Poisoning the Spindle - Canadian Bulletin of Medical History

Poisoning the Spindle: Serendipity
and Discovery of the Anti-Tumor
Properties of the Vinca Alkaloids
JACALYNDUFFIN
Abstract. In 1995, Canadian scientistsRobert Noble and Charles Beer were inducted into the Canadian Medical Hall of Fame for their 1950s "discovery" of
Vinblastine. Their "chance" finding of an anticancer drug in the leaves of the
periwinkle plant Winca rosea, Lim.), is used to explore the historical issue of
discovery, accidental discovery, and priority. The elements of the discovery are
reconstructed through the oral testimony of key players and their published
and unpublished records. Several "unsung heroes" played key roles in this
project and reasons f ~their
r relative invisibility will be presented. Special attention is paid to the relationship between the small Canadian academic group
working at UWO and the large pharmaceutical company (Eli Lilly) engaged in
similar research at the same €be.
RCsumC. En 1995, les scientifiques canadiens Robert Noble et Charles Beer
ont et6 accueillis dam le Canadian Medical Hall of Fame en raison de leur
dhuverte, au cours des anndes 1950, de la Vinblastine. La dkouverte, qu'ils
firent par @chance*d'w m&dicament anti-cancClreux dam les feuilles de Ja
plante de la pervenche (Vinca rosea, Linn.) est utilide ici our Clhdier les questions historiques de la dlcouverte, de la dkouverte acci entelle, et de la priorit& Les elements de la dkouverte sont reconstruits B partir du tkmoinage oral
des acteurs principaux et A partir des n5cits et documents publies ou non publies qu'ils en ont laisds. Plusiers hkos non-celkbr6s ont jouk un r8le cl6 dans
ce projet et l'on expose les raisons qui expliquent leur relative invisibilitk. On
accorde une attention particulihre aux rapports qui existaient entre le petit
groupe academique canadien qui traivaillait A l'Universit4 de Western Ontario
et 1a grande compagnie pharmaceutique (Eli Lilly) qui poursuivait, au mGme
moment, des recherche similaires.
S
I
In 1997, distinguished researchers Charles Beer (b.1915) and the late
Robert Noble (1910-1990)were inducted into the Canadian Medical
Jacalyn Duffin is H a n d Professor of the History of Medicine at Queen's University,
Kingston,OntarioKR3N6.
CBMH/BCHM / Volume 17: 2000 / p. 155-192
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JACALYNDUFFIN
Hall of Fame for their "chance" discovery of the first cancer remedy in
periwinkle. Noble was recognized for "his discovery of "vinblastine"'
(VLB) a drug derived irom the Madagascar periwinkle plant (Vinca
mm, now called Catharanthis mm); Beer, "for isolating' it in 1958. The
Hall of Fame tells us that the first clinical trials were conducted at Princess
Margaret Hospital in 1959.' Among other questions, this paper will ask:
did Canadian scientists really discover the cancer remedy in periwinkle?
Was their find, as they said, owing to "chance"? And if so, how exactly
did chance lead them to study a plant that does not grow in this country?
Forty years later, Vinca derivatives continue to hold pride of place in
combination chemotherapy, making them among the earliest and most
durable of effective anti-cancer agents. They were the first in a new class
of drugs, now called stathmokinetic agents, or spindle poisons, which
are said to "work" by attacking the microtubule spindle that pulls the
chromosomes apart during mitosis, or cell division. Not only do they
kill malignant cells, they bring dividing cells into synchrony thereby increasing their susceptibility to subsequent treatments with other drugs.
The class includes the podophyllotoxins, derived from the May apple
plant, and taxol, derived from the Pacific yew tree.
Hematologists the world over have treated countless turnors, especially leukernias and lyrnphomas, with Vinca derivatives. The drugs are
also applied to autoimmune conditions, sometimes with imaginative
methods. For example, the drug's property of binding to platelets inspired the "washing" of donor platelets in Vinblastine (VLB) to create
the "poison-platelet" cocktail for treatment of immune thrombocyto~ e n i aA. ~VLkoated platelet would kill any hapless reticuloendothelial
cell that dared to ingest it.
Canadian hematologists know that these drugs were first isolated in
our country and they are familiar with the charming story of the "discovery." From a historical perspective, however, one of the most intriguing aspects of this tale is that the original scientific declaration of the
discovery contained what the authors themselves called a "somewhat
unorthodox" account that assigned a starring role to chance.3
Chance is a contested issue in the historical, sociological, and philosophic literature pertaining to discovery. Some contend that it has no
role in discoveries; others think that it is crucial. Many would suggest
that discovery itself is contentious-a process honed through retrospect
rather than a momentary flash of insight. Long intrigued by the Vinca
story and having just crawled out from under a lengthy project on another "big discovery" (auscultation), I used the excuse of this conference to examine the Vinca story a little further, hoping to bring it into
the context of the now burgeoning but highly diverging histories on scientific discovery. My sources include the publications of periwinkle re-
Poisoning the Spindle
searchers in Canada and the USA, transcripts of Charles Roland's interviews with several key figures, and my own contacts with these and
other players. My paper is divided in four. First I will summarize the
historical literature on chance and discovery; then I will briefly recount
the master narrative as told by Robert Noble; then I will expand on that
narrative in four ways using variations in subsequent retellings and
other evidence. The results show that many different things were
discovered in (and around) the periwinkle plant by many different
people and over an extended period of time. Finally I will bring the
Vinca tale back to the historiographic problem of chance in discovery,
trying to situate the former in the latter and the latter in the former.
