
subsidize domestic energy and food production in the name of national
security. How do
those subsidies compare to government support for homegrown
pharmaceutical
research? Anybody have any thoughts (he asks, knowing full well that
he'll probably be
buried in answers)?
Posted by: Troublesome Frog | January 22, 2007 4:37 PM
Guide to conspiracy theories regarding Big Pharma (or the US
government or some other
powerful 'bad guy') and Disease X:
1. Big Pharma suppresses the cure for Disease X because there is no
money in it for
them.
2. There is no Disease X; Big Pharma just wants us to think that there
is because there is
money in it for them.
3. There is a Disease X, but Big Pharma can't cure it; we'd never get it
in the first place if
we would just (eat raw foods, see a chiropractor etc).
4. Big Pharma created Disease X, either a) as a side effect of its 'cure'
for Disease Y or b)
deliberately, because it wants to make more money.
Posted by: Colugo | January 22, 2007 5:34 PM
If Ray thought of 'Big Pharma' instead of 'Stay-Puft Marshmallow Man'
in Ghostbusters,
what would they have had to fight?
Posted by: Lucas McCarty | January 22, 2007 6:15 PM
The kneejerk backlash against pharma companies really irritates me.
But then I would say
that wouldn't I. The pharma companies have had a huge impact on
quality of life, as well
as length of life. Just off the top of my head, antidepressants,
bisphosphonates,
antiepileptics and antiparkinsonism drug have had massive impacts. I
could go on and on.
Yes, 'Big Pharma' is a bit naughty from time to time. They introduce
isomers that have no
benefit over the parent compound (compare esomeprazole with
omeprazole), and they
play about with dosage forms: Tritace (ramipril) caps were withdrawn a
few months before
the patent ran out and tabs introduced, the same with Flomax
(tamsulosin). They bring out
modified release preparations that have no advantage over standard
products: Cardura
(doxazosin) and Cardura XL. But part of my job is to guide doctors
through this maze and
advise them on the most cost effective choice.
Colugo, conspiracy theory 2 does has a ring of truth to it. Of course the
condition actually
exists, but once a new drug is approved for it the marketing and
education machines go
into overdrive - I got stacks of information on restless legs syndrome
from GSK once
Mirapexin was approved for it.Theory 4 also has a ring of truth:
corticosteroid induced
osteoporosis and gastric ulceration anyone? 1 and 3 are total bollocks
though.
Posted by: ukcommunitypharmacist | January 22, 2007 6:20 PM
I hope I'm on record as solidly rejecting any and all conspiracy theories
claiming that
pharmaceutical companies have suppressed or are suppressing new
discoveries in order
to protect their profits.
With that out of the way, let me gently suggest that there is a reason
people find such
theories plausible: it's because pharmaceutical company executives
behave like
unprincipled scum. From the Wall Street Journal, 03 Jan. 2007, we
have an article titled
"Inside Abbott's Tactics to Protect AIDS Drug." Here's an excerpt:
At one point the executives debated removing Norvir pills from the U.S.
market
and selling the medicine only in a liquid formulation that one executive
admitted
tasted like vomit. The taste would discourage use of Norvir and
competitors'
drugs, the executives reasoned, and Abbott could claim it needed
Norvir pills
for a humanitarian effort in Africa. Another proposal was to stop selling
Norvir
altogether.
(Chart showing US sales of Kaletra climbing from $20M in 2000 to
$400M in 2005, with
$500M projected for 2006)
A third proposal carried the day: quintupling the price of Norvir. One
internal
document warned the move would make Abbott look like a "big, bad,
greedy
pharmaceutical company." But the executives expected a Norvir price
hike
would help Kaletra sales, and they bet any controversy would
eventually die
down.
They were right. Kaletra sales in the U.S. rose 10% over the next two
years.
Some objected that the price hike made it harder for patients who
needed drug
combinations pairing Norvir with non-Abbott pills to get their medicine.
After an
initial burst, the criticism faded, partly because Abbott exempted
government
health plans and AIDS drug-assistance programs from the Norvir price
increase.
Anyone else think there's more than Norvir that tastes like vomit here?
This is the central contradiction in the existing system for drug R&D.
On the one hand,
Abbott executives see sick people as a resource to be exploited by any
means, fair or foul.
On the other hand, without Kaletra, Norvir and the rest of the
pharmacopeia, there are a
lot of living people who would be dead.
Posted by: jre | January 22, 2007 6:44 PM
Just for clarification, does DCA stand for 'dichloroacetic acid', or for
'dichloroacetate',
implying that it is in a salt form, or perhaps an ester of the acid?
Posted by: Renee | January 22, 2007 6:45 PM
Troublesome Frog,
Well, we could stop doing so much of that pesky safety and efficacy
testing. Don't hold
your breath for that, though. The current push is in the other direction.
Recent criticism of
the FDA says it should be doing even more to ensure that rare but
serious side effects are
detected before approval.
But never fear, there's an easy solution. One that doesn't compromise
safety or efficacy
testing at all. We just need to get better at predicting which drugs are
worth testing in the
first place.
Right now, a drug that enters Phase 1 testing has something like a
10% chance of being
approved. Bump that up to 30% or 50% and drugs will get a lot
cheaper.
By the way, if you figure out how to do that, please PLEASE let me in
on the secret. Your
net worth will probably make Gates look middle class.
Humor aside, I don't know what else we can do. No doubt there are
some other changes
that would have modest benefits (although which changes is hotly
debated). But for
dramatic improvements, we either need to decrease the cost of getting
a successful drug
approved, or decrease the amount of money spent on unsuccessful
ones. IMO, of course.
Posted by: qetzal | January 22, 2007 6:54 PM
Points well taken. I may have been a bit hyperbolic in the title and
content of my post (Will
Cancer Panacea Go Unfunded?), but from the information from the
NewScientist.com
article, DCA did sound rather promising. Regardless, thank you for your
comments and
your post. It's easy to read something that reinforces preconceptions
and jump to
conclusions. I am not a doctor or a scientist, nor am I intimately familiar
with the process
of testing and bringing medications to market. From the content of the
article DCA didn't
sound as though it was going to be a profitable venture, and as such
may well have been
ignored by the pharmaceutical industry. You have informed me that I
may have been
incorrect on this count. I did however state that I believed that DCA
would receive public
funding, and if it is promising it certainly should.
That said, my point was not to make DCA out as a surefire cure for
Cancer, nor was it to
raise expectations of some miracle drug. Rather, it was to highlight
some of the problems
that exist today in the development and distribution of useful and
important drugs, and to
point out that profit motives for big corporations is not always a positive
force.
I will admit that I am rather reflexively distrustful of big corporations, not
because I think
they're inherently evil, but because they are largely amoral constructs,
whose purpose is
not to serve the public good, but rather to generate profit. This is
certainly not all bad; we
know that corporations help drive the economic engine of the US and
provide both goods
and services for public consumption. But they do not make decisions
based on what is
good for the nation or the world at large, instead they make decisions
to make money and
please their shareholders. In the case of pharmaceuticals this can have
some negative
consequences, including unprofitable drugs being ignored, drugs being
rushed to market
before adequate testing has taken place, or drugs being priced at too
high a level for
people who need them to afford them.
Finally, while I am not wholeheartedly opposed to alternative medicine,
I am by no means
an "altie." I place a great deal of importance on the development and
distribution of
medications which will serve the public. It is for this reason that the
article on DCA caught
my attention in the first place.
Posted by: akaoni | January 22, 2007 6:58 PM
Renee, they are the same.
Posted by: Robster | January 22, 2007 7:34 PM
Lucas McCarty: "If Ray thought of 'Big Pharma' instead of 'Stay-Puft
Marshmallow Man' in
Ghostbusters, what would they have had to fight?"
The familiar 'fat cat'?
http://www.newstarget.com/019956.html
As much as I enjoy making fun of conspiracy theorists, I have to admit
that there are small
elements of truth to some of the recycled chestnuts I listed, as UK
Community Pharmacist
points out.
Posted by: Colugo | January 23, 2007 1:47 AM
When you see a ridiculous title from some who should know better, you
should
consider that it might just be a joke...
It sure didn't sound like a joke to me, Ezra. Look at what your first
words were after your
ridiculous title "Objectively Pro-cancer":
Digby lights on the sort of story that makes my blood boil:
So the title's a "joke" but you're outraged enough to say that the story
"makes your blood
boil"? Sorry, I don't buy it. You said something stupid, and I called you
on it. Just admit it.
We all screw up every now and then and put our foots in our mouths,
so to speak.
Posted by: Orac | January 23, 2007 9:08 AM
Two points:
1) It's possible to criticize our current drug development system without
indulging in
conspiracy theories. I thought Matt XIV, a commenter on my post, really
nailed the
problem: "This is a major blindspot of the incentive structure of the
patent/FDA approval
system. If you can't patent the compound, it is often impossible to make
a profit on it after
the expenses of clinical trials. DCA as a compound may be cheap, but
DCA as a drug is
expensive, because it isn't considered a legit drug until it goes through
clinical trials, which
aren't cheap whether the money is recouped by charging monopoly
prices for the finished
product or collected via taxation." I don't expect pharm companies to
fund drugs that aren't
lucrative or potentially profitable. However, unless the system is fixed,
promising
treatments (like DCA) will end up being ignored because they are too
cheap. That seems
nonsensical. We shouldn't make it more difficult to fund clinical trials for
less expensive
medicine.
2) It's possible to talk about possible cancer drugs that seem promising
in rodents without
engaging in a celebration of "woo," as you like to call it. As I noted in
my blog post,
"Chances are, of course, that DCA won't turn out be a miracle cure.
(This isn't the first
anti-cancer drug to look great in the lab, and it won't be the last.)" If you
want to have a
serious discussion about the state of research and drug development
then I suggest you
stop labeling all who disagree with you as conspiracy mongers who
peddle false hope.
Posted by: Jonah | January 23, 2007 12:29 PM
Thanks for doing this post. I've had something very similar in the works
for a few days
now, but Movable Type troubles behind the scenes have kept me from
posting.
As someone who has been earning a living doing oncology drug
discovery, I can tell you
that this is a very interesting idea - and is nothing more than that until it
gets into humans.
Which, as you point out, it most certainly can, considering it's already
used in humans for
other indications. More when I can get it onto my site!
Posted by: Derek Lowe | January 23, 2007 1:17 PM
Thanks for posting a very interesting and informative article! I don't
think "Big Pharma"
"suppresses" cures, but the disconnect between the social benefit
produced by cheap
treatments, vaccines, etc., in the form of reduced mortality and
morbidity, reductions in
lost economic productivity, etc., and the relatively low levels of profit
derived from their
sale proves that we cannot rely exclusively on the private market to
develop new
treatment and therapy strategies.
Posted by: knutsondc | January 23, 2007 7:31 PM
Jonah:
Three points (because when you're as long-winded as Orac always is,
two is never
enough):
1. I didn't once use the word "woo" in this post. I did, however, point out
that some of the
bloggers ranting against "big pharma" on this on this were clearly
exhibiting magical
thinking that is bordering on altie-like, if not already there, Read the
specific posts that I
linked to (particularly Digby and akaoni) if you don't believe me. I stand
by my
characterization. And, no, I am not labeling "all who disagree" as
"conspiracy mongers
peddling false hope" and tried to be specific in picking my targets,
restricting my
"insolence" to some egregious examples of specific bloggers who are
guilty of that. In
addition, my comments were so vociferous because I really believe this
sort of thing is
harmful. Again, I stand by everything I wrote in this post.
2. You were pointedly not one of the bloggers mentioned as
demonstrating that magical
thinking, although I did take you to task in the comments of your own
blog for repeating
the half-accurate factoid that it would take "hundreds of million" dollars
to test this drug in
humans. At the risk of irking you again, though, it is hard not to remind
you that you did
entitle your post "When promising cures are ignored" (emphasis mine),
not "When
promising drugs are ignored." Whether that was just sloppy on your
part or done in order
to tweak, it did catch my attention. In any case, DCA is almost certainly
not a "cure" and is
certainly not being ignored; it's getting more attention at the moment
than just about any
anticancer compound I can think of. In any case, I only mentioned that I
had learned of the
story through you (and some readers) at the very beginning of my post
in order to send a
little traffic over to a fellow ScienceBlogger. You seem to have taken
this a bit more
personally than is warranted.
3. Nowhere did I say that it isn't possible to talk about promising cancer
drugs that work in
rodents without engaging in a "celebration of woo" (a term, again, that I
did not use in my
post or in either of the two comments that I left on your blog). In fact,
my main objection to
the sort of spin being put on the DCA story by the Kos diarist, Digby, et
al is that it is
unproductive and muddies up the very discussion you want to have
about problems
getting pharmaceutical companies interested in drugs that aren't
patented and therefore
have little profit potential. In short, it generates a lot of heat and no
light. Quoth I:
I'm not in any way saying that it isn't a problem that drug companies
show little
or no interest in potentially promising new compounds that they can't
patent. It
can be a problem, just as "orphan" drugs often don't make it to market
because
there aren't enough patients who could benefit from the them to make it
profitable for drug companies to invest in developing and marketing
them.
See? I acknowledge that it there is a problem with the incentive
structure for developing
new drugs. And here's me explaining why the blogosphere's take on
this story irritated me
so much:
What irritates me about the hysteria some bloggers are whipping up
over this is
that it is at its heart basically paranoid conspiracy mongering, and the
reason
this story has any legs at all is because people are inherently distrustful
of big
pharma. There are some good reasons for this and many reasons that
boil
down to little more than an inherent distrust of big corporations.
[...]
What is most pernicious about the conspiracy-mongering stories being
spread
about DCA is that it builds false hope. People with cancer hear about
this drug,
and they think there's an amazing cure out there that's being withheld
from
them because of the greed of big pharma. That's a very distorted
version of the
true situation.
[...]
Yes, it's very easy and satisfying to take this promising preliminary
study and
build from it a conspiracy theory of evil big pharma "keeping cures from
the
people." It's just not very accurate and it adds too much heat and noise
to the
debate over the real shortcomings in our system of developing new
drugs that
make drug companies reluctant to pursue research on drugs that show
promise
but little profit potential.
I realize that I may be a tad on the blunt side sometimes, but I think
you're over-reacting.
Derek:
Thanks for chiming in. It's good to hear from someone actually in the
business. (I'm in
academia.)
"Read the specific posts that I linked to (particularly Digby and akaoni)
if you don't believe
me. I stand by my characterization."
Orac, I can't agree with you here , particularly on your slagging off of
Ezra.
Proving a drug's safety and efficacy takes $$$. Not as much as the
numbers the pharma
industry throws around (which come from two academics at Tufts:
basically, they're are
economic costs [i.e. including expected return on investment] counting
in discovery
overhead and failures, not accounting costs for one specific drug). A
pharma company
CFO is *required* by fiduciary duty to get a return on capital for their
shareholders. They
can't get the requireed return on investment. It isn't a question of
individual morality of the
CEO or CFO or any conspiracy here.