HISTORY OF DISCOV~RY
101:OBSERVATION, CHANCE,PRIORITY, AND GREAT MEN
I
When scientific discovery is mentioned, the names of great men (and
maybe a few women) spring to mind: Galileo, Kepler, Leeuwenhoek,
Sernmelweis, Einshin, Curie, Banting, Fleming. This natural reflex creates a problem for historians who study discovery. In an historical climate that is hostile to biography and suspicious of great men, priority
easily dissolves into a reductionist soup of context and jealous precursors. Individual observation and rare flashes of insight-the famous Archimedean "Eureka!"-are mistrusted for being vested with retrospective value. A number of distinguished historians, A. C. Crombie, Rene
Taton, and my own thesis advisor Mirko Grmek among them, cautioned against succumbing to the hkjtoriographic "myths" of discovery
that tend to frame and enhance retrospective a c c o ~ n t sIn
. ~his long list
of cautions, Grmek included the suspectseliability of existing historical
records about any discovery and the tendency to describe events in
structural terms. Heargued that accounts of discovery are necessarily
(though innocently) constructed post hoc. Only with other evidence,
such as laboratory notebooks or clinical records, can we actually attempt to reconstruct discoveries as functional processes, in physiological
terms, rather than in anatomical or structural terms that tend to feature
the accumulation of discrete nuggets of understanding. Yet, even with
access to these privileged sources, ~bjectivitycan continue to be elusive.
Possessing only the subset of accounts that were actually recorded and
then managed to survive, we must view both the printed and manuWe can diligently try to
script records as merely partial te~timony.~
gather additional papers and oral testimony from survivors and descendants, but all evidence is a product of who does the recording, who
does the preservation, and who does the seeking. Historical objectivity
is difficult, and it may well be a pretence.
Sociologistsof science agree with historians that priority is a complex
tangle and that individual flashes of insight are less brilliant than they
158
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JACALYNDUFFIN
may at first seem. Inspired by a 1922 article published in a political science periodical, R. K. Merton argued famously (and convincingly to my
mind) that most discoveries are "multiples," or the result of simultaneous, independent work; singletons are the exceptions? He assembled
more than 200 examples to make his case. With Merton, sociologists
have shown how personal and national pride, perceived "races," priority disputes, and other forms of competition are a product of the norms
of the "reward system" of science that demands originality and can act
as a stimulus to scientific activity-even in retrospect. But they can also
lead to what Merton called "deviant" behavior such as fraud and plagiarism, or (more often) accusations of both?
In a pragmatic response to Merton's views, Augustine Brannigan argues that discoveries are singletons after all, especially because scientists see them that way.,Precursors aside, the discovery is not only the
observation, but also collective agreement with that observation and
justification of the claim to priority. He suggeststhat the unsung precursors should not matter or count; recognition for a discovery rightly belongs to the person who succeeds in convincing others, usually through
the printed record? In ather words, discoveries are not events; rather
they are constructs that have won acceptance.
The creative component of discoveryhas been likened to the aesthetic
impulse and judged to be "i~rational."Consequently, philosophers of
science tended to dwell on the "logic'" of scientific judgment and
method, but they avoided addressing discoverybecause of its supposed
inherent lack of logic. Even those who purported to write about discovery, including Karl Popper and Thomas S. Kuhn, have been accused of
sliding around the central issue of discovery in favor of its preconditions and its consequence^.^^ Recognizing these difficulties, scholars
have recently reconstructed the problem by altering the focus on "discovery" to a focus on "innovation," a term that is both lesser and
gredter than its precursor."
Examples of discoveries that have been attributed to chance or accident abound.12But chance has suffered in the scholarly literature of the
late 20th century, togetherwith priority, creativity,and great men. After
a decade or more of trying to minimize the role of chance, sociologists
now tend to ignore it.13 Nevertheless, some scientists of the 1960s and
1970s were so impressed with the connection that they fretted aver how
to generate policies and funding conditions that could eomehow foster
chance.14Even when the scientists involved wish to give chance centre
stage, historians and sociologists are sceptical. They contend that
chance may help to juxtapose two events, but something else is needed
to take advantage of the accident. To win the lottery you need a lucky
ticket-the Pastorian "preparation of the mind."'%e
observation of
Poisoning the Spindle
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Alexander Fleming is often trotted out as a case in point: for decades,
scientists had reported having their plates spoiled by mould; the difference between Fleming and his precursors was that he had long been
conscious of the search for magic bullets.lgIn other words, to discover B
while looking for A, you must also know that B is being'sought.
Some writers attempt to distinguish between chance and its near synonym serendipity; they refer to Horace Walpole's original definition,
featured in the Oxford English dictionary, that serendipity was "accident combined with sagacity."" The choice of this "serendipity" over
,"chance" allows for a return of great men through the "sagacity" of individual imagination. According to some, however, this definition of
serendipity diminishes chance by replacing it with "genius" or a "prepared mind."l8
Careful examination of any seemingly discrete achievement usually
uncovers a labyrinth of precursors, both conceptual and personal. These
are what Brannigan referred to as the "naturalistic-historical or psychological-preconditions," which require further "attributional" preconditions to turn an observation into a discovery.19Identificationof precursors
tends to reduce the breadth of the heuristic quantum leap of a discovery,
as judged through a distance of time and familsarity. If these precursors
are taken as evidence of multiple discoveries, the role of chance melts-if
not into necessity-then, at least, into cultural inevitability.
Recently, one philosopher bravely tried to create an' "evolutionary
epistemology" to bring back "serendipity" into gn equation of discovery. Like the scientist-observersof two decades ago who worried about
the stifling narrowness of kunding arrangements, he goes so far as to advocate "rules" for fostering opportunities for chance in researchFOBut
he does so against a tide of opinion.
In short, scholars do not leave room for chance in discovery; some
even suggest that discoveries d a not exist naturally without attributional c o n s t r ~ c t i o nOne
. ~ ~gap in this literature can be discerned. A nurnber of histories of the pharmaceutical industry have been written, but few
address questions of its relationship to academe or its impact on the process of scientific discoveryF2It is clear that the change to increased industrial support has been compatible with continued discovery; several
scientists have conducted Nobel-award-winning work while in the employ of major pharmaceutical f i r m ~ ? ~isI tnot clear, however, how this
'important shift in research support has altered the nature of the questions, methods, and especially the justifications of discoveries. The
Vinca research could eventually be seen not only as a case study of
chance in discovery, but as ari example of this interface between academic science and industry in a larger history that has yet to be written.
ROBERT NOBLE AND HIS MASTER NARRATIVE
L
Son of a Toronto doctor, Robert Noble was just 11 years old when his
older brother, medical student Clark, worked close to the Toronto team
that would win the Nobel prize for insulin. He grew up with and absorbed a partisan version of the tale about Frederick Banting and
J. J. R. Macleod. He remembered "quite distinctly" that his brother
Clark and Charles Best "were great friends.. . they tossed a coin to see
who would go with [whom] . ..my brother won the toss and he'd never
heard of Banting so he went with Ma~leod.''~~
Friction within the team
led Banting to share his half of the Nobel prize with Best, and Macleod
to share his with the biochemist, J. B. Collip. As a result, the coin toss can
be taken as evidence of how chance caused a Noble to narrowly miss a
Nobel, Indeed, the younger Noble later admitted, "the family was sort
of bound up by it."25 Discovery, priority, fame, fortune, jealousy, betrayal, and chance-that controversial "coin tossu-were themes that
haunted the people around him. It is scarcely surprising that the same
themes recurred in his own life.
AS a medical studelk himself, Robert Noble became a prot6g6 of
Macleod who was a friend of his father as well as his brother. Noble
studied medicine in both Aberdeen p d Toronto, completing his MID.
at the university of Toronto in 1934. Wanting to pursue a career in cancer research, he was nudged by Macleod into endocrinology instead.26
After a fiveyear association wi* the Courtauld Institute, he earned a
doctorate from the University of London in 1937. He returned to Canada to take up a position at McGill University with Collip. During the
war, Noble and Collip studied motion sickness and w5ys to minimize
it. They also devised a rotating d d m to create the conditions of traumatic shock in experimental animals. In 1947, when Collip moved to
UWO, Noble followed to become Pr~fessorof Medical Research and
Associate Director of Collip's new laboratory. The isolation of VLB was
that laboratory's bigge~tdiscovery.
IP March 1958, speaking on behalf of his small team, Noble read the
original vinca paper with its master narrative at a cancer research symposium at the New York Academy of Science. He said the "chain of
events" began in 1949 when the Collip lab-ever devoted to endocrinology-was investigating the presence of hormone activity in "various plant extracts to which historical hearsay had ascribed empirical
uses by primitive peoples." He continued,
The disease of cancer was certainly far from our minds when we learned of a
tea made from the leaves of a West Indian shrub that was supposedly useful in
the control of diabetes mellitus. C .D. Johnstonof Black River Jamaica,... had
been curious about the benefits of a tea made from. . .periwinkle.. .and he forwarded a supply of the material to
Poisoning the Spindle
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Researchers everywhere were keen to find a source of oral hypoglycemic agents that would eliminate the needle injections required by insulin. But oral administration of periwinkle extracts in rats had no effect on
blood sugar or glucagon levels. Noble sent pediatrician John C. Rathbun
and endocrinologist Hugh A. McAlpine to visit Johnston in Jamaica to
find out more about the preparation of the tea. Much later the investigators learned that the antidiabetic potential of oral periwinkle had already been investigated and refuted by Australian researchers in the
late 1920s.~"
Trying to improve on their own results, Noble's team decided to inject
the water extracts of periwinkle into the rats. This time, he said, the animals were "obviously affected but in an unexpected manner": they all
died. Autopsy revealed multiple abscesses. The team noted that the offending bacteria (Pseudomorias)were the same as those "isolated in rats ...
receiving large doses of cortisone." Noble continued: "Apparently some
natural barrier to infection was being depressed by both types of treatment. Further studies readily localized the action of the V[inca] rosea
extracts-a rapidly falling white blood count, granulocytopenia, and
profoundly depressed bone marrow."29
Noble's lab worked "spasmodically" on the problem, he said, and
"an intensive study was not started until 1955."~~
He went on to explain
the elegant biochemical work accomplished to isolate the active substance by extraction and chromatography, using the white blood count
as an assay. Preliminary studies of the activity of the unpurified extracts
were published in 1955 and 1957.31A photograph of the crystalline
product accompanied the 1958paper. He concluded with a report of the
effects on blood and bone marrow of healthy rats given the purified
substance. Due to a lack of materials, only "limited investigations for
carcinostatic [anti-cancer] activity" had been made in vitro on a transplantable mammary adenocarcinoma of the mouse and a transplantable rat sarcoma.32
In framing his remarks, Noble acknowledged the "awe" that "the
cancer worker in the smaller institution" must feel in viewing the "vast
chemotherapeutic screening projects" of industry; however, he continued, "perhaps the role of chance observation is neglected in his consideration of ways of searching for new agents."33
MASTER NARRATIVE REVISITED: #l WHO? WHAT? WHEN?