Now, it's not out of the question the non-patentability could be worked
around given that a
pharma company, with smart medicinal chemists like Derek, could
derivatize DCA to both
improve it and make it patentable (a methyl group here, a phenyl group
there, and soon
you're talking real money). Or a synergistic patentable co-formulation
could be found,
analogous to the augmentin antibiotic.
But there is a structural problem with developing non-patentable
molecules as drugs, and
with developing drugs for diseases with small patient pools ('orphan
drug' incentives aren't
sufficient). A possible solution might be to have a non-profit fund the
drug, or have the
government have [smaller] firms bid on a contract to develop the drug,
using CRO's for the
clinical trials and relying on the generic drug makers to pick it up once it
went through
Phase III. We do have potential policy levers to solve this problem
(although the DHHS's
experience sponsoring vaccine development in Project BioShield
doesn't give one hope
on its effective execution.)
Posted by: No Longer a Urinated State of America | January 24, 2007
11:29 AM
Orac, you write: Lastly, there was nothing stopping the investigator
from patenting the
idea of using DCA to treat cancer. I know someone who is doing just
that for a use of a
drug that's FDA-approved for treating something totally unrelated to
cancer.
I'm confused by this, and would like you to expand on it... My
understanding of the patent
system is that you can patent an inventions, but you can't patent an
"idea". To give an
example from the high-tech world, if you have a patent on an algorithm,
you can't restrict
people from describing that algorithm, but you can stop them from
selling computer
software that uses that algorithm with a license from you.
So how is a patent on the "idea of using DCA to treat cancer" supposed
to work? As long
as it's legal to sell DCA without a license from a patent holder, and it's
legal for doctors to
prescribe it, how can a patent holder get royalties when a doctor
prescribes DCA for a
patient with cancer?
What I can imagine is getting a patent on a particular treatment that
has DCA as part of
the treatment... Maybe the researcher finds that you need to use it with
a different drug to
be safe and effective, and patents the combination. If one then takes
this combination
through clinical trials, only the combination would be available by
prescription, and the
inventors would be assured of their royalties.
But my understanding of the patent system is that treating new
conditions with old drugs is
not protectable with a patent. Am I wrong on this?
Posted by: Alex R | January 24, 2007 11:32 AM
The researchers did, in fact, file a 'use' patent:
more on DCA
Posted by: Peter K | January 24, 2007 1:36 PM
Today there are thousands of pets dying from CANCER! Let's try DCA
on them in the
hope that they may live. This could speed up the approval process for
human trials.
Posted by: Bill Oldknow | January 26, 2007 4:00 PM
Bill Oldknow, I agree. That's actually the reason I'm browsing these
sites to get a fuller
picture of the efficacy of this DCA treatment for possibly my dog
suffering from cancer.
DCA seems like a safe treatment as an alternative to chemotherapy.
However, I'm going to try to find out more. This blog doesn't explain
much with vague
unscientific negatives such as the following statements:
- "However, remember the saying: "If it sounds too good to be true, it
probably is." Well, it
probably is in the case of DCA."
- "They are not miracle cures, and I'd be willing to bet that DCA isn't,
either."
What role does "probably" or "bet[ting]" play in an objective blog? None
whatsoever,
unless the article is biased. It's really deceptive to claim to be a science
blog ... However,
as a reader, I do appreciate the effort in providing an alternative
perspective, even if it is
biased, as it provides me another data point.
As for the defense of pharmaceutical corporations ... I have personally
stayed away from
all forms of drugs for the last decade or so with no ill effects. I think it is
more than
possible to avoid these drugs if a healthy lifestyle is substituted. These
pharma drugs are
for profit NOT necessarily for health since there are inexpensive, safer
alternatives
available. These pharma drugs are probabilistic ventures into our
health; seems like more
a risk than its worth. However, it probably provides a job support
structure for all those NIH
research applicants out there and provides an appearance of validity
for the
pharmaceutical corporations.
Posted by: Arun | January 28, 2007 11:47 AM
Arun,
Give me a break. You cherry picked two statements from a very long
post and then
dismissed them as "not scientific." In actuality I explained exactly why
caution is
warranted, after summarizing the results of the reported research and
how DCA is thought
to function and correcting misinformation that's being spread about how
much it would
cost to do the next clinical trial necessary to demonstrate DCA's
efficacy. Long is the list of
drugs that seemed to be almost miraculous cancer cures in mice but
failed in humans. It is
possible that DCA may be just as miraculous as it's being billed as.
However, based on
my experience doing cancer research and studying antiangiogenic
compounds, I tell you
that it's far more likely than not that it is no miracle cure.
As for your comment that big pharma "provides a job support structure
for all those NIH
research applicants out there and provides an appearance of validity
for the
pharmaceutical corporations," well, that's exactly the sort of conspiracymongering I was
talking about in my post. By the way, perhaps you could "educate" me
as to the
"inexpensive, safer alternatives available" to treat cancer. DCA may
turn out to be just
such a thing, but I'm unaware of any cheap "alternatives" that are as
efficacious as the
combinations of surgery, chemotherapy, and radiation. I (and pretty
much every doctor
that deals with cancer) wish there were such "alternatives." In any
case, here's your
chance to shine and teach us all a lesson.
Posted by: Orac | January 28, 2007 12:59 PM
Peter K, I checked the official U.S. patent office website, the For
Dummies website, and
other websites for more information and found out that the U.S. has 3
basic patent types:
utility, design and plant. The most common kind and the kind which I
think applies to drugs
is the utility patent. SCOTUS has also, apparently, extended patents in
other ways, to
include other (non-plant) living organisms.
I couldn't find any information, even on Canada's patent website, on
"use patents."
Perhaps they're known by a different name or perhaps it's because
searching with "use"
returns a million unrelated results.
Could someone in the know clarify this? Also, like Alex R questioned,
how could
something like this be enforced regardless of jurisdiction beyond
perhaps advertising?
FYI, I think the "no ideas" thing only applies to copyrights, not patents.
Posted by: Nathan J. Yoder | January 30, 2007 2:45 AM
I have a Google Alerts set for DCA and this is the best and most
complete series of blog
posts that I have seen.
In the face of hopig for miracles, it is important to be realistic in ones
expectations.
I am not sure what patents they might or might not have. None are
evident at
http://patents1.ic.gc.ca/intro-e.html
I was curious about one thing. I have seen DCA refered to as Sodium
Dichloroacete also.
Is this the same as what is refered to in the article or is it a variation?
Phil
Posted by: Phil Monk | January 30, 2007 10:45 AM
Would like to point out the chemotherapeutic drug DFMO which acts as
a depressor of the
ODC enzyme,which has a key role in the Synthesis process of
Polyamine molecules.
The drug showed very promising results at the the in vitro stage but did
poorly at the
human experimental stage. big disappointment.
I would also like to suggest that you write a post about the polyamines
molecules. this
important molecules receive little if any exposure to the public
eye(though I'm sure most of
the public couldn't care less).
Posted by: areh | January 30, 2007 11:22 AM
It's pretty easy to believe that money is more important than human
lives to many powerful
entities.
If we pretended for a moment that we lived in a world without Cancer
and AIDS, the
money that would be lost would certainly be in the billions, a number
that would be out of
touch with the average individual.
The sad part is that while no cures have been found that I know of,
there are scientists
that have created much better treatments than chemotherapy with
exponentially higher
success rates, keeping cancer in remission while giving a better quality
of life - and you'll
never hear about these treatments.
There have been doctors and scientists in jail under claims of fraud and
violating various
FDA laws - families destroyed and lives lost - according to law and a
justice system that
doesn't care if the treatment "works", only if it was processed or sold
according to rules set
up by the FDA.
What if these treatments were natural and couldn't be patented by a
drug company?
Truth is stranger than fiction.
Posted by: Mike | January 30, 2007 11:49 AM
Peter and Nathan,
A "use" patent loosely refers to a utility patent with claims drawn either
to a new use for a
compound (e.g., "Use of DCA for curing cancer.")or to a method
employing the compound
(e.g., "A method of curing cancer comprising administering a
therapeutically effective dose
of DCA."). Generally, using a new compound in an old method may be
patentable. You
may not have found teh applications because patent applications are
not published until
18 months after they were filed.
Posted by: Alan | January 30, 2007 1:01 PM
Mike stated: The sad part is that while no cures have been found that I
know of, there are
scientists that have created much better treatments than chemotherapy
with exponentially
higher success rates, keeping cancer in remission while giving a better
quality of life - and
you'll never hear about these treatments.
So, do you have any references where I can find documentation of the
exponentially
higher success rates for these treatments?
Posted by: tonyl | January 30, 2007 3:59 PM
there are
scientists that have created much better treatments than chemotherapy
with
exponentially higher success rates, keeping cancer in remission while
giving a
better quality of life - and you'll never hear about these treatments.
Do tell.
I agree with tonyl: Educate us about these treatments with
"exponentially higher success
rates." Oh, and intravenous vitamin C doesn't count, nor does Laetrile;
neither has an
"exponentially higher success rate" in treating cancer. In fact, neither of
them does much
of anything against cancer.
Re the type of patent called by the name 'utility' This is the legal term for what is commonly called a 'use' patent. There
are 3 main things
which must be satisfied for a use patent to be granted:
1. The item/substance/thing must have some practical application, and
have been
reduced to practice, that is shown by some testing to be useful in this
application.*
2. It must be a novel idea, that is a new idea to use the
thing/substance/item for this
practical application.
3. The novel idea to use the item/substance/thing in this practical
application must be
unobvious to one skilled in the art of that particular field.
Which means, in this case of DCA, that this substance has the practical
application of
treating cancer, that it has been shown by some testing that it has utility
in treating cancer
(even if it's in vitro), that using this substance to treat cancer is a new
idea, and that it
would be unobvious to persons in fields like medical/pharmaceutical
research that this
substance would/could be useful in treating cancer.
Patent-wise, it doesn't matter that DCA is a substance that's been
around a long time, that
it's an organic acid that probably has use in organic synthesis, etc.
If there had already been any scientific papers out there by prior
researchers who have
worked with DCA and shown that it does/might have some cancerfighting properties, than
this would keep the Alberta researchers from being able to file for a US
patent. And now
that the Alberta researchers have announced publicly that DCA has
promise as a cancer
drug, this would keep a pharmaceutical company from being able to
patent this substance
for treating cancer.
If the Alberta researchers had checked to see that there were no prior
publications or
public presentations on DCA and cancer, then they could have filed a
patent application (it
can take 1-3 years for the actual patent to be granted). Only after the
application could
they have gone public with their findings. As it is, the cat is out of the
bag, so to speak.
*You cannot patent a new, practical application of a
thing/item/substance without showing
by some sort of testing that it has practical value. A person can't just
say, "I'm sure that
DCA can fight cancer in vitro. Now I'm going to file for a patent!" The
patent office will ask
for proof (i.e., tests of some sort) that DCA actually has a negative
effect on cancer cells.
Getting a patent is not the same as getting FDA approval to market a
drug for a particular
illness/condition. The patent office does not require clinical trials.
However, without getting
FDA approval, the drug company can't sell the drug. What patents do is
protect a
company from having their competitors sell the same
substance/item/thing for the
specified practical use, for a specified number of years.
In those blogs and stories on DCA, DCA is referred to as a drug well
tested and used as a
therapy for other (unspecified as fas as I've seen) conditions. Is this
true?
If so, what's to stop me from getting this from my doctor regardless of
trials or patents?
How would a patent for a drug already in use for other condition(s) be
applied to its use for
cancer(s)?
Thanks.
Posted by: Luckynumberxiii | January 30, 2007 5:46 PM
there are scientists
that have created much better treatments than chemotherapy with
exponentially higher
success rates, keeping cancer in remission while giving a better quality
of life - and you'll
never hear about these treatments.
Kevin Trudeau, ladies and gentlemen. He'll be on your 2 a.m.
informercial all week. Be
sure to buy two copies of "Natural Crap That Doctors Don't Know About
Because It's
Bogus" and receive a free membership to his equally bogus "Natural
Crap" website.
There have been doctors and scientists in jail under claims of fraud and
violating various
FDA laws - families destroyed and lives lost - according to law and a
justice system that
doesn't care if the treatment "works", only if it was processed or sold
according to rules
set up by the FDA.
Kevin, let me make this clear. People who got busted by the FDA for
selling bogus cancer
drugs were busted because their drugs were bogus. If the Hoxsey
therapy or laetrile
actually worked on cancer, the drug companies would've found a way
to make money off
it. But they don't work, so they can't. You don't get to violate the law
because you think
your magic drug works, and you don't get to circumvent the standard of
care in medicine
because it's keeping you from your profitable work.
Posted by: anonimouse | January 30, 2007 5:50 PM
Why do you even bother arguing with him? As much as he
concerned,you may very well
be a part of the conspiracy :P
Posted by: areh | January 30, 2007 5:56 PM
Isn't it possible to develop this using an open/free source approach?
Like in Linux, Oscar (the car) or Free Beer, for instance.
Posted by: Anonymous | January 30, 2007 7:37 PM
This looks like the patent (application):
http://www.wipo.int/pctdb/en/ia.jsp?IA=CA2006/000548
Its presumed "toxicity is predicated mainly on data obtained in inbred
rodent strains
administered DCA at doses thousands of times higher than those to
which humans are
usually
exposed"
(http://www.ehponline.org/members/1998/Suppl-4/989994stacpoole/stacpoole-full.html
Off label use is a tricky thing. There needs to be some kind of general
consensus before it
would be commonly used for something it is not approved for.
Pharmaceutical marketers seek out early adopters when they launch a
new drug. These
are usually Key Opinion Leaders (KOLs) who set the trail for others to
follow. Without that
push and pull, the early adopters need to take the lead themselves.
In a case like this, it will usually follow the publication of (case) studies
that show benefit. It
could also be that some KOLs starting using it and word of mouth
spreads. Lord knows
that there are likely enough people who would be willing to take a
chance.
The thought in the back of the minds of those who follow would be that
if ever brought to
task, they could point to some body of understanding that would
remove at least some of
their liability should an adverse event occur.
Posted by: Phil Monk | January 30, 2007 10:12 PM
Renee, thank you for the response. Are you a lawyer? I ask not out of
insult, but because
issues like this tend to be complicated (in terms of understanding all
the specific
precedent--not just word of law) and generalized descriptions don't help
much without the
guidance of an expert who knows how it really applies in a specific
case. I am curious to
see such a patent is/would be even valid in the first place, but mostly
I'm curious about the
enforcement aspect (ala off-label use).