Noble had occasion to amplify on his story because he was asked to retell it many times in person and in print. It was picked up (and disand repackaged in vartorted) by the media, including Reader's Dige~t,~"
ious guises-the "small-local-hero" version, or the "new-cure-for-can-
cer" version or the "amazing-but-true!" version-most of which, as he
later told Charles Roland, made the team quite unc~mfortable.~~
In his Terry Fox lecture of 1984, Noble provided more context and
added to the story." He attributed the observation of the drop in white
cell counts to Dr. Vemon C~lpitts."~
Noble also revealed that C. D. Johnston of Black River Jamaica was a surgeon who had graduated from
McGill University in Montreal. Johnston's 1914 graduation photograph
shows that the Jamaican-born graduate was black (Figure l).38Noble
made this interesting observation to Charles Roland, but it was never
mentioned in print, although it must have been known to the Noble
team following the Jamaican journey of McAlpine and Rathbun.
Figure 1
Dr. C. D. Johnston and JuhaSeager Johnston.Family photographs provided by
their granddaughter, Sandy Macintosh of Kingston, Jamaica.
Johnston's connection to Canadian research demands some explanation. Bom in 1885, Johnston was already officially retired at the time of
the Vinca research. He had been given the Order of the British Empire in
1947 for his more than 30 yearsof service to the BlackRiver community.
His first wife Julia Seager (d. 1958) had met Johnston when they were
both in nursing school at Battle Creek, Michigan. They embarked together on medical studies, which he alone completed. 39 Periwinkle was
only one of hismany interests. He died on 15October 1968.
Poisoning the Spindle
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After the Canadians noticed the effect on white cells, a sufficient supply
of leaves for further studies became an issue. Dr. Johnston organized
troops of boy scouts to collect leaves in the forest. His granddaughter recalls that it was Mrs. Johnston,who presided over the collection of leaves,
drying them on her verandah and packaging them for shipping to OntarioPO
Another person entered the Vinca story. Almost always referred to by
Noble as "a Miss Farquharson," she was the first to bring the supposedly
anti-diabetic leaves from Dr. Johnston in Jamaica to Robert Noble's
brother, ClarkP1 Interested still in insulin, but no longer in research,
Clark gave the leaves to his brother. Unfortunately, Clark Noble's children have no records pertaining to these events, although they are $amiliar with the storyP2And so far, Miss Farquharson has eluded identification. She has been variously described as "a patient of Clark Noble,"
a Jamaican maid, an employer of a Jamaican maid, an employee of the
Banting Institute, and a relative of Toronto Professor of Medicine
Dr. Ray Farquharson (the latter connection, fervently denied by Ray's
hematologist daughter, Helen ["Nell"] Farquharson). I'm still looking
for Miss Farquharson, but I fear that she will remain shrouded in mystery like so many other obscure women of medicine's past, such as
Jenner's dairymaid, Mrs. Hutton of digitalis fame, and the "ignorant
Scots woman" who brought ergot to the attention of James Steams.
Supply continued to be a serious problem. The quantity of leaves
needed to make the drug was often described as an ounce of drug from
15 tons of leavesP3Noble eventually entered into a supply agreement
with the large family-owned Swain greenhouses, still located in West
Lorne, 0 n t a r i 0 . ~ ~
In these later versions of his story, Noble reported that when confronted with the abscesses, Collip abandoned hope that the leaves contained insulin and began wondering if Vinca might be a source of corti~ o n eThey
. ~ ~had been following the work of Hans Selye, their former
colleague in Montreal. In 1951, Selye published on the effect of adrenocortoid hormones; toxic doses in the rat produced multiple abscesses
with Pseudornonas bacteriaP6
In all versions of his story, Noble acknowledged that the extraction,
isolation, and purification of vinblastine was the achievement of his
chemist, Charles T. Beer. Born in England, Beer first came to Canada in
1954 as a British Empire Cancer Campaign Fellow, having spent three
years at New York's Sloan Kettering Institute for cancer research. Beer's
work in London, Ontario, was interrupted by a year at McGill in
1955-56. When he returned, he was able to isolate, purify, and crystallize the active agent, which he and Noble named "vincaleukoblastine"
(later shortened to vinb1astine)-for its derivation from periwinkle
164
JACALYNDUFFIN
(Vincg) and its effects on white cells. Beer's method consisted of making
extracts with various solvents and then separating the components using fractimal precipitations, paper and column chromatography. He
injected the separated components into rats and used the fall in the
white cell count as an "assay"--the indicator of activity?' Beer described the chemical process to Charles Roland:
[yhis was old-time organic chemistry.. .. you have a very crude mixture, and
we had a little brown gummy mess really; you try and dissolve it in an organic
solvent,. .. Then you allow it to cool slowly and the hope is that the substance
you're interested in will come out crystalline but leave the impuritiesbehind . . .
then you filter, you pour off,. . . the brown gucky liquid on the top and you
have this liktle pad, tiny pad of white crystals. . .
I didn't have enough ..,and so I was doing it on amicroscope, under a microscope slide. Running lit& amounts of solvent in under the coverslip and then
watching the edge of the coverslip, where the liquid was oozing out, and it's
evaporating, and if you see a crystal there, then you think you are beginning to
see the fdx, even if you haven't got it.
You have a tremendousrange of solvents. Benzenes, alcohols, acetone, petrol
~ ether.
, Sometimes you use mixtures.. . . These compounds we already
knew were in the class known as alkaloids, and this gave us a little bit of an extra handle on it.. Just a matter of trial and error. Mostly error for several
montl'p. ...
It took about 5,000 attem ts. About 250 columns were tried.. ..
[Y]ou would get 100 to 1 fractions off leach column], and the assay of these
[using white cell counts in rats injected with the extracted fractiom] ... was of
course quite a big job.. ..demanding in time. Since most of the fractions weren't
activeanyway. We designed the column. ..on the basis d t h e results we obtained.
Che night I'd had supper in the restaurant at the University of Western Ontario campus,. .. somewhat depressed, and talking to a colleague and he said,
"How's the crystallization going?" I was on the point of going home, but this
remark goaded me or stimulated me to go back and have one more shot in the
lab. I was looking down the microscope Held and I saw like a tiny dot of light In
the field, and suddenly a long $fining spear-like object radiated from this little
dot. Eventually the whole field was filled with a mesh of little crystals and that
was it!48
.
.
6
Beer was right that the work, which he described so eloquently,
placed the research in enticing but established territory. Plant alkaloids
had first been identified and isolated in the second'decade of the nineteenth century, with *workon morphine, ipecac, and quinine; indeed,
these achievements produced a conceptual shift in chemi~try.4~
In the
first half of the twentieth century, mu& excitement and many Nobel
prizes-for hormones, vitiimins, and antibiotics-had emerged from
the tradition of identifying activity, isolating the agents, purifymg, and
eventually synthesizing, the praducts.
Noble later revealed that the original 1958 paper had been submitted
to the cancer symposium at the last minute when he was approached by
Poisoning the Spindle
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165
the organizer, Dr. Chester Stock. The meeting ran late. When the team
from Canada rose to present their findings, it was already midnight; the
audience was reduced to a handful of willing listeners, mostly members
of a team from the Eli Lilly drug company, led by the director of research, Irving S. Johnson. As Noble told it, the title of the paper had
"caught Johnson's eye." Johnson himself told me that he, too, was
speaking at the meeting; having seen the abstract circulated with the
program, he had telephoned Noble in advance to ensure their meeting50 Beer described the phone call as "frantic";51 Johnson was more
sanguine.
According to Irving Johnson, the Eli Lilly company had been engaged in "a huge screening program" of the awe-inspiring type alluded
to by Noble. It was "conducted by the WC1 under the auspices of. . . the
Cancer Chemotherapy National Service Center (publishers 'of Cancer
Chemotherapy ~ q o r t s ) . ' " Lilly
~
had been supporting Johnson and his
team in a search for anti-cancer agents by testing up to 5,000 materials a
year, including a wide range of plant extracts, against various animal
tumors. They had heard reports from the Philippines about periwinkle
and diabetes; however, the plant screening project was not specifically
targeting diabetes, although Noble, Beer, and others often said that it
was, an assumption based on Lilly's connection to insulin poduction in
the past.
The Eli Lilly company had originally wanted its team to use just one
line of tumor cells in screeningtests (L-1210 mouse leukemia), but Johnson knew that drugs might be effective far only some tumors. He had
argued for the use of others, including the P-1534 mouse leukemia.
Years later, he expressed justified satisfaction that his view$ had prevailed: Vinca had no effect on the first cell line, but it was effective
against the additional cell line.s3 By the time Noble's team went to the
New York meeting, Eli Lilly company already had documented the
anti-tumor effect of the drug in mice. But, Johnson admitted, they had
yet to publish those results. In convpsation with me, he pointed out
that 60 different alkaloids were eventually isolated from the plant. He
readily acknowledged that Charles T. Beer "certainly did" hold priority
for devising a method for isolating the alkaloiq V L B . ~
During 1958, Lilly adopted,Beerlsmethod and quickly began trials on
animal tumors with VLB (called Lilly 29060-LE). Johnson reported the
anti-tumor effects at two qeetings in the followin&year. In both abstracts, his team took the opportunity to retrospectively stake their own
claim to priority by situating their observation of the anti-tumor activity
in December 1957-four mg-nth befort the meeting in New York
Until late 1959, Qlly labs acknowledged the provision of "authentic"
VLB from Noble's team.s6Lilly's isolation chemist, Cordon H. Svoboda,
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JACALYN DUFFIN
began working on another isolate, Leurosine, which he had named for
his father, Leo.57Some reports imply that he had isolated the chemical
before Beer had isolated VLB; however, published reports of Leurosine
did not appear until late 1 9 5 8 . ~ ~
A "controversy" between Beer and Svoboda ensued.59Tension can be
traced through the footnotes of their publications. Svoboda's isolate
had weaker activity over a narrower range of tumor types, but he doggedly kept up work on his father's namesake, always emphasizing
Lilly's priority and the drug's effectiveness. Leurosine was found to
have an effect on animal tumors similar to that of VLB,6O and an effect
on human tumors transplanted into animals.61It was brought tohuman
trials, Johnson told[ me, but never licensed c~mmercially.~~
Nob&
thought that Svoboda's Leurosine appeared to have activity because it
was contaminated with VLB.63But Beer told Charles Roland that spectrophotometry of VLB and Leurosine initially showed superimposable
spectra-despite differences in the two substances. Beer said "they had
got out something which was essentially inactive. Very very negligible
activity. The reason it was overlooked" was owing to methods "used
for measuring the spectra [that] used a mineral oil mull, in preparing
the sample, and that makes an opaque area in the scan. ...It took quite
some months before it was pinned down as to what was going on."@
Once the Leurosine-VLB situation was sorted out, the Canadian lab
had "from that point m, quite a close, very happy arrangement with Eli
L i l l ~ . "Noble's
~~
team vlited the Lilly lab in Indianapolis and the Lilly
team came to Western. Beer described the differences to Dr, Roland:
Our columns that we used for separating things were about half an inch in diameter and perhaps fifteen inches long. Tiny things. The liquid would be
drained, go through quite slowly, and come out in a drip, and it dripped quite
slowly. . . When I went down to the Eli Lilly crzmpany, I would see a pipe about
ten inches or a foot in diameter and thirty feet long, going up through the building, and solvent going in at the top from a barrel and running out like water
from a faucet at the bottgm, so they had -and they were processing, I am sure,
literally tons of the plant.66
.