I tried asking in one particular forum with lawyers, but they didn't seem
to know much
about it. I'm too lazy, but someone could perhaps try asking on
lawyers.com.
The main thing about this that makes me doubt the patentability is that
it would seem
virtually impossible to enforce (and IIRC continued enforcement is a
criteria to keep a
patent valid), so even if the courts would uphold it initially, it would
crumble if they didn't do
anything to thwart violations.
Phil Monk--I don't know about Canada, but in the U.S. a doctor is not
legally required to
have any kind of consensus to prescribe for an off label use. The only
regulation I know of
in this regard is that the pharmaceutical company can't
advertise/endorse a new use
without FDA approval.
This is why I can't conceive of how it would be enforced, especially
because a doctor
doesn't even need to specify on the prescription what it's being used to
treat.
So what does prevent a U.S. doctor from simply prescribing it off-label?
Hugs and cinnamon buns,
Nathan
Posted by: Nathan J. Yoder | January 30, 2007 11:08 PM
Orac,
I appreciated your comments on the DCA paper, and I understand your
skepticism, but
there is no reason for including these unscientific statements in an
otherwise informative
article. Maybe you have to deal with crackpots on a daily basis, but I
still don't agree with
dismissing an idea without full understanding (I consider that
unscientific). Personally, I
don't care about all the false miracle drug cases out there; but I do care
about DCA since
it seems scientifically plausible.
As for my statement regarding safer alternatives, it is not for cancer
(that's too late). It's
regarding the obvious alternative of leading a healthy lifestyle. I feel
there's far more
emphasis on curing rather than prevention, and I believe that has more
to do with profit.
For me it seems obvious. Long time ago, I used to conduct
microbiology research as an
undergrad on the natural mechanisms of fever, but apparently this area
wasn't very well
funded because it doesn't provide an incentive to the profitable industry
or to NIH. I ended
up switching my major to physics which I found to be far more
objective.
It's ridiculous how NIH is driven by industry. Other government
agencies suffer from the
same problem, so it's not just NIH. Far too often do I hear people either
selling their own
research or disparaging other people's research; it seems like a big
marketing game ...
maybe I'm wrong ... I doubt it.
Posted by: Arun | January 30, 2007 11:11 PM
Jumping Jesus on a pogo stick!
"Dismissing the idea without understanding it"? I read the article and
thought the science
as highly interesting--and said so! That's hardly "dismissing" the work
in the paper. I
merely put things in context and pointed out that DCA was not a cure
and probably won't
do nearly as well in humans. That's hardly "unscientific," given the
relatively low rate of
drugs that work in mice and work as well in humans. That's hardly
"unscientific" or
"unskeptical."
What I was "dismissing" was the misinformation and conspiracymongering, and I
explained exactly why I considered it such. As for whether there is
insufficient emphasis
on prevention over cure, that is mostly irrelevant to the discussion of
this particular drug,
which is intended as a treatment/cure.
Off label use is the same in Canada as it is in the US.
But how does Dr. Joseph Average use DCA? At what dose? For how
long; only as long as
the chemo, or should it continue after the chemo; or only after the
chemo ends? Should it
be used daily or pulsed? One could go on ad infinitum.
The point is that there needs to be understanding among the average
treatment
community on how to use it based upon the experiences of the leaders
of the community.
Posted by: Phil Monk | January 30, 2007 11:31 PM
It's totally off-topic, but as a former PET researcher, I just had one point
of clarification
based on your comment:
"Indeed, increased glucose metabolism resulting in increased avidity in
taking up glucose
is the entire basis of positron emission tomography (PET scans)."
I have to disagree. The basis of PET is the labeling of interesting
compounds with positron
emitters and the ability to measure accurately, in 2 or 3D, the source of
the photons
emitted from a positron annihilation event.
The connection between glucose metabolism and glucose uptake is,
indeed, the basis of
18-Fluorine-2-Deoxyglucose (FDG) pet imaging of glucose metabolism
and can delineate
high-metabolism cancerous areas. I believe that 15-O water can also
be useful as it maps
blood flood and shows highly vascularized tumors (c.f. that part about
angiogenesis and
tumors).
So yes, PET is interesting for cancer studies, but it has uses way
beyond cancer (e.g.
dopamine D2 ligands such as 11C-raclopride) and its "basis" is
certainly not metabolic
imaging, even if that was the first application. Its basis is some fairly
simply underlying
radiochemistry and computer algorithms that make it work.
Keep fighting for the truth!
Posted by: Neil | January 30, 2007 11:58 PM
Alright, alright, I should have said the "basis for the ability of PET
scanning to detect
cancer" or something like that. ;-)
Anonimouse,
I don't know much about Kevin Troudeau - I only know those things that
myself and my
family have experienced first hand.
Why is it so easy to believe that companies profit from war and
destruction but so hard to
believe that people are kept from being as well as they could be for
others' financial
benefit?
Posted by: Mike | January 31, 2007 1:41 AM
others' financial
benefit?
Because businessmen are quite smart; keeping secrets like that are
HARD. Much harder
than you seem to think. Other corporations, other large businesses,
other smaller
businesses can put pieces together and figure it out.
And from the other end, it's usually more expensive to keep such things
secret (at the
level they need to be in order to to keep the conspiracy effective) and
generally isn't worth
the problem.
Posted by: gwangung | January 31, 2007 2:33 AM
In the US you can patent an invention for up to a year after it has been
publicly divulged.
This is not true in the rest of the world, with possibly a very few
exceptions (Phillipines?).
Posted by: bob. | January 31, 2007 3:34 AM
destruction but
so hard to believe that people are kept from being as well as they could
be for
others' financial benefit?
Maybe because I have a much easier time understanding how a
Halliburton executive
could keep his son out of Iraq than how a Pfizer executive could keep
his daughter from
getting cancer.
Remember that there are lots of non-Big-Pharma major economic
players who would
seriously benefit from a major reduction in the cost of medical care.
Their collective
economic clout greatly exceeds that of Big Pharma. A good conspiracy
theory doesn't
require most of its wealth-mad participants to act against their own
economic interests.
Posted by: ebohlman | January 31, 2007 5:15 AM
It's the insurance companies who are paying those high prices for
drugs. The billion
dollar organizations have enough clout to get testing done. They could
fund it themselves.
Just think of how DCA could, if it turns out to be what we all hope it is,
reduce medical
costs and keep people alive longer so they'll pay medical premiums
longer. This is a
potential windfall for the insurers that they will not let go by.
Posted by: Warren | January 31, 2007 6:44 AM
1) Read the book "The Hidden Story Of cancer by Brian Peskin, 2006.
2) Big Pharma is good and bad. Now if they would stop making some
"bandaid" drugs and
get down to the root cause of the problem they'll find that they can't
change it because the
root problem is in our poor food supply and in the 50,000+ chemicals
created that pollute
us.
3) Many answers are simple but sometimes the eggheads can't help
but trip over their IQs
looking for their brilliance in a solution.
4) Big Media won't tell all the news because big media gets a ton of
money from BP.
Here's an equation that is used 1,000s of times a day. M=PIC...Money
= Power, Influence
and Control.
5) Health is big money and to keep the big money flowing it just makes
sense to keep as
many people popping pills on a monthly basis as possible. And if you
need more revenue,
one tactic is to change the "healthy range" of whatever so you can
increase the population
that "needs" to take your bandaid drug. Statins (which are proven to be
close to useless)
comes to mind...hmmm...me thinks its time to change the "healthy
range" again 'cause my
coffers need a fill'n.
Health should always come before money.
Posted by: Otto's the man | January 31, 2007 12:51 PM
"But it hasn't been tested human", LOL!
Its already used on humans for other things! There is no reason to not
start testing...
Posted by: Sturmrabe | January 31, 2007 2:36 PM
others' financial
benefit?
Ah, the "big conspiracy" theory.
The reason that can't work is simple - too many people would have to
be involved. Public
health agencies, government regulatory bodies, medical professionals
and big Pharma
would all have to be working in relative concert. And historically, all four
of entities are too
busy beating up on each other to pull something like that off.
It's far easier to pull a string here and there to move a cushy
government contract to the
"right" vendor than it is to systematically keep people unhealthy.
1) Read the book "The Hidden Story Of cancer by Brian Peskin, 2006.
Is he related to Kevin Trudeau? Maybe you should get together with
Mike and form a woo
comedy team. ("one of these homeopathic remedies is not like the
other, not like the
other...")
2) Big Pharma is good and bad. Now if they would stop making some
"bandaid" drugs and
get down to the root cause of the problem they'll find that they can't
change it because the
root problem is in our poor food supply and in the 50,000+ chemicals
created that pollute
us.
Yeah, because our food supply a hundred years ago was so much
better - you know,
before refigeration and a clear understanding of bacterial
contamination. Next you'll tell
me that the Hunzas live to be 200 years old or other such nonsense.
3) Many answers are simple but sometimes the eggheads can't help
but trip over their IQs
looking for their brilliance in a solution.
The answer isn't simple. Reductionist thinking like yours wants to
MAKE it simple so you,
excuse me, Brian, can easily sell books and diet plans.
4) Big Media won't tell all the news because big media gets a ton of
money from BP.
Here's an equation that is used 1,000s of times a day. M=PIC...Money
= Power, Influence
and Control.
Yeah, because Big Media really backed off the Vioxx story. Big
Tobacco used to throw
tons of money at Big Media as well - however I remember the tobacco
controversy was
covered pretty regularly. What a horribly, stupid argument.
5) Health is big money and to keep the big money flowing it just makes
sense to keep as
many people popping pills on a monthly basis as possible. And if you
need more revenue,
one tactic is to change the "healthy range" of whatever so you can
increase the population
that "needs" to take your bandaid drug. Statins (which are proven to be
close to useless)
comes to mind...hmmm...me thinks its time to change the "healthy
range" again 'cause my
coffers need a fill'n.
Perhaps there's a germ of truth in that. But in other cases, there's
statistical evidence that
shows that additional subgroups of people ARE helped by those drugs.
If you think DCA is a magic cancer cure, you might be disabused by
searching for 'DCA
neurotoxicity'.
According to this paper, "Dichloroacetic acid (DCA) is commonly found
in drinking water
as a by-product of chlorination disinfection. It is a known neurotoxicant
in rats, dogs, and
humans."
So the same people screaming that DCA is being ignored by Big
Pharma are probably the
same that are screaming about toxins in drinking water.
Their suspicions may not be grounded in this particular case (i.e. DCA
may not be the
silver bullet that could cure cancer) however general distrust of the
medical and
pharmaceutical industries that underlies these suspicions has very
solid grounds:
receiving institutionalized medical care as currently practiced subjects
one to risks of
infection and medical error that are huge, with studies suggesting that
40,000 - 90,000
people in the U.S. die (and many times that number are seriously
debilitated) due to side
effects of drugs and preventable medical errors. Look into 'iatrogenic
disorders'. Here is a
wikipedia article based on reports in IOM and JAMA, two peerreviewed medical journals.
Posted by: Circumspect | January 31, 2007 4:18 PM
I never get why people think the onus is on "Big Pharma" to pay for
clinical trials for such
"they can't make any profit on them" drugs.
Although it might be true that "Big Pharma" isn't funding such trials (or
at least, for the
sake of argument, suppose it is), it's equally true that the people
complaining about it
aren't paying either. That is, they're just as much to blame. There's
nothing stoppping
them from raising money for the testing, either.
Posted by: El Christador | January 31, 2007 4:44 PM
This kind of discussion frequently makes me laugh. Orac, thanks for
attempting to bring
some critical examination to the hysteria.
I've worked in pharmaceuticals in various jobs since 1981, and from
what I've seen people
have no idea how complicated it is to bring a new drug to the market. I
have seen industry
articles on pharmacoeconomics (which, by the way, are included in
many or most
applications for drug approval). One that particularly struck me was a
study reporting that
line extensions (new doses or other modifications to existing drugs)
were noticeably more
profitable than new drugs.
There are many parties worthy of blame in our system of bringing
drugs to market, but I'd
like to suggest you devote some thought to a couple of them.
First, the Waxman-hatch act that essentially created the generic drug
industry. Why is
this? Because it gives a fixed period of time in which profits can be
made from a new drug.
Most people don't understand what is actually involved here. What this
act permits is the
filing of an ANDA (abbreviated new drug application) that references
the safety and
clinical efficacy data from the original product.
In college they call that plagiarism and kick you out. In the
entertainment industry, the
RIAA or MPAA comes after you. For perspective, consider that the
current life of a
copyright has been extended to almost 100 years. Is Mickey Mouse
worth more to our
culture than an effective safe drug? Our current laws say so. The
relatively short patent
life of drugs simply amplifies the effect of corporate greed.
Another culprit that escapes attention is the public. Yes, I mean all of
us. Most especially,
our elected representatives who are given plenty of attention and news
coverage when the
criticize the FDA. Whoops, where did that come from? Quite frankly, I'd
estimate that half
of the cost of getting a new drug to market is regulatory. Worse, the
ongoing regulatory
cost of keeping a drug on the market is probably higher than fifty
percent. There's not
enough room here to detail what it takes to keep a drug on the market.
If you're curious,
research what DDMAC is. (Hint, it's a division of the FDA)
Wait a minute, what do public and government criticism of the FDA
have to do with
regulatory costs? Why, each public flogging of the FDA over some real
or imagined failure
gets translated into tighter restrictions on all drug manufacturers
whether they need it or
not. That's right, remember the Tylenol scare a few years back? It
wasn't just the OTC
drugs that wound up with safety seals.
Unlike most corporate manufacturing environments, FDA regulated
industries really are on
a tight leash. While firms that have established good reputations might
get somewhat
relaxed treatment, it's only by being even more restrictive internally.
Why is this?
Remember with a fixed time window in which to harvest profits from a
new drug, even a
week's delay in drug approval is worth millions. Most corporations
abhor risks, and risks
are frequently mitigated by throwing money at them. After all, it's just
another cost factor.
Posted by: Joe | January 31, 2007 4:49 PM
Someone previously asked me if I'm a patent lawyer. I'm not; I'm an
industrial chemist, but
I've been involved in patent issues with some of the chemicals I've
worked with, so that's
where my limited knowledge of patents come from. ( Please be advised
of my limits!)
That being said, I'd like to use an example of a drug called Neurontin
(generic name is
gabapentin), and how it's history shows the interplay between patents
and FDA approvals.
This drug is now made by Pfizer, who bought Warner Lambert, the
originator of Neurontin.
The first patent for gabapentin was issue to Warner Lambert in 1978 or
so, and it claimed
it could be used to treat epilepsy. This is original medical condition that
won FDA-approval
for Warner Lambert around 1993. However, over the years, Warner
Lambert had also
been patenting gabapentin for other conditions, using a variety of
evidence such as:
1. US patent 5,084,479 - "Novel methods for treating
neurodegenerative diseases"
(Parkinson's, ALS, etc). Claims based on studies on rat brain neurons.
2. US patent 5,025,035 - "Method of treating depression" Claims based
on case reports of
patients, while taking gabapentin for epilepsy, felt less depressed.
3. US patent 5,510,381 - "Method of treatment of mania and bipolar
disorder."
For this one, I've quoted the following claim made by Warner Lambert:
"In studies of epilepsy, gabapentin has been noted to reduce anger and
irritability,
enhance concentration, and improve decision-making abilities. These
effects will be
beneficial in the symptomatic treatment of patients suffering from
mania who exhibit
irritability, distractibility, and poor judgement. This is a novel use for
gabapentin which
would not be obvious to a medical practitioner of ordinary skill." I've got
to say, this is a
real stretch. (to read the text of the patents, go to the US patent quick
search page, and
type in the above patent numbers : http://patft.uspto.gov/netahtml/PTO/
search-bool.html )
The above illustrate that a company does not need solid clinical
evidence to claim a drug
is a treatment for a medical condition; there just needs to be some
evidence. On the other
hand, a company must provide a great deal of evidence from clinical
trials to get FDA
approval to market a drug; these trials cost a great deal in money and
time.
Gabapentin, under the brand name Neurontin, was approved by the
FDA to treat epilepsy
in ~1993, after Warner Lambert showed through clinical trials that it did
indeed work to
treat this condition. Over the years, however, Warner Lambert also
decided to expand
their marketing of the drug, claiming it could treat depression, bipolar
disorder and ALS
(and more), conditions for which the drug was not approved, but for
which Warner
Lambert held the patents.
Warner Lamber, now Pfizer, got in a lot of trouble for this. The company
was fined $430
million
for
the
fraudulent
marketing.
See
"fda.gov/fdac/features/2004/404_wl.html".
What I'm trying to show is that for a company to successfully sell a drug
for a condition,
they must have both FDA approval to treat that condition with the drug,
and the company
must have a patent that claims the drug is a treatment for that
condition. The latter is
necessary to keep other companies from also marketing the drug for
that same condition.
And this is why it's a big problem once a patent for a successful drug
expires. At that point,
other companies can legally market the drug for its FDA-approved
condition(s).
With respect to DCA - right now it is not FDA-approved to treat any
condition, which is why
you can't go to a retail or hospital pharmacy, and get it. It is in clinical
trials to treat a rare
disorder that causes lactic acid buildup; if you google for 'clinical trials
dichloracetate', the
trials will come up. Please note, one of the trials had to be discontinued
because DCA
caused nerve damage (neuropathy) in most of the patients who took it.
To Joe above - What's wrong with safety seals? Today I opened a new
jar of
McCormack's Grillmates barbeque spice. It had an outer plastic seal,
and an inner paper
seal. I doubt this has seriously burdened the McCormack spice
company.
Renee
There is nothing wrong with safety seals per-se. The point I was
making is that most
packaged prescription drugs never leave the pharmacy. What exactly
are we being
protected from? The safety benefit is marginal, while the cost is
significant. Unlike meat
tenderizer, the volumes on prescription medications tends to be a bit
smaller, so the cost
of the equipment, training, materials, etc. is spread out across fewer
units.
My general point about regulatory overhead is that it increases the cost
of products
without any real assessment of the cost versus benefit.
You might find this example more enlightening. At a previous employer,
we filed an ANDA
for an oral solution product. One of the significant points about the
formulation was that it
was completely non-aqueous. The formulation (can't discuss specifics)
used a liquid
similar to sorbitol for the vehicle. When the review letter came from the
FDA, it asked why
we did not include a pH test for release.
On the one hand, this is completely absurd. On the other hand, arguing
with the reviewer
could easily have delayed approval, which could have ruined the
economic viability of the
product. Faced with this dilemma, what would you do?
The root of this problem is similar to the safety seals problem. The FDA
does not appear
to exercise critical thinking before asking questions...they follow a
checklist. Unfortunately,
the economics of our product delivery system mean that is difficult to
argue about stupid
questions.
Hope that more or less answered your question.
Posted by: Joe | February 1, 2007 9:27 AM
What's the big deal about doing a pH test? It takes a minute. You do it
with something
called a pH meter, an instrument that's been around since the 1930's.
I used to work for a detergent company, studying dishwashing
detergents. We had to
moniter the pH, because these solutions come in contact with the skin.
Anything above pH
8 or so could be a problem, since above that value, the detergent could
start to hydrolyze
skin proteins. We did the pH readings on the concentrated detergent as
sold, and
dissolved in water, as would be used in a sink full of water.
I'm not clear about your reference to using something like sorbitol to
make the oral
solution you mention above. Sorbitol is a solid sugar, melting point
98-100 degrees C. If
you were using a sugar like sorbitol, than you would have had to
dissolve it first in water,
to use it as the vehicle for your new drug. Instead, do you mean that
you were using
glycerol? That is not a sugar, though it is a liquid.
Doing a pH test, even for a non-aqueous solution, is not so far-fetched.
An oral solution
will first come in contact with saliva, then the contents of your stomach,
both of which are
aqueous. The oral non-aqueous solution will become diluted and
dissolved in water, and
then in contact with mucous membranes upon ingestion. I can see why
the FDA would
require a pH test, probably done on a diluted aqueous solution of your
oral medication.
Posted by: Renee | February 1, 2007 10:15 AM
Informative retort to all the hype - I enjoyed being lifted up by the
original article to the very
moment of being thrown back down to the ground with your blog :)
I sometimes wonder if the whole world revolves around Snopes half the
time and am
thankful that there are people such as yourself that go to a lot of trouble
to dispel certain
hyped up rubbish :)
Posted by: Soulgirl | February 1, 2007 11:29 AM
...Anyone thought to call the U in Alberta to get more of the straight
scoop...? Might save a
lot of typing. There are people just DYING to know...
Posted by: DRL | February 1, 2007 1:43 PM
Renee
Don't need to get too out of hand for this. A pH test for initial release
and long-term
stability testing has nothing to do what what happens when you take
the drug. This is a
purely abstract physical property test.
Sorry I got distracted and said sorbitol. I did a little more digging. I
meant polyethylene
glycol, which is not a solid, and is not dissolved in water. There is
absolutely no water in
this product.
Stop and think. What is the definition of a pH measurement, and how
does a pH probe
actually work? Is a pH measurement with a standard electrode even
valid for a nonaqueous
solution? (Try this yourself, go get a jug of antifreeze and read the pH.
You say
you're an industrial chemist, I think you should know better than this.)
Now, the meter will certainly give you a reading. Does this number
actually mean
something? Further, how do you establish valid measurement limits on
a meaningless
measurement? Most importantly, how often will you have to recall a
product (increasing
the overall cost of the product line) based on nonsense? That's the
point here.
Product specifications are supposed to support ongoing product
quality. If the
measurement does not do this, it is no longer a quality tool but a
bureaucratic checklist
item.
It is the extended implications of seemingly simple decisions that can
spiral out of control
and raise the cost of manufacturing a product without providing any
real benefit to product
quality. I guess I've lived with the industry long enough that it seems
obvious, but it
probably is not.
Every test and every specification increase the cost of the product to
the manufacturer
and the consumer. Specifications must be met by each new batch of
product, and must be
met over the shelf life of the product. Roughly 10% of the commercial
product batches are
tested on long-term stability. If the specifications are not met during the
life of the product,
the product must be recalled. If this happens often enough, it opens
questions on whether
the product should be allowed to remain on the market.
Does this sound like a trivial issue? That's why it's hard to explain why
drugs cost so
much. These kinds of issues are present throughout the entire process
from development
to market.
Don't get me wrong, I'm not trying to blame the FDA for all the
industry's problems. The
industry is one large example of the law of unintended consequences.
The FDA is trying
to do it's job. The industry is trying to sell a profitable, ethical, quality
product. The public
simultaneously wants perfect products but balks at perfect product
prices. Congress tries
to juggle the interests of the public and the industry that makes
significant contributions to
their campaigns.
Me, I just work here.
Posted by: Joe | February 1, 2007 5:09 PM
Thanks for the extra information, Renee. From information I got from a
new lawyer (not an
expert in patents, but still) I gather that one condition is that you need
to repeatedly
"renew" the patent for a new use to be valid (Neurontin was given as
an example-patented in the 70s). And of course, as Renee mentioned, DCA wasn't
FDA approved for
general use to begin with, so it's enforceable.
As for the bottle safety measures, it is silly and probably started with
the whole
Tylneol/poison killer. Bottles should be protected if they're OTC, of
course, but given the
security measures "behind the counter" for prescription drug, what's the
point?
Posted by: Nathan J. Yoder | February 1, 2007 9:31 PM
Ok, I understand now, since one of the liquid forms of polyethylene
glycol was used as the
base for the drug. You are right, measuring the pH would be
meaningless. Dare I ask, how
was this pH issue resolved?
In case anyone's wondering, there's a fair amount of regulation of the
chemical industry.
Instead of having one large federal agency like the FDA to deal with,
we've got a multitude
of federal, state and local agencies to reckon with, some of whom have
competing
interests with each other. There have been projects I've worked on
where we've had to
contend simultaneously with the air pollution division of the EPA and
the new chemicals
division of the EPA (neither of which coordinate their efforts together),
each of the air
quality districts of Los Angeles, San Francisco and the San Joaquin
valley, U.S. Customs,
the Dept. of Transportation, and OSHA. Each of which could either levy
fines or prohibit
the sale or shipment of any of our products. And during the project,
fines were indeed
levied, and sales temporarily prohibited. All of these issues are
magnified when trying to
work with a new chemical, even if it's no more hazardous than older
ones in the same
class.
We've had a small development program dropped because one of our
German suppliers
could not figure out how to ship us a new chemical, since they would
have had to deal with
the German equivalent of the EPA, German Customs, the German and
American Depts.
of Transportation shipping rules, the shipper's shipping rules (probably
DHL), US
Customs, and the US EPA.
All for a chemical that was no more hazardous than polyethylene
glycol.
This discussion has veered quite a ways from DCA and cancer.
Posted by: Renee | February 1, 2007 9:33 PM
May I just say that Autism Diva blogged the New Scientist article on
January 27th without
going all "Big Pharma hates us" or "Whoopee! a cure for cancer at
last!"? :-) she also
blogged "A cure for all cancers" parasitic woo queen, Hulda Clark (no
relation).
http://autismdiva.blogspot.com/2007/01/cancer-depressionparasitesautism.html
Thanks for all the additional info on DCA. It sure sounds wonderful. I
hope it turns out to
work on lots of human cancers.
Posted by: Ms. Clark | February 2, 2007 2:13 AM
I'll be honest. This article just makes you look like a sad bitter
competitor in the race to
make cancer drugs.
Your four points say NOTHING about the possibilities of the drug. In
fact you even point it
out in the first paragraph. How can you tell people not to jump to
conclusions when you
yourself have already done so by taking the negative?
Get over yourself, realise that you don't know everything, and if you
had ANY experience
in the treatment of cancers you'd know full well that some hope for
cancer patients is
better than little or none. People having positive mental health is a big
benefit in cancer
treatment - false hopes occur in ANY CASE when many of the current
therapy treatments
fail, and with horrible side-effects.
I find your assumptions and conclusions baseless, and even more so
than the article
because at least the article bases itself on a "could be" stance, rather
than your blog that
attempts to already disprove something not even in testing.
Also, your indifference to big pharma companies and the way they
manipulate markets is
almost laughable. There is not a single company that isn't share market
driven, and thus
at the mercy of their shareholders & board to produce results - no
matter the costs. There
are a massive number of recent examples of this within the US, and
many other countries.
I think you need to take a bit of a more careful view toward these types
of companies,
since they are simply economically driven, not morally or ethically
driven, and many
assumptions people are making about many of the larger ones couldn't
be any more
accurate.
You aren't god.. you don't know everything, so don't pretend to.
Support all the great
number of 'possibles' out there - one day, you might need one of them.
Posted by: Meh | February 2, 2007 11:17 AM
Meh Did you read the article? Or did you just read the title and make a lot of
assumptions?
Your charecterization is truly stunning - one of the reasons for this
article is to cut through
the bullshit, to get to the legitamate discussion of the problems with our
system of drug
developement. Hysterics are not going to help change things - rational,
accurate
depictions of the situation are essential to fixing the problems.
It is the same with people who refuse to discuss anything other than
mandated single
payer, as the solution to our health care crisis. All that bullshit rhetoric
accomplishes is
preventing solitions that will actually provide the increasing millions of
Americans, with
access to care.
Many of us would rather find solutions to the problems. Whining like a
small child does not
accomplish this. Hysterical exageration does not solve the problem.
Only when we cut
through this bullshit, can we begin to solve the problems.
Posted by: DuWayne | February 2, 2007 1:37 PM
Get over yourself, realise that you don't know everything, and if you
had ANY
experience in the treatment of cancers you'd know full well that some
hope for
cancer patients is better than little or none. People having positive
mental
health is a big benefit in cancer treatment - false hopes occur in ANY
CASE
when many of the current therapy treatments fail, and with horrible
side-effects.
Uh, Meh, read these.
I do treat cancer patients. I'm a cancer surgeon. And while I agree that
hope is important
to cancer patients, you're wrong about false hope. False hope is what
leads patients to
exhaust their bank accounts going to Tijuana to visit quacks instead of
making the most of
what time they have left. False hope is what leads some patients to
forego effective
conventional therapy in favor of quackery until it is too late. False hope
leads patients,
when they hear the overblown hype about DCA, to become enraged
because they think
that a cure for their cancer is being withheld from them.
As for my saying "nothing" about the possibilities of DCA, well, I can't
help but put it bluntly
here: That's a load of crap. My point was simply that it's a promising
drug (which is true)
but that. compared to a lot of promising compounds that come along
it's not that different
and it's almost certainly not the miraculous "cure for cancer" that some
in the blogosphere
are claiming. I certainly hope that DCA turns out to be a potent new tool
in our
armamentarium of cancer chemotherapy, but I have no illusion that it's
a "cure," mainly
because we in the biz have been down this road before, as I explained
in this post. Many
compounds show promise in cell culture and animal studies and fail
utterly in human trials,
far more than the number that ultimately prove efficacious.
Posted by: Orac | February 2, 2007 2:19 PM
I am reminded of a story I heard years ago about some promising
treatment for AIDS that
"cured" the virus in test tubes.
The commentator or scientist finished the report by saying that we
should remember that
gasoline also kills the virus in a test tube (but that did not make it a
promising treatment).
The promise is that this is not some far off compound in phase I studies
that may or may
not work, either because of lack of efficacy or because of side effects.