I
The Canadians tried to maintain their own supply of periwinkle, but it
soon became obvious to all concerned that they "could not compete"
with the resources available at L i l l ~Th&
. ~ ~earliest trials conducted in
Canada indicate that the VLB was "prepared in the Collip Laboratory.. .from material kindly supplied by the Eli Lilly Co."68
Beer and Noble had funding from the Medical Research Council
(MRC) and the National Cancer Institute of Canada (NCIC).These bodies required that a patent be sought for all discoveries made in research
that it funded. Beer's method for isolating vincaleukoblastine was patented in the names of Noble, Cutts, and Beer in late 1962.69Eli Lilly com-
Poisoning the Spindle
167
pany helped in drawing up the patent and were the original leaseholders. According to Noble, the patent was offered to the MRC and the
NCI, but, Noble claimed, they "did not wish to hold it."70It was taken
over by President Edward Hall of UWO to which Noble's team sold
their interests for a dollar. But Noble and Beer left for Vancouver in
1960. Noble said the funds "helped," but he complained to Charles
Roland that the arrangements might have provided "a lot more research funds if we'd stayed at Western where they created a fund with
royalties .. [which] continued for 17 years."71 Yet Harold Warwick, the
former Dean of Medicine at UWO, remembers writing cheques to Noble on the proceeds of the patent, and he told Charles Roland that if Noble "didn't get the money, he'd always write to [me] and say, 'Where is
it?"'72
The question of who discovered the anti-cancer properties of the
Vinca alkaloids seems less clear now than at the outset of this paper.
Two teams were involved in the process researching the issue from two
different angles, although they relied on the same well-established
methods in biochemistry. Behind the teams were a number of lesser
known (and less knowable) individuals, in Jamaica, Australia, and the
Philippines, who had investigated the healing properties of these
plants. When the discovery was made is even more difficult to determine. In fact, isolation of the drug notwithstanding, "discovery" of its
anti-cancer properties still required proof in real patients.
MASTER NARRATIVE REVISITED:#2 CLINICAL TESTING
l
Until late 1958, only rabbits, rats, mice, hamsters, and cells in petrie
dishes had been treated with the promising new drug. Using VLB on
humans was the next step. From this distance, it appears that there was
a race-even a little stampede-to~be the first to do so, although the
people whom I interviewed hesitated to call it that (seeTable 1).
Noble seems to have hoped that the clinical testing would be done in
Canada. In his lectures, he credited the first human trials to Dr. Harold
Warwick at the Princess Margaret Hospital and to Dr. Mac Whitelaw of
Vancouver, each of whom published a large series with impressive results in Hodgkin's disease and lymphosarcoma. Almost as an afterthought, Noble mentioned Dr. M. E. Hodes of Indianapolis who "also
observed beneficial effects on cancer patients" using VLB supplied by
Lilly company." But in an interview with Dr. Roland, Noble acknowledged Hodes' priority?* Warwick may hold the honm for Canada, at
least, and his trial was without question the largest.
Harold Warwick was newly returned to Canada from Royal Cancer
Hospital and Brornpton Hospital in London, UK. There he had directed
a clinical trial of nitrogen mustard in 41 patients with bronchogenic car-
168
JACALYNDUFFIN
cinoma of the lung--one of the first large series of single agents used in
solid turn or^.'^ He spent a year at McGill before being recruited to
Toronto in 1947 as the first executive director of the Canadian Cancer
Society and the newly established NCIC. Desirous of maintaining his
clinical skills, he worked at Toronta General Hospital. Eventually he
was asked to head up the first Canadian progwm for chemotherapy trials at the Princess Margaret Hospital (opened in May 1958).At the time,
cancer chemotherapy was new and consisted of only a few drugs:
alkylating agents, including nitrogen mustard, and the folic acid antagonists. Most cancer care was predicated on the radiation therapy model.
The chemotherapy ward was to study new drugs for possibleeffectiveness and more probable side effects. Incidentally, it provided hope to
the terminally ill.
Table 1
Early Clinical Testing af Vincaleukoblastine, 1958-61
Author
# of patients
1st Trial Submitted Published
Hertz
Hodes
Warwick
Hertz
Hodes
Hertz
Warwick
Hodes
Hertz
Warwick
Whitelaw
8
20
22
8 (old pts)
32 (20 old pts)
8 (OMpts)
24 (new pts)
13 (new pts)
14 (8 old pts; 6 new)
120 (46 old pts)
55
? Nov 58
?
3 Jan59
May 59
11 Jan60
14 Jan60
14 Jan60
Jun6P
Jun60
Jun60
?
?
?
Jan60
?
May 59
Jun60
?
?
?
?
Apr 59a
Nov 59
Aug60
A U 6ob
~
Aug 60
HHCC 61C
HHCC61
HHCC61
Apr 61
Sep G1
Sep 61
a 8 pts total 26 courses. longestremission 5 mos
8 pts total 26 courses.most 6 courses.longest remission6mos
c 8pts total 26 courses.most6 coureq.longestremission6rnos
4
Dr. Warwick recalls that Noble and Beer came to Toronto, somewhat mysteriously without an app~intment,bearing dark brown ampoules of purified vincaleukoblastirie and explaining what little they
had been able to determine of its mode of action.7BWarwick was already well-acquainted with Noblie for his contributions to the research advisory board of the NCIC. He understood that Noble had
tried to interest clinicians in London, Ontario without success. To this
day, he marvels that the dose that they selected to use in humans, based
on their experience with rats, continues to be the dose used today.=
Warwick a h remembers that the first patient to whom he gave VLB
was a 29-year-old male lawyer with Hodgkin's disease. Before the
man's death, a marked decrease in the size of his lymph nodes was ob-
Poisoning the Spindle
I
169
served, but the drug had to be stopped because of gastrointestinal
bleeding; the case was counted a treatment failure with drug side eff e c t ~In. ~retrospect
~
it was neither.79
Warwick slowly began to accumulate the first large clinical series
with VLB as a single agent. His early report noted "mental changes" or
"effects on the nervous system,"80but he still berates himself for failing
to document the neurotoxicity of the drug in absent deep tendon reflexes.
It would have appeared, he said, "if we had done the e~amination."~'
The head nurse on Warwick's Metabolic Research Ward from 1958 to
1961 was Rosemary Grant. Fresh out of her training at Wellesley Hospital, she witnessed the desperation and gloom surrounding the admission of patients to the small service of 10 private rooms on the fifth floor.
These people were expected to die, she explained, "at the end of the
line." Even those who actually responded to the drugs would die
sooner rather than later; the drugs were being tested in them "instead of
the animals." In fact, she told me, the animal laboratories were just a
little further down the same corridor. The nurses were to offer comfort
and "monitor changes." "Chemotherapy was such a new thing" that
no protocols had been established;we were "just groping," she said. We
did a "heck of a lot of blood work" and were "really tuned in," making
observations, and prepared to "report the least thing." The only way to
cope with the sadness was to aim simply for the patients' comfort, to
help them die with dignity. The patients were "incredible," she recalls;
"they really felt you were trying to help them" and "their confidence
was rewarding"; it kept you going.8a
Nurse Grant cannot remember the details of Vinca testing-all the
drugs had numbers instead of names-but she does remember something special happened that year, because for once one of the drugs
seemed to work, sometimes. "It was quite a dramatic response" with
"few side effects" arid "people were quite excited."83
Warwick's resident, the future distinguished oncologist Dr. Ruth
Alison, has similar memories. The VLB research was already underway
when she joined the team, but she was a co-author on the final paper
that reported on 120 patients. Of the 27 patients with Hodgkin's disease in
the series, more than half (14) had responded to VLB.&The experience of
collecting so many cases as evidence made a strong impression on her. At
the oncology meetings in 1960, she was disturbed by reports of small
samples of 20 patients or fewer. With nurse Grant, she remembers the excitement-"Canadian excitement1'-about involvement in a carefully
conducted study on a promising new drug in the very early days of cancer
chemotherapyon the investigativeward of the fledglingh o ~ p i t a l . ~
Although Noble repeatedly told Warwick that he was the first to perform clinical tests, Warwick himself suspected that the Americans had
170
I
JACALYNDUFFIN
used the drug in humans first.86Dr. M. E. Hodes of Indianapolis certainly could stake a claim to priority: his abstract on experience with 20
patients was printed in November 1959.87Hodes remembers that "Lilly
wasn't happy with my results (Leurosine I believe). The stuff I was
given was, as I recall, very toxic."s8 Similarly Dr. Roy Hertz of Washington could stake a claim for priority. He had already led chemotherapeuand quickly treated
tic trials with other drugs on chorio~arcinorna,~~
eight women with VLB for choriocarcinoma; five of the eight responded. Hertz reported on this same experience at several meetings
and he tested the Vinca Qsugson choriocarcinoma maintained in an animal host. On at least one occasion he thanked Hodes for advice based
on his "earlier" experience?O
In 1999, when I asked them, neither Hertz nor Hodes would claim
priority; they remember only the pleasant collaboration with the Canadians and Lilly's support. Both clinicians were already engaged in large
programs to provide clinical testing of other cancer drugs-VLB was
just another agent. Hertz described I. S. Johnson as a "most cooperative
Director of r e ~ e a r c h . "Hodes
~ ~ wrote that the Lilly "people I dealt with
admired Noble's observation (leukopenia after administration of an antidiabetic potion) and its follow-up. "First rights" or right of first publication, at least at the clinical level, were a precious commodity'r92-a
commodity that commanded respect. Hodes recalls that chemotherapy
was in such disrepute that colleagues teasingly referred to VLB as "Krebiozen," linking it to a widely publicized and eventually discredited
cancer "cure" that first captured public imagination in 1951 and continued to evoke polemic as late as 1963.9~
All the researchers I have interviewed emphasize that the Vinca alkaloids were promising because they represented an entirely new class of