One would assume that there will be enough off-label use in this case
so that some
indication of its effectiveness, or lack thereof, will soon percolate to the
surface.
Some drugs are commonly used because they offer benefit to 1
patients vs 99 who do not
show any (statitically) significant benefit.
Even If it only helps a little bit, for a small group of patients, it is help
nonetheless,
especially for those who it will likely be tried on first.
If is does not, then at least it seems to have renewed some interest into
a different way in
treating cancer (Warburg's Principle), which in of itself, is a benefit.
This is a complex
disease that needs to be attacked on as many fronts as possible.
In terms of it being a platform for making money, there are many many
generic companies
out there who make considerable amounts of money selling commodity
products faced
with umpteen competitors.
Posted by: Phil Monk | February 2, 2007 3:56 PM
Meh:
People having positive mental health is a big benefit in cancer
treatment
Anybody who has had a friend or loved one fall victim to cancer wants
to believe in the
importance of "positive mental attitude." When there is so little we can
do to help, we want
to believe that we are accomplishing something material by offering
emotional support.
Emotional support from family and friends can help when a patient is
trying to find the
courage to persevere through the unpleasant side effects of chemo- or
radiotherapy. But
hard evidence that "positive mental health" is a big benefit when it
comes to prognosis is
hard
to
come
by.
See,
e.g.
http://www.bmj.com/cgi/reprint/325/7372/1066. And the risk of
offering hope associated with untested treatments is that it may lead
people to abandon
well-established treatment modalities in favor of ones that are less
effective.
Once one has seen a few of these compounds that are miracle cures in
cell culture or
experimental animal tumor models come and go, it is hard to avoid
developing a
somewhat jaded perspective on the big cure that is always just around
the corner.
One thing that hardly anybody who thinks that the drug companies are
withholding or
neglecting cancer cures ever bothers to think about is just how
ubiquitous cancer is.
Above a certain age, pretty much everybody has experienced some
kind of cancer-related
personal tragedy, and that includes the people managing the
pharmaceutical companies
and those working in the labs. So while a business must necessarily
keep an eye on the
bottom line (and if you've followed the business news, you know that
pharmaceutical
companies have not been doing so well for quite some time), I think
that there are very
few companies that would be able to resist the lure of a compound that
might really make
a big difference in cancer therapy. Besides, if you did have such a
miracle drug, even if it
wasn't patentable, perhaps you could figure out how it works and
produce an even better
variant that is patentable.
Posted by: tgibbs | February 2, 2007 5:28 PM
1. This drug has only been tested in cell culture and rats. Yes, the
results were promising
there, but that does not--I repeat, does not-- mean the results will
translate to humans. In
fact, most likely, they will not.
Hey I Have an Idea.
How about let me have some and I will test it on myself.
How about I can't EF-ing wait for this stupidity called big pharma, the
fda and the codex.
(word of mouth could solve all that beauracracy)
Worse yet, tell me how to make it, and how to use it. A regular HOWTO DCA or DCA for
Dummies. Yeah Yeah, I hear something about toxicity. Teach me not to
do that, I'll be
fine. It'll be on me, if I screw up, I pay the price.
Hey, now that I solved this dilema, (actually not) in 60 seconds.
How about everyone stop the bickering, back-stabbing, boasting, and
lawyer /doctor and
patent crapping and work on a cure for West Nile Virus. I see the god
damned HORSES
have a vaccine. Still not a DAMNED THING for humans. I'm ready to
break into a
vetranery hospital. Do you know how painful WNV is?!
DO YOU!? ARGHHHH!
Okay, now imagine, having BOTH WNV and Cancer and NO
MEDICAL, NO INCOME, NO
DOCTOR.
Oh that's right, you have maid service.
Okay where's the Purchase 50mg DCA button?!
Or the manditory WNV school vacinations?!
Posted by: Invisible Death | February 6, 2007 8:26 PM
Here's an idea Invisible Death: Click on the link for the Cancer Cell
paper right there in the
paragraph that comes after the first block quote. Right down on a piece
a paper the
authors' names and the institution listed.
Then get a piece of paper and write them with your dosage questions
and where the stuff
can be bought. You might also want to volunteer as their first human
subject.
Posted by: HCN | February 6, 2007 9:32 PM
There will be no need to place blame anywhere if funding is secured,
we will just wait for
the results. I must admit that I do not, with all the information that is
generated via
technology today, believe that big pharma is interested in anything but
profits. There are
many drugs that were shown effective, (Hydrazine Sulfate), to name
one, where shady
trials and misinformation was generated by the powers that be. Why
did they test synthetic
vitamin E instead of natural Vitamin E? I hate to believe what appears
to be true in the
case against big pharma because it undermines everything we have
placed our faith and
trust in. Even though we don't all have a PHD, we are mostly
intellegent and full of
common sense. The fact remains that if green beans end up curing
cancer than I guess
there will never be a cure. If the people who represent these
companies, making trillions
per year on our various sicknesses, are not as intent on keeping us
sick as it appears,
than test it all. I'm sure that if treating cancer patients everyday,
watching this degrading
inhumane desease take the life out of one more person with such
suffering, was how I
made my living then I would be sqeptical too, and with good reason,
BUT WE CANNOT
GIVE UP, we cannot stop hoping. So test all the promising treatments,
Its not as if the
scientist at the University of Alberta is a "quack", he is well recognized
and trusted, and so
the testing should move foreward. I shall be forewarding my installment
to the University
for the testing to proceed, and if it proves unsuccessful, then we wait
for the next one.
Polio would never have been cured if we believed that the possibilities
were hopeless.
People are not as weak as you assume, we don't just sit and hold our
breath and believe
without merit. That is why we have any trust at all for big pharma,
because deep down we
just want informed answers, and relied on the research that they put
foreward. The
outrage with DCA is that it's inability to get funding, makes us renege
the trust we so
innocently placed in the hands of those corporate giants. If they back
away from this
research, than the Canadian Cancer Society better step up to the plate.
Where's Bill
Gates when you need him, I'm sure he could afford to waste a million
dollars. Bottom line
for me is this, because of the undignified horrible months spent fighting,
winning, or losing
the battle with this desease, the pain, the weight loss watching
someone you love just
waste away,it is immperitive that every avenue is travelled down. We
can deal with it if it is
not the wonder drug, what we can't deal with is that the circumstances
surrounding this
drug and it's lack of patentability might keep it from being tested
properly. Any person
currently taking a form of cancer treatment has hope, at least in the
beginning, to hope is
to be human otherwise we wouldn't even bother with treatment. It isn't
mindless hope it is
just hope. Sometimes a cure is found.
Posted by: Denise Julien | February 8, 2007 8:26 PM
Denise Julien wrote "Where's Bill Gates when you need him, I'm sure
he could afford to
waste a million dollars."
If you want to help decide how Mr. Gates disposes of his charitable
funds then apply for
employment here:
http://www.gatesfoundation.org/AboutUs/WorkingWithUs/Jobs/
Oh, actually the "outrage" with DCA are those who are jumping the gun
thinking that some
testing on rats is all you need to approve a drug, especially a drug that
has some
problems with toxicity. The "outrage" are those who want to ignore any
and all safety
concerns.
Posted by: HCN | February 8, 2007 9:22 PM
Y'know, with all these drugs which work so well on rats and mice, if my
pet *rat* gets
cancer, it's pretty much curable, right?
Posted by: Nathanael Nerode | February 9, 2007 3:00 PM
First, thanks for all the very informative posts! I've been reading like a
madman for the last
few months since I first read about DCA in the paper.
The dilemma I have with DCA is the apparent contradiction.
First, it appears that it has been used (successfully at the right dosages
http://www.ncbinlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=PubMed&list_uids=12892
050&dopt=Abstract
http://www.epa.gov/iris/subst/0654.htm ) for lactic acidosis for many
years.
Second, it has been shown at the U of A to have anti cancer properties
on test animals
Yet, a cancer patient who has been told by their doctors that there are
no available
conventional treatments, that chemotherapy at best will extend their life
by one month with
wicked side effects and that the patient's only real option is palliative
care, when that
patient asks about DCA they are told that, 'it is not an approved
treatment for cancer but,
we will make you comfortable while you die'.
Naively, could we not offer the above patient a second option to, 'make
them comfortable
while they die and offer them DCA at the aforementioned safe
dosage?'.
I know, it's crazy talk, I mean we'd be wasting $2 per day in chemicals!
Alternatively could
some chemist out there reply with the recipe or url for an oral dose
(preferably cherry
flavoured)?
Posted by: Kam | February 16, 2007 1:41 AM
Kam - you cribbed that from the Anti-Med/CancerWooShillers(tm)
phrasebook, didn't you?
Posted by: anonimouse | February 16, 2007 11:53 AM
anonimouse - alas no, it is my own crazy rambling. I believe 100% in
our doctors, our
health care system, their ethics and the scientific approach. I have met
wonderful caring
people in the medical profession and in our hospital system, but when
they give up, must
the patient also?
I'm definitely not anti-med and hate the predators that are preying on
the helpless with
their snake oil, but when you're told that there is no hope, that the
medical profession can
do no more, I say wheel out the experimental cart and let's start mixing
our own! What's
the worst that could happen, it kills you? And if we stick to the
heretofore mentioned safe
dosage, what's the worst that can happen? Well actually nothing will
happen, but that will
kill you also!
PS> if cherry flavoured is a problem, banana or grape are fine!
Posted by: Kam | February 17, 2007 2:23 AM
Kam, the worst that can happen is that it makes one's passing more
painful and difficult.
At least clinical trials can record this and prevent others from following
the same route.
They also help determine the doses that work, the doses that cause
severe side effects,
and where the overlap begins. Just because you have the right drug
doesn't mean that
you have the right dose, or even the right dosing schedule.
Posted by: Robster | February 17, 2007 11:25 AM
I can see that I am very late coming to this thread, but let me say my
peice.
"DCA attacks a unique feature of cancer cells: the fact that they make
their energy
throughout the main body of the cell, rather than in distinct organelles
called mitochondria.
This process, called glycolysis, is inefficient and uses up vast amounts
of sugar."
This is very wrong, and does point to a fatal flaw. The brain has its own
immune system,
the Glia, which is made up of Astrocytes and microglia. They are both
able to combat
infections by chemical warfare, in doing so theyr release a lot of nitric
oxide (NO). Now NO
inhibits mitochondrial respiration, and so these cells have a robust
anaerobic glycolytic
pathway in operation. Indeed, you can make these (clutured) cells
hypoxic for up to an
hour and they survive reperfusion very well.
If you give a patient a drug that attacks the glycolitic pathway, then the
brains inflamitary
immune resposen is going to be compromised.
The idea of compromising the glias glycolitic pathway, by one way or
another, MAY
Possibly actually underlay some diseases, I thank the Blog for this post
as it has given me
an idea.
Posted by: DocMartyn | February 23, 2007 7:30 PM
How will we know if we never try? Saying that it may not translate to
humans simply isn't a
good enough excuse. Big pharma won't pay for its trials - no patent,
there is no money to
be made. Delusion is your problem if you really think that pharmy
companies aren't
thinking (even on the surface) of their pockets.
Posted by: dev | March 11, 2007 3:55 AM
Straw man argument. I never said we shouldn't try it in humans. Do try
some reading
comprehension sometime before spouting off.
What I was saying is that hyping DCA before it has been proven
efficacious in humans is
harmful because it very well may not work. At the very least, we do not
know what doses
to use against cancer (they may very well be higher than for the
metabolic conditions DCA
is used to treat) or what cancers it will and won't work against, nor will
we know how long
to treat.
That's what clinical trials are for.
If you click on some of the later links in my list of followup posts, you'll
see that
unscrupulous "entrepreneurs" are actually selling the stuff to desperate
cancer patients to
self-medicate without the supervision of an oncologist.
Posted by: Orac | March 11, 2007 8:32 AM
Interesting, but you get a bit incoherent when you start talking about
alleged conspiracies.
"Conspiracy" is a easy strawman to knock down, but it's a fact that drug
companies, like
any corporation, are trying to make money, and they are not going to
waste money testing
unpatentable treatments (and good luck trying to patent the "idea" of
treating cancer with
DCA and selling it to them; that's exactly the sort of legal dodge that will
either end up in
court with the horrible publicity of dying cancer patients on TV
demanding to know why
they're being screwed, or people just using DCA on their own and
daring Pfizer or
whoever to sue dying cancer patients for doing it without paying them
for the privilege).
Now, to be clear, I'm not blaming Pharma for the problem. This is just
the way capitalism
works, and I have little common ground with the nutters at Dkos on that
issue. But that
doesn't mean we can't do better. I'd like to see something like an X
Prize for cancer,
where capitalism and competition are harnessed and put to good use. I
would also like to
see terminal cancer patients given better opportunity to try novel
treatments; even if they
don't work, at least their death helps prove that, and thus has some
greater meaning.
"What I was saying is that hyping DCA before it has been proven
efficacious in humans is
harmful because it very well may not work."
Well, of course it may not work; in fact, it probably won't, but that's
been true of every
cancer drug ever tested.
Posted by: TallDave | April 2, 2007 12:59 PM
"you'll see that unscrupulous "entrepreneurs" are actually selling the
stuff to desperate
cancer patients to self-medicate without the supervision of an
oncologist."
Horrors! Dying people practicing medicine on themselves without the
benefit of an
overpaid bureaucratized cartel! Next they'll be asking for the right to
vote, or carry guns.
Where will the madness end??
Posted by: TallDave | April 2, 2007 1:22 PM
Just wanted to wrap up my thread, my Mom was diagnosed in January
and was dead mid
March. I guess her quality of life didn't suffer, nothing was tried, nothing
was learned,
except maybe for another data point for the mortality stats. The good
news is the status
quo was maintained, the system withstood another desperate family.
Take a decade to
study DCA, debate endlessly if you want, most of us are only eager for
a cure when we
desperatly need one.
Posted by: kam | April 7, 2007 5:24 PM
The deadly deviousness of the cancer cell, or how
dichloroacetate (DCA) might fail
Category: Cancer • Clinical trials • Medicine
Posted on: March 6, 2007 9:02 AM, by Orac
One byproduct of blogging that I had never anticipated when I started
is how it sometimes
gets me interested in scientific questions that I would never have paid
much attention to
before or looked into other than superficially. One such scientific
question is whether
dichloroacetate (DCA), the small molecule that was shown to have
significant anti-tumor
activity against human tumor xenografts implanted in rats, media
reports about which
caused a blogospheric hysteria in late January representing DCA as a
"cure" for cancer
that "big pharma" doesn't want you to know about, mainly because it's
relatively cheap
and unpatentable in its present form. I gathered some minor notoriety
by pointing out that
the hype was excessive and that the drug had not even been tested
against cancer in
humans yet, adding that most drugs that show promise in cell culture
and against
experimental tumors end up failing to show efficacy in humans.
Unfortunately, none of that
stopped unscrupulous "entrepreneurs" from selling DCA as "Pet-DCA"
supposedly
intended for use "in pets only," even though the most cursory reading of
the discussion
boards revealed that desperate cancer patients are trying to buy it to
use themselves, nor
did it stop ignorant dupes like DaveScot from cheering them on in
doing so or credulous
bloggers who think far more of their scientific knowledge than is
warranted from blathering
about DCA as an allegedly "suppressed" or "ignored" cure like vitamin
C.
It is not my purpose today to rehash all of this or to rail yet again
against the dubious
marketing of a "cure" that hasn't even been shown to be a cure yet. I'm
more interested in
discussing an interesting bit of science related to DCA and the whole
concept that altered
bioenergetics are important to the development of cancer.
The entire concept behind the use of DCA is to target a phenomenon
known as the
Warburg Effect. This effect was first observed by a biochemist named
Otto Warburg back
in the late 1920's in tumor cells. In brief, Dr. Warburg noted that tumor
cells avidly
consumed glucose and produced what is normally the byproduct of the
anaerobic
metabolism of glucose for energy (glycolysis) even in an aerobic
(oxygen-containing)
environment, conditions under which normal cells usually use a
process that requires
oxygen, oxidative phosphorylation. Normal cells usually use oxidative
phosphorylation,
which takes place in the mitochondria, when oxygen is available and
only switch over to
anaerobic glycolysis in conditions of low or no oxygen (anaerobic
conditions), producing
lactate as a byproduct. (Normally, the end product of glycolysis,
pyruvate, is then used in
the Kreb's cycle and oxidative phosphorylation. In the absence of
oxygen, the pyruvate is
used for energy and turned into lactate. Lactate buildup makes your
muscles sore after
intense exercise, when the energy demand of the muscles can exceed
the amount of
oxygen available.) The problem in normal cells is that glycolysis
produces much less
usable chemical energy per molecule of glucose than oxidative
phosphorylation, and
normal cells normally cannot survive on anaerobic glycolysis alone for
very long. However,
many tumor cells can. Indeed, many tumor cells continue to use
glycolysis and produce
lactate even in aerobic conditions, an observation that led Dr. Warburg
to postulate that in
tumor cells the mitochondria (which is where oxidative phosphorylation
takes place) are
reduced or functionally impaired. Indeed, he postulated more than that,
namely that
impaired mitochondrial function contributes to tumorigenesis.
The reason that I became more interested in DCA is because my main
research interest is
tumor angiogenesis. Because blocking tumor angiogenesis works by
decreasing oxygen
and nutrient delivery to tumors, in essence, "starving" them, one might
imagine that one
way in which tumors could be or become resistant to antiangiogenic
therapy might
conceivably be through cranking up the Warburg Effect, allowing tumor
cells. As it turns
out, DCA targets the Warburg Effect. It also turns out that the enzyme
that DCA happens
to inhibit to accomplish this targeting, pyruvate dehydrogenase kinase
(PDK), is activated
by a gene called HIF-1, which itself is activated by hypoxia. PDK
inactivates an enzyme
complex called the pyruvate dehydrogenase complex (PDH), which,
when turned off
attenuates mitochondrial respiration and oxidative phosphorylation.
Consequently, I've been checking out papers about the bioenergetics
of tumors, and I
found a doozy of one last week in the February 15 issue of Cancer
Research, entitled
Adaptation of Energy Metabolism in Breast Cancer Brain Metastases.
Basically, the
investigators found a fascinating (and disturbing) adaptation that
occurs in breast cancer
cells when they metastasize to the brain that shows just how
unbelievably complex and
difficult a foe cancer can be.
The investigators at the Scripps Research Institute led by Brunhilde
Felding-Haberman
asked the question: What are the changes in the amounts and types of
proteins made by
breast cancer cells that metastasize to the brain that make them able
to grow there? To
attack this question, they isolated tumor cells from the blood of a
patient with stage IV
breast cancer, cultured them, and then grew them into SCID mice (a
strain of immune
deficient mice in which human tumors can grow as xenografts). The
tumors grew and,
even more than that, they metastasized to brain and bone. Metastases
from brain and
bone were isolated, injected again into new mice, and then the
metastases were isolated
again. It turns out that the cells from the brain metastasis became
much more likely to
metastasize to to and avid for growing in the brain than the parental
cell line from which
they were derived, as the cells from bone metastases became more
avid for bone. This is
a common technique used to study metastasis and why certain tumors
tend to
metastasize to certain organs. Basically, tumor cells are subjected to
one or more rounds
of selection for clones that are able to grow in the organ desired.
Now here's where things get interesting. They next did a technique
called
multidimensional chromatography and tandem mass spectroscopy.
There's no need to
sweat the details other than to understand that this is a proteomics
technique by which it is
possible to simultaneously compare the levels of hundreds of proteins
between cell types.
Basically, the idea was to see which proteins were expressed at higher
or lower levels in
the brain metastases than in the parental cell line from which the
metastatic cells were
involved. The results were startling. In essence, the brain metastases
made lots more of
the proteins involved in oxidative phosphorylation.
In other words, they underwent what might well be characterized as the
anti-Warburg
effect. Although they had increased levels of glycolysis, they also
cranked up their
oxidative phosphorylation, as well as and had increased activation of
pathways that
minimize the production of or damage from reactive oxygen species
(a.k.a. free radicals,
the production of which was stimulated by treatment with DCA in the
Michelakis
experiments and contributed to tumor cell apoptosis in response to the
drug). The overall
effect of these changes in gene expression leading to increases in the
enzymes
responsible for oxidative phosphorylation is that the brain metastatic
cell line became
resistant to drugs that affect the cellular oxidation-reduction balance.
Drugs like DCA.
It's rather disappointing that they didn't actually test DCA, but, then, the
work on this paper
and the work on Michelakis' paper were likely going on at the same
time. The drug they
did test is 2-deoxyglucose (2-DG) a drug that is being tested because
of its ability to inhibit
glycolysis and shift the balance of energy production towards aerobic
oxidative
phosphorylation by a mechanism different from that of DCA. Consistent
with the increased
levels of proteins involved in oxidative phosphorylation, the cells
derived from brain
metastases were over two-fold less sensitive to 2-DG than the parental
cell line, probably
because the cells were no longer exhibiting the Warburg Effect, making
them not nearly
as dependent upon glycolysis for their energy. More than likely, these
cells would also be
as resistant to the effect of DCA.
The authors speculate that breast cancer cells that successfully
metastasize to and
colonize the brain take on characteristics that allow them to thrive in
the environment
found in the brain, and that their observations imply a link between a
preference for
oxidative phosphorylation and "homing" to the brain. The reason for
this might well be that
the brain is has a high blood flow and high oxygen tension, with the
surrounding brain
tissue always operating at a high oxidative metabolic level. As the
authors state:
Our experimental metastasis data and proteomic analyses indicate that
the
brain metastatic cells, selected in vivo for their ability to establish brain
metastases, possess a phenotype distinct from the parental circulating
tumor
cells and their bone metastatic counterparts. The protein expression
profile of
the brain metastatic cells and its functional validation imply a
predisposition or
bioenergetic adaptation of the tumor cells to the energy metabolism of
the
brain, conferring an advantage for tumor cell survival and proliferation
in the
brain microenvironment.
What these results suggest is something that those of us studying
cancer have known for
a long time. Cancer is an unbelievably devious and resourceful foe; if it
weren't we'd be far
better at curing it now than we are. As much as we would like to wish it
to be so, there will
almost certainly never be a "magic bullet" that will cure all cancers.
Antiangiogenic therapy
was touted as one eight years ago and, in the time since then, has
shown only modest
success against cancer. Certainly it was no magic bullet. My guess is
that DCA (and drugs
designed to target the Warburg Effect) will similarly show modest
success against cancer
in humans. My guess (and remember, it is just an educated guess) is
that it may well be
ineffective against many forms of brain metastases and against some
forms of brain
tumors, while being most effective against tumors that are most avid in
taking up glucose,
which happen to be the tumors that show up the most brightly on PET
scans. However,
more work needs to be done, as one glaring weakness of this study
(and probably the
reason that it wasn't accepted to a journal like Cancer Cell) is that the
2-DG experiments
were all done in vitro. There were no experiments in which mice
bearing brain metastases
created by direct injection of either the parental cell line or the cell line
derived from brain
metastases were treated with 2-DG to see if in vivo results recapitulate
in vitro
sensitivities; so the tumor microenvironment could conceivably be
sufficiently different
than cell culture that these results might not hold up.
The bottom line is that cancer is always more complex than we think it
is, and there are
always wrinkles that we don't think of. Moreover, cancer cells are
incredibly adaptable
and--dare I say it?--evolve rapidly to infiltrate and colonize new
environments. (Indeed one
depressing possibility raised by these experiments is that drugs
designed to target the
Warburg Effect might actually select for cells able to metastasize to the
brain.) An
adaptation that allows tumor cells to grow in the brain appears to have
the byproduct of
eliminating the Warburg Effect and rendering them resistant to attempts
to manipulate the
energy balance.
Sadly, all too often, cancer is like that.
ADDENDUM: Walnut has posted his critique on Daily Kos as well.
"pharma shill"
2. Will donations fund dichloroacetate (DCA) clinical trials?
cancer
even?
what I'm finding
now)
(DCA) might fail
mainstream
media
Biology 101
travesty of science
Canada
(DCA)
5. F our days, four dichloroacetate (DCA) newspaper articles
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Comments
My naivete about human physiology is clearly showing through here,
but wouldn't DCA
also seriously poison the metabolism of cardiac and skeletal muscle?
Posted by: Jesse | March 6, 2007 9:17 AM
As I have indicated in the past when we discussed DCA and its effects
on energy
metabolism, this molecule is a derivative (toxic one) of acetate, a
monocarboxylate that
can be used as an energy substrate by astrocytes. Astrocytes are glial
cells in the brain
that usually fulfil housekeeping functions and protect neurones against
toxic effects of
certain excitatory neurotransmitters such as glutamate and aspartate
(excitotoxins). There
are several known toxins that are selective against astrocytes through
interference with
these cells' energy metabolism pathways. When astrocytes are
eliminated, neurons
usually lose the protection astrocytes provide them with. DCA could
very well be one of
those astrocytic toxins and may help rather than hinder brain cancer
cells.
The weakened effect of 2-deoxyglucose on brain cancer cells in the
study mentioned by
Orac is interesting, since one must asks where the mitochondrial
energy substrate of the
cancerous cells come from when glycolysis is inhibited? Let's
remember that for
mitochondria to work efficiently, they must be provided with the
glycolytic product,
pyruvate, which originates from glucose. Thus, in the presence of 2deoxyglucose,
cancerous cells must be able to use other molecules as energy
substrates (fatty acids?).
As a side bar; my main expertise is brain energy metabolism and as
such I can attest to
the fact that much of the classical formulation of the pathways of
energy metabolism as
presented in textbooks for the past 60 years is now being re-evaluated
as more and more
studies show that even glycolysis, the more primitive and much less
efficient energy
making pathway, had been somewhat wrongly formulated, especially in
regard to its main
aerobic end-product, pyruvate. There are indications that whether
glycolysis is anaerobic
or aerobic, its end-product is lactate rather than pyruvate, and that
lactate is actually the
substrate that mitochondria use for their oxidative phosphorylation.
Posted by: S. Rivlin | March 6, 2007 10:37 AM
Yes, several of the enzymes involved in fatty acid oxidation were
expressed at higher
levels in the brain metastases. Consequently, that's one possible
explanation. In addition,
I forgot to mention that one protein, AMPK, was also expressed at a
much higher level.
AMPK turns off fatty acid biosynthesis and turns on fatty acid oxidation
and glycolysis.
Also, remember that the cells were only less sensitive to 2-DG (by a
roughly two-fold
ratio), not totally insensitive to 2-DG. Consequently, it could be that,
when glycolysis is
inhibited by 2-DG, the cells can survive on fatty acid oxidation and
whatever small amount
of pyruvate is still being made.
Posted by: Orac | March 6, 2007 12:03 PM
Great post and a very timely article. I've also been thinking about DCA
as a research
question I wouldn't have delved into had I not been blogging and
thought very simply
about what all cancer pharmacologists do when a new drug is
discovered: they select
cancer cell lines that evolve resistance to the drug in question. The
process is quite easy,
given the inherent genetic instability of most tumor cell lines and give
insight as to how a
drug actually works. The proteomic angle of the Felding-Haberman
group is great but I
agree that it needs to be coupled with 2-DG or DCA in vivo.
As for Steven Chang, he was also over at my site talking about
flavonoids but failed to
produce any data when queried.
Posted by: Abel Pharmboy | March 6, 2007 12:20 PM
Yes, pyruvate can be produced from other sources than glycolysis,
including, of course,
fatty acids. 2-Deoxyglucose (2DG), over time, will inhibit glycolysis
completely as it
interacts with hexokinase, an enzyme that is being fooled by 2DG to
phosphorylate it.
2DG-6-P occupies the next glycolytic enzyme in the pathway,
phosphohexose isomerase,
and brings glycolysis to a halt. Hence, under 2DG, most, if not all the
energy supply would
come from other sources than glucose.
Posted by: S. Rivlin | March 6, 2007 12:34 PM
I believe I have already found a potential cancer cure, using flavonoids.
For more info, please email:
[email protected]
remove REMOVETHIS
Posted by: Steven | March 6, 2007 12:35 PM
Steven,
You are on the wrong blog trying to sell your snake oil.
Posted by: S. Rivlin | March 6, 2007 12:37 PM
I'm not selling, I'm serious.
Posted by: Steven | March 6, 2007 12:59 PM
Steven,
It's brilliant marketing. Go on highly trafficed blogs discussing the flaws
inherent in an
alleged cancer cure, and then spam those blogs with another alleged
cancer cure. I
admire your thought process, if not your actual thoughts.
Posted by: anonimouse | March 6, 2007 1:08 PM
I've had enough. I'm banning the guy, as this isn't the first post that he's
done this on. His
comments will now all be moderated. If they have something
substantive to say, I will
approve them. If it's just more of the same, they will remain in my Spam
Folder.
Interesting stuff. I'm actually struck by an odd thought: "If God had
meant us to cure
cancer, he would have made it easy!" Seriously, your description of the
stubborn
adaptivity of cancer made me wonder if some of the hyperactive
alternative medicine
market isn't driven by a sort of theological replacement issue. Cancer,
in effect, has
become the Satan of the modern world: sneaky, deadly, related to sin
(and warded off by
healthy lifestyles, sometimes) but not limited by it, implacable. The
alternative therapies,
etc., are indeed "faith-based" because they see cancer as evil not just
a structural issue.
This raises all kinds of other issues: doctors as priests, etc.....
Posted by: Jonathan Dresner | March 6, 2007 1:56 PM
Beautiful post, Orac.
I would like to add to the topic saying that the Warburg effect and "lack
of oxygen" are
often used in fuzzy explanations on why an "oxygen therapy" could
cure cancer. Many
supplements on the market claim they can increase the "amount of
oxygen in your blood"
- some like microhydrin, based on the flamboyant quackery of Mr.
Flanagan, others like
hydroxygen plus (which had to change name) that are claimed to be
able to "split water
into simple H- and O-.
If oxygen were the magic bullet, we would not be posting about cancer
right now...but
people keep being bought into such things, no matter how hard one
tried to disprove them
logically.
Posted by: steppen wolf | March 6, 2007 3:29 PM
Orac,
I also wonder if DCA might apply enough selection pressure to select
for tumor cells that
are better adapted to live in the brain. It wouldn't be much of a stretch
(certainly less of a
stretch than the DCA purveyors are making) to postulate that DCA
might increase the risk
of metastasis.
Just a happy thought.
Prometheus
Posted by: Prometheus | March 6, 2007 4:06 PM
I'm not a biologist, so what I'm about to write may be dumb.
As I read the news, DCA has a double take on the cancer cells. The
one is the attack
through the glycolytic metabolism, and the other is the activation of a
mitochondrial
apoptosis program. In fact, Michelakis seems to emphasis this later
one in his interviews.
Is this a total misunderstandig? Thanks.
Posted by: incze | March 6, 2007 5:10 PM
I'm not surprised that a cancer cell can switch its energy source from
glycolysis and back
again, it is after all emryonic in origin, using many of the same genes
and tricks as an
embryo. The fetus runs on glycolysis, then switches to normal glucose
use later on.
Cancer is just a cell using fetal tricks to execute its program.
No I'm not Dave Scott.
Posted by: Robert Smith | March 6, 2007 10:10 PM
I think my biggest complaint about folks who push "cure-alls" for cancer
is addressed well
here. I've wondered if terminology is the root of the problem for some
people...the fact that
there's one word for something as vastly complicated as cancer leads
people to believe it
can be cured like polio.
The differences still amaze me on a personal level. I lived with a
LARGE giant cell tumor
in my right hip for several months with (relatively) little damage to
myself. (Apparently that
type of tumor is extremely benign, and when it does metastasize, it
does so in the lungs,
for reasons I'm not sure are understood.) Yet a friend's mother was
diagnosed with a peasize
breast tumor and it had spread through her body within a month. And
I've talked to
dozens of people, each with radically different stories.
(Yeah, I know, it's anecdotal, but even that's been enough to convince
me to be wary of
any supposed cancer 'cure' I've ever read or seen a news report
about.)
Posted by: Jason W | March 7, 2007 1:59 AM
"The overall effect of these changes in gene expression leading to
increases in the
enzymes responsible for oxidative phosphorylation is that the brain
metastatic cell line
became resistant to drugs that affect the cellular oxidation-reduction
balance."
...and there will be those who will say blithely that this is not evidence
that selection
pressures can generate new information, or will claim that the selection
applied here was
'artificial,' as if this in some unexplained way magically negates any
possibility that the
same sorts of changes could take place in response to 'natural'
phenomena. (This is not
to discount potentially significant differences the post points out
between in vitro and in
vivo environments.)
Posted by: Jud | March 7, 2007 12:01 PM
I'd like to rephrase my previous question, being not really neutral (sorry,
if I seem to be
offensive, last try, I promise). Michelakis' team has found that DCA
attacked cancer cells
in *two* ways:
(i) through glytolytic metabolism (Warburg effect); AND
(ii) by (suprise!) activating a mitochondrial pathway to cell apoptosis.
Seems to me, that it is different from other designated cures targeting
just the starvation of
cancer cells, as the synchronous apoptotic processes might
successfully interfere with the
well established adaptiveness of cancer cells.
Is this reconstruction a total crap, or has some meaning? Thanks
(really).
Seems to me, that it is different from other designated cures targeting
just the
starvation of cancer cells, as the synchronous apoptotic processes
might
successfully interfere with the well established adaptiveness of cancer
cells.
If you read the paper in detail, it is explained how the apoptotic
pathway is linked with the
function of mitochondria. As I understand it, the increased oxidative
stress from the
reactivation of the mitochondria and increased production of NADH can
lead to activation
of the mitochondrial apoptotic pathway. Indeed several of the proteins
involved in
apoptosis are mitochondrial. That's one reason why targeting the
Warburg effect in
general can lead to apoptosis. 2-DG treatment can also lead to tumor
cell apoptosis.
Thank you. (It's not me. That would be all right.)
I wish there were more people here sharing real DCA-Cancer self test
results.
Patient: Woman, 65, Lungs cancer, brain cancer, spread in many other
parts of the body,
even visible on the ouside. Doctors not sure where it started anyway.
Stage IV. Given
weeks to live. Went 3 chemios, 2 radiation sessions, brain operation some tumors
shrank after that for 4 months, now growing again. Patient will not
survive another
Chemio.
Will receive 50mg/kg/day in drinking water for first week, with 500mg
B1.
after first week will recive 25mg/kg/day with 500mg B1
I got DCA from Cole Parmer.
If anyone has any GOOD reason why I should stop - let me know now.
Otherwise I will
keep you all updated as we go along. Please share all you can.
Posted by: Seb | March 9, 2007 10:51 AM
It is my understanding that a lot of tumors are hypoxic, and that hypoxic
tumors are more
difficult to treat than non-hypoxic ones.
If there isn't enough O2 (or mitochondria) available to oxidize lactate, I
think that it gets
used as a substrate to make stuff with, ie fat or ectopic fat. Most cells
derive lots (or even
most) ATP from glycolysis. It is only highly metabolicly active tissues
like muscle, liver,
heart, brain and kidney that have lots of mitochondria and that mostly
rely on oxidative
phosphorylation.
The flux of lactate in the body is quite high, comparable to that of
glucose. Most of the
metabolic studies were done on healthy college students, with intact
livers, kidneys and in
good health. Some of what is in the literature on metabolism might not
pertain as closely
to people under metabolic stress, diabetics, metabolic syndrome,
chronic fatigue, and the
various degenerative diseases.
What we need to remember about cancer cells, is that typically they
have genetic
deletions, and so are actually "less complex" than "normal cells". That
when "normal cells"
have massive deletions and yet are extremely difficult to kill, shows
how complex and
redundant normal cells actually are.
Posted by: Dave Whitlock | March 12, 2007 4:33 PM
DEAR SEB,MY FUTHER HAS SAME CONDICTIONS LIKE
YOU.PLEASE CONCACT
ME.MY E-MAIL IS [email protected] YOU.
Posted by: SLAVICA | March 14, 2007 3:10 AM
jegyzetek, hivatkozások 20:
Castanea sativa Mill. bibliográfiák:
FAO:
http://www.fao.org/DOCREP/006/AD235E/ad235e00.htm#Contents
--------doi:10.1016/S0367-326X(00)00185-4
Copyright © 2000 Elsevier Science B.V. All rights reserved.
Antibacterial and allelopathic activity of extract from Castanea sativa
leaves
A. Basile , , a, S. Sorboa, S. Giordanoa, L. Ricciardib, S. Ferraraa, D.
Montesanoc, R.
Castaldo Cobianchia, M. L. Vuottob and L. Ferrarac
a Dipartimento di Biologia Vegetale, Universitŕ degli Studi di Napoli
‘Federico II’, via Foria 223,
80139 Naples, Italy
b Istituto di Patologia Generale ed Oncologia, Facoltŕ di Medicina e
Chirurgia, Seconda Universitŕ
degli Studi, Naples, Italy
c Dipartimento di Chimica Farmaceutica, Universitŕ ‘Federico II’,
Naples, Italy
Available online 3 August 2000.
Abstract
Following the extraction of Castanea sativa with an aqueous solution of
sulfuric acid (pH 3.0), the
ethyl acetate soluble fraction was tested for its antibacterial and
allelopathic activity. The extract
was shown to have pronounced antibacterial effects against seven of
the eight strains of Grampositive
and Gram-negative bacteria used (MIC in the range of 64–256 μg/ml
and MBC in the range
of 256–512 μg/ml). The active fraction was analyzed by TLC and HPLC
showing the presence of
rutin, hesperidin, quercetin, apigenin, morin, naringin, galangin and
kaempferol. Standards of the
identified flavonoids were tested against the same bacterial strains.
The highest activity was shown
by quercetin, rutin and apigenin. The allelopathic effect was tested
against Raphanus sativus seed
germination. The extract, quercetin, rutin and apigenin caused a
decrease in the percentage of seed
germination and root and epicotyl growth.
Author Keywords: Castanea sativa; Flavonoids; Antibacterial activity;
Allelopathic activity
Corresponding author. Tel.: +39-81-2538556; fax: +39-81-2538523;
email: [email protected]
Fitoterapia
Volume 71, Supplement 1, 1 August 2000, Pages S110-S116
Comparison of hydrodistillation and ultrasonic solvent
extraction for the isolation of volatile compounds from two
unifloral honeys of Robinia pseudoacacia L. and Castanea
sativa L.
Jerković I, Mastelić J, Marijanović Z, Klein Z, Jelić M.
Department of Organic Chemistry, Faculty of Chemistry and
Technology, University of Split, N.
Tesle 10/V, 21 000 Split, Croatia. [email protected]
A comparative study of ultrasound-assisted extraction (USE) with the
mixture pentane:ether (1:2)
and hydrodistillation (HD) with the same trapping mixture is presented
for the isolation of volatile
compounds from two unifloral honeys of Robinia pseudoacacia L. and
Castanea sativa L. All HD
isolates contained many thermally derived artefacts (especially
phenylacetaldehyde with lower
percentages of furfural, cis- and trans-linalool oxides and others). USE
method gave the most
representative profile of all honey volatiles (without artefacts). In
addition, USE enabled extraction
of low molecular weight semivolatile markers (especially benzoic,
vanillic and phenylacetic acids)
that were not extracted by HD. In this regard, low percentage of
benzoic acid (0.7-7.4%), vanillic
acid (0.0-1.6%) and phenylacetic acid (0.5-4.1%) was determined in Rp
USE extracts, while Cs
USE extracts contained phenylacetic acid (20.2-23.5%) as the major
constituent with low
percentage of benzoic acid (2.5-5.5%).
PMID: 17321190 [PubMed - indexed for MEDLINE]
1: J Nat Prod. 2007 Jan;70(1):60-6. Links
Structural characterization and cytotoxic properties of a 4Omethylglucuronoxylan
from Castanea sativa.
Moine C, Krausz P, Chaleix V, Sainte-Catherine O, Kraemer M,
Gloaguen V.
Laboratoire de Chimie des Substances Naturelles, EA 1069, Faculté
des Sciences et Techniques,
Université de Limoges, F-87060, France.
A glucuronoxylan was purified from a delignified holocellulose alkaline
extract of Castanea sativa
(Spanish chestnut) and its structure analyzed by means of FT-IR, GC
of the per-trimethylsilylated
methylglycoside derivatives, and 1H and 13C NMR spectroscopy. The
results supported a structure
based on a linear polymer of xylopyranose units linked with beta(1-->4)
bonds in which, on average,
one out of every six units is substituted at C-2 by a 4-Omethylglucuronic acid unit; this structure is
typical of a hardwood acidic 4-O-methylglucuronoxylan (MGX) with an
estimated degree of
polymerization of 200. The MGX from C. sativa inhibited the
proliferation of A431 human
epidermoid carcinoma cells with an IC50 value of 50 microM. In
addition, this xylan inhibited
A431 cell migration and invasion. Preliminary experiments showing that
secretion of
metalloproteinases MMP2 and MMP9 by A431 tumor cells was
inhibited by the purified C. sativa
MGX strongly suggest that this mechanism of action may play a role in
its antimigration and antiinvasive
properties.
1: J Agric Food Chem. 2005 Jan 26;53(2):282-8. Links
Castanea sativa Mill. leaves as new sources of natural
antioxidant: an electronic spin resonance study.
Calliste CA, Trouillas P, Allais DP, Duroux JL.
Laboratoire de Biophysique and Laboratoire de Pharmacognosie,
Faculté de Pharmacie, UPRES EA
1085, Biomolécules et Cibles Cellulaires Tumorales, 2 rue du Dr.
Marcland, 87025 Limoges,
France.
The antioxidant potential of Castanea sativa Mill. leaf (sweet chestnut)
was explored as a new
source of active extracts. The capacity of the different fractions issued
from aqueous, methanol, and
ethyl acetate extracts to inhibit the stable free radical 2,2-diphenyl-1pycryl-hydrazyl, superoxide
anion, and hydroxyl radical was measured by electronic spin
resonance. Their scavenging potential
was analyzed versus their amount of phenolic compounds. Among the
active fractions, the most
effective one was A6, an ethyl acetate fraction, which contained a high
level of total phenolic
compounds (29.1 g/100 g). Thus, a different extraction procedure was
performed to concentrate the
active compounds of A6 in the new C. sativa leaf extract (CSLE).
Compared to reference
antioxidants (quercetin and vitamin E) and standard extracts
(Pycnogenol, from French Pinus
maritima bark, and grape marc extract), it was observed that A6 and
CSLE have high antioxidant
potentials, equivalent to at least those of reference compounds.
PMID: 15656662 [PubMed - indexed for MEDLINE
1: Plant Physiol. 2004 Apr;134(4):1708-17. Epub 2004 Apr 2.
Links
Protein cryoprotective activity of a cytosolic small heat shock
protein that accumulates constitutively in chestnut stems and
is up-regulated by low and high temperatures.
Lopez-Matas MA, Nuńez P, Soto A, Allona I, Casado R, Collada C,
Guevara MA, Aragoncillo
C, Gomez L.
Departamento de Biotecnología, Escuela Técnica Superior de
Ingenieros de Montes, Universidad
Politecnica de Madrid, E-28040 Madrid, Spain.
Heat shock, and other stresses that cause protein misfolding and
aggregation, trigger the
accumulation of heat shock proteins (HSPs) in virtually all organisms.
Among the HSPs of higher
plants, those belonging to the small HSP (sHSP) family remain the
least characterized in functional
terms. We analyzed the occurrence of sHSPs in vegetative organs of
Castanea sativa (sweet
chestnut), a temperate woody species that exhibits remarkable freezing
tolerance. A constitutive
sHSP subject to seasonal periodic changes of abundance was
immunodetected in stems. This
protein was identified by matrix-assisted laser-desorption ionization
time of flight mass
spectrometry and internal peptide sequencing as CsHSP17.5, a
cytosolic class I sHSP previously
described in cotyledons. Expression of the corresponding gene in
stems was confirmed through
cDNA cloning and reverse transcription-PCR. Stem protein and mRNA
profiles indicated that
CsHSP17.5 is significantly up-regulated in spring and fall, reaching
maximal levels in late summer
and, especially, in winter. In addition, cold exposure was found to
quickly activate shsp gene
expression in both stems and roots of chestnut seedlings kept in
growth chambers. Our main finding
is that purified CsHSP17.5 is very effective in protecting the cold-labile
enzyme lactate
dehydrogenase from freeze-induced inactivation (on a molar basis,
CsHSP17.5 is about 400 times
more effective as cryoprotectant than hen egg-white lysozyme).
Consistent with these observations,
repeated freezing/thawing did not affect appreciably the chaperone
activity of diluted CsHSP17.5
nor its ability to form dodecameric complexes in vitro. Taken together,
these results substantiate the
hypothesis that sHSPs can play relevant roles in the acquisition of
freezing tolerance.
PMCID: PMC419844
1: Protein Expr Purif. 2003 Nov;32(1):44-51. Links
Purification of castamollin, a novel antifungal protein from
Chinese chestnuts.
Wang HX, Ng TB.
Department of Microbiology, College of Biological Science, China
Agricultural University, Beijing,
China.
A novel antifungal protein, designated castamollin, was isolated from
Chinese chestnut (Castanea
mollisima) seeds with a procedure involving ion exchange
chromatography on DEAE-cellulose,
affinity chromatography on Affi-gel blue gel, ion exchange
chromatography on CM-Sepharose and
FPLC-gel filtration on Superdex 75. Castamollin possessed a novel Nterminal sequence
demonstrating little similarity to N-terminal sequences of Castanea
sativa chitinase. Castamollin
exhibited a molecular mass of 37kDa in gel filtration and SDS-PAGE. It
inhibited the activity of
human immunodeficiency virus-1 reverse transcriptase with an IC(50)
of 7microM and translation
in a cell-free rabbit reticulocyte lysate system with an IC(50) of
2.7microM. Castamollin displayed
antifungal activity against Botrytis cinerea, Mycosphaerella
arachidicola, Physalospora piricola, and
Coprinus comatus but was devoid of lectin activity.
1: Fitoterapia. 2002 Feb;73(1):22-7. Links
A new pyrrole alkaloid from seeds of Castanea sativa.
Hiermann A, Kedwani S, Schramm HW, Seger C.
Institute of Pharmacognosy, Karl Franzens University, Universitätsplatz
4, A-8010 Graz, Austria.
[email protected]
A
new
pyrrole
alkaloid,
methyl-(5-formyl-1H-pyrrole-2-yl)-4hydroxybutyrate (1), was isolated
from sweet chestnut seeds and its structure elucidated on the basis of
data from NMR spectroscopy
and by comparison with synthetic analogues.
http://www.ncifcrf.gov/about/readingroom/css/COTS/Cyborg/50/Regulat
ory/regulatory.pdf
1: J Agric Food Chem. 2001 Jul;49(7):3321-7. Links
Free radical scavenging activities measured by electron spin
resonance spectroscopy and B16 cell antiproliferative
behaviors of seven plants.
Calliste CA, Trouillas P, Allais DP, Simon A, Duroux JL.
UPRES EA 1085, Biomolécules et Cibles Cellulaires Tumorales,
Laboratoire de Biophysique,
Faculté de Pharmacie, 2 rue du Dr. Marcland, 87025 Limoges Cédex,
France.
In an effort to discover new antioxidant natural compounds, seven
plants that grow in France (most
of them in the Limousin countryside) were screened. Among these
plants, was the extensively
studied Vitis vinifera as reference. For each plant, sequential
percolation was realized with five
solvents of increasing polarities (hexane, chloroform, ethyl acetate,
methanol, and water). Free
radical scavenging activities were examined in different systems using
electron spin resonance
(ESR) spectroscopy. These assays were based on the stable free
radical 1,1-diphenyl-2picrylhydrazyl (DPPH), the hydroxyl radicals generated by a Fenton
reaction, and the superoxide
radicals generated by the X/XO system. Antiproliferative behavior was
studied on B16 melanoma
cells. ESR results showed that three plants (Castanea sativa,
Filipendula ulmaria, and Betula
pendula) possessed, for the most polar fractions (presence of phenolic
compounds), high antioxidant
activities in comparison with the Vitis vinifera reference. Gentiana lutea
was the only one that
presented a hydroxyl scavenging activity for the ethyl acetate and
chloroform fractions. The
antiproliferative test results showed that the same three plants are the
most effective, but for the
apolar fractions (chloroform and hexane).
1: Fitoterapia. 2000 Aug;71 Suppl 1:S110-6. Links
Antibacterial and allelopathic activity of extract from
Castanea sativa leaves.
Basile A, Sorbo S, Giordano S, Ricciardi L, Ferrara S, Montesano D,
Castaldo Cobianchi R,
Vuotto ML, Ferrara L.
Dipartimento di Biologia Vegetale, Universitŕ degli Studi di Napoli
'Federico II', via Foria 223,
80139 Naples, Italy. [email protected]
Following the extraction of Castanea sativa with an aqueous solution of
sulfuric acid (pH 3.0), the
ethyl acetate soluble fraction was tested for its antibacterial and
allelopathic activity. The extract
was shown to have pronounced antibacterial effects against seven of
the eight strains of Grampositive
and Gram-negative bacteria used (MIC in the range of 64-256 microg/
ml and MBC in the
range of 256-512 microg/ml). The active fraction was analyzed by TLC
and HPLC showing the
presence of rutin, hesperidin, quercetin, apigenin, morin, naringin,
galangin and kaempferol.
Standards of the identified flavonoids were tested against the same
bacterial strains. The highest
activity was shown by quercetin, rutin and apigenin. The allelopathic
effect was tested against
Raphanus sativus seed germination. The extract, quercetin, rutin and
apigenin caused a decrease in
the percentage of seed germination and root and epicotyl growth.
1: J Agric Food Chem. 1999 Dec;47(12):5023-30. Links
Low molecular weight organic compounds of chestnut wood
(Castanea sativa L.) and corresponding aged brandies.
Canas S, Leandro MC, Spranger MI, Belchior AP.
Estaçăo Vitivinícola Nacional, INIA, Quinta d'Almoinha, 2560 Dois
Portos, Portugal.
Oak and chestnut species have been largely used for the aging of
brandies, but nowadays chestnut is
rarely used. There have been no previous studies regarding the
cooperage utilization of chestnut
wood. This study provides, for the first time, specific information about
the characterization of the
northern Portuguese Castanea sativa wood and examines the
influence of this wood and its heat
treatment on the chemical composition of two-year-aged brandies, by
the quantitative determination
(HPLC) of low molecular weight phenolic compounds. The
predominance of gallic acid among the
analyzed extractable compounds both in chestnut wood and in the
corresponding aged brandies was
remarkable. The heat treatment has a very significant influence on the
majority of extractable
compounds analyzed. Thus, it could be responsible for the related
sensorial properties of aged
brandies and greatly affect their general balance.
1: Plant Mol Biol. 1998 Dec;38(6):1235-42. Links
A chestnut seed cystatin differentially effective against
cysteine proteinases from closely related pests.
Pernas M, Sánchez-Monge R, Gómez L, Salcedo G.
Unidad de Bioquimica, E.T.S. Ingenieros Agrónomos, Ciudad
Universitaria, Madrid, Spain.
Cystatin CsC, a cysteine proteinase inhibitor from chestnut (Castanea
sativa) seeds, has been
purified and characterized. Its full-length cDNA clone was isolated from
an immature chestnut
cotyledon library. The inhibitor was expressed in Escherichia coli and
purified from bacterial
extracts. Identity of both seed and recombinant cystatin was confirmed
by matrix-assisted laser
desorption/ionization mass spectrometry analysis, two-dimensional
electrophoresis and N-terminal
sequencing. CsC has a molecular mass of 11,275 Da and pI of 6.9. Its
amino acid sequence includes
all three motifs that are thought to be essential for inhibitory activity,
and shows significant identity
to other phytocystatins, especially that of cowpea (70%). Recombinant
CsC inhibited papain (Ki 29
nM), ficin (Ki 65 nM), chymopapain (Ki 366 nM), and cathepsin B (Ki
473 nM). By contrast with
most cystatins, it was also effective towards trypsin (Ki 3489 nM). CsC
is active against digestive
proteinases from the insect Tribolium castaneum and the mite
Dermatophagoides farinae, two
important agricultural pests. Its effects on the cysteine proteinase
activity of two closely related mite
species revealed the high specificity of the chestnut cystatin.
1: Plant Physiol. 1997 Sep;115(1):71-7. Links
Purification and in vitro chaperone activity of a class I small
heat-shock protein abundant in recalcitrant chestnut seeds.
Collada C, Gomez L, Casado R, Aragoncillo C.
Departamento de Biotecnologia, Escuela Tecnica Superior de
Ingenieros de Montes, Ciudad
A 20-kD protein has been purified from cotyledons of recalcitrant
(desiccation-sensitive) chestnut
(Castanea sativa) seeds, where it accumulates at levels comparable to
those of major seed storage
proteins. This protein, termed Cs smHSP 1, forms homododecameric
complexes under
nondenaturing conditions and appears to be homologous to cytosolic
class I small heat-shock
proteins (smHSPs) from plant sources. In vitro evidence has been
obtained that the isolated protein
can function as a molecular chaperone; it increases, at stoichiometric
levels, the renaturation yields
of chemically denatured citrate synthase and also prevents the
irreversible thermal inactivation of
this enzyme. Although a role in desiccation tolerance has been
hypothesized for seed smHSPs, this
does not seem to be the case for Cs smHSP 1. We have investigated
the presence of
immunologically related proteins in orthodox and recalcitrant seeds of
13 woody species. Our
results indicate that the presence of Cs smHSP 1-like proteins, even at
high levels, is not enough to
confer desiccation tolerance, and that the amount of these proteins
does not furnish a reliable
criterion to identify desiccation-sensitive seeds. Additional proteins or
mechanisms appear
necessary to keep the viability of orthodox seeds upon shedding.
PMCID: PMC158461
Journal List > Plant Physiol > v.115(1); Sep 1997
Summary
Selected References
PDF (1.5M)
Contents
Archive
Related material:
PubMed articles by:
Collada, C.
Gomez, L.
Casado, R.
Aragoncillo, C.
PubMed related arts
1: Plant Mol Biol. 1996 Dec;32(6):1171-6.Links
Bacterial expression of an active class Ib chitinase from
Castanea sativa cotyledons.
Allona I, Collada C, Casado R, Paz-Ares J, Aragoncillo C.
Departamento de Biotecnología, E.T.S. Ingenieros de Montes, Ciudad
Ch3, an endochitinase of 32 kDa present in Castanea sativa
cotyledons, showed in vitro antifungal
properties when assayed against Trichoderma viride. The
characterization of a cDNA clone
corresponding to this protein indicated that Ch3 is a class Ib
endochitinase that is synthesized as a
preprotein with a signal sequence preceding the mature polypeptide.
Bacterial expression of mature
Ch3 fused to the leader peptide of the periplasmic protein ompT
resulted in active Ch3 enzyme. A
plate assay was adapted for semi-quantitative determination of
chitinase activity secreted from
cultured bacteria, which should facilitate the identification of mutants
with altered capacity to
hydrolyse chitin.
1: Biochem Biophys Res Commun. 1993 Nov 15;196(3):1086-92. Links
Purification, characterization and N-terminal amino acid
sequence of a new major allergen from European chestnut
pollen--Cas s 1.
Kos T, Hoffmann-Sommergruber K, Ferreira F, Hirschwehr R, Ahorn H,
Horak F, Jager S,
Sperr W, Kraft D, Scheiner O.
Institute of General and Experimental Pathology, University of Vienna,
Austria.
Pollens from trees of the order Fagales (e.g. birch, alder, hazel, and
hornbeam) all contain one major
allergen--the main cause for tree pollen allergy. So far the major
allergens from birch (Bet v 1),
alder (Aln g 1), hazel (Cor a 1), and hornbeam (Car b 1) have been
characterized, showing high
sequence similarity with each other (1-4). We present the molecular
and immunologic
characterization of Cas s 1, the major allergen from the European
chestnut (Castanea sativa). From
aqueous pollen extracts from European chestnut a protein was purified
to homogeneity and was
subjected to further investigation. The protein revealed a Mr of 22 kDa
and was shown to represent
the major allergen of the European chestnut (immunoblotting,
histamine release) and designated
Cas s 1. Despite a marked difference in Mr, Cas s 1 shows significant
amino acid sequence
similarity at the N-terminus and is antigenically closely related to the
major birch pollen allergen
Bet v 1 (17 kDa), as shown by binding to the anti-Bet v 1 monoclonal
antibody BIP-1 and by IgEinhibition
tests using recombinant Bet v 1.
1: Plant Physiol. 1992 Oct;100(2):778-783. Links
Basic Endochitinases Are Major Proteins in Castanea sativa
Cotyledons.
Collada C, Casado R, Fraile A, Aragoncillo C.
Departamento de Bioquímica, Escuela Técnica Superior Ingenieros de
Montes, 28040 Madrid,
Spain.
Basic endochitinases are abundant proteins in Castanea sativa Mill.
cotyledons. Three basic
chitinases were purified with molecular masses of 25, 26, and 32 kD
(Ch1, Ch2, and Ch3) and with
isoelectric points between 8 and 9.5. Antibodies raised against Ch1
cross-reacted with Ch2 and Ch3.
However, Ch3 showed differences when compared with the other two
enzymes, especially in its
higher cysteine content. The size, amino acid composition, and Nterminal sequence of Ch1 indicate
that it is a class II endochitinase and, therefore, has no cysteine-rich
hevein domain. Ch1 inhibits the
growth of the fungus Trichoderma viride. The biological role of these
endochitinases is discussed.
PMID: 16653058 [PubMed - as supplied by publisher]
PMCID: PMC1075626
1: Glas Srp Akad Nauka [Med]. 1974;25:69-78.Links
[Pharmacognostic study of the sweet chestnut (Castanea sativa
Mill.) in Yugoslavia. Areas of spread in Yugoslavia. 1]
[Article in Serbian]
Glisić M, Tucakov J.
- end of the document ------------------------------------------------------------------------------------------------------------------------The mitochondrial theory of cancer
© Copyright 2008. Czimbalmos-Kozma, Ferenc, MD., GP., DCH., Dr. Papp, Erika MD.,
(excluding from © some NOTICES and WIKIPEDIA and other images!)
------------------------------------------------------------------------------------------------------------------------

harmadik rész - cancer, mitochondria, mithochondria, modelling

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