drugs with a new mode of action. The ability to combine drugs with differing toxicities against the same tumor target was the eventual making
of combination chemotherapy as a powerful treatment choice.94These
days of new successes were heady indeed. Hodes recalled, "My friend
Elliott Osserman wasn't too happy with me when I presented data at
Columbia over an hour late, because we were held up by questions during presentation of the same data at S[loan] K[ettering] I[in~titute]."~~
When asked what he recalled of the early trials, Hodes replied: "the remarkable thing about the drug was that it worked."96
Hodes mentioned the "Hertz-Hodes race" and wondered if Hertz
had been brought into the trials early because of his friendship with
Gordon S ~ o h o d aBut
. ~ ~Hertz himself-now 90 years old--credits Bob
Noble for sending him "a generous sample of the extract.'f9sThe two
men knew each other from meetings and they shared an interest in hormones and ~ancer.9~
Hertz eventually claimed that these single drug tri-
Poisoning thr Spindlr
l
171
als were useful more for delineating the side effects than they were for
provoking cures.loo
Did Noble actually have enough of his precious commodity to give
some away to an American scientist so early in his work? Clearly he was
frustrated with local clinicians for not accepting the challenge. Princess
Margaret Hospital had only just opened its doors and Warwick seemed
stubbornly bent on collecting large numbers of patients before pronouncing on the drug.lol Hertz was already set up for clinical testing
and understood the relationship of hormones to malignancy. Noble
seems to have forgotten that he had involved Hertz so early in the research. Indeed, the printed record is obscure. In their publications, both
Hertz and Hodes thank Lilly for providing VLB, and both began their
clinical trials in humans before Beer's method appeared in print and
less than a year after it was announced.
Almost simultaneously in January 1960, the Canadian and American
teams submitted five different articles about Vinca clinical testing to the
leading journal Cancer Research; they were published in the August issue.lo2By June 1960, a conference was held at Honey Harbour in Georgian Bay. Noble, Beer, Cutts, Warwick, Hodes, Hertz, Whitelaw, and
Johnson of Lilly, a 1 attended to communicate the results of their chemical
and clinical testing. Noble gave the introduction.lo3Hodes and Warwick
both reported on new experiencewith new patients; Hertz reported again
on his original cases; Beer presented the results of his studies on the metabolism of the drug, and Cutts gave evidence of its anatomical toxicity.
Unfortunately no one appears to have taken (or kept) any photographs.
On 3 March 1961, at around 2 p.m., Eli billy Co. announced the commercial availability of a new anti-cancer agent, vincaleukoblastine,
which they called Velbe. This news had been heralded by a mysterious
jump in Lilly stock of 12 points over the preceding week and another
five points on the morning of the announcement. The fianeial mystery
was dispelled only to be replaced with a potential crisis when an anonymous cancer researcher was quoted in theNew York Times as having said
that his test results were "not of sufficient moment to encourage the
pursuit of further work."lo4 Three months later, the economic costs of
grants and benefits for cancer treatment were the subject of another report in Toronto's Financial Post. In that article, VLB was described as a
plant chemical "developed" at London, 0ntario.lo5
From a commercial as well as a clinical perspective, VLB was just the
beginning. According to Johnson, only three alkaloids of the more than
60 isolated from periwinkle made it to human trials;lo6the most active
alkaloid of all was never developed because it was found in amounts
too small.lo7Using their impressive methods, Lilly later went on to isolate the drug vincristine, another perwinkle alkaloid found in even
172
I
JACALYN DUFFIN
smaller quantities.losMore potent, with an unusual neurological toxicity, and owned completely by industry, vincristine always attracted
more media attention than did VLB. As soon as the first clinical trials
with vincristine were announced by Hodes's team at an Atlantic City
meeting in April 1962, the new Eli Lilly product received media attention, in which it was compared favorably to "ineffective" VLB, despite
the great similarity of their chemical s t r ~ c t u r e s . Almost
'~
in retaliation
just two months later, Noble's team at Vancouver used the excuse of a
visit by Charles Dodds of the Courtauld Institute to feature their own
discovery of VLB and its antileukemia potential in the financial press.l1°
Vincristine, together with other agents, enabled the Boston team of Emil
Frei I11 to announce an e4fective treatment for childhood leukemia in
1962."' It was released for the treatment of childhood leukemia in July
1963,112 and it was the subject of numerous international conferences.
Almost 40 years later, it still is the mainstay of remission induction in
childhood leukemia.
In 1985,vincristine brought Lilly's research director Johnson the prestigious Bruce F. C a b Memorial Award for Cancer Research-a prize he
was awarded jointly with Robert Noble for the discovery of vinblastine.
The title that Johnson used for his Cain lecture picked up on Noble's
theme of "chance" and indicated his opinion of the favorable contribution of industry in pharmaceutical research: "Rational Drug Screening:
Serendipity to Selectivity.'He opened with these words: "The Vinca alkaloids were discovered independently in two Separate laboratories by
a combination of serendipity and what I have called rational broad
spectrum tumour ~creening.""~
If the discovery of the anti-tumor properties and the isolation of the
alkaloid responsible had been a complex process involving several
teams in several places, demonstration of its beneficial effects on living
patients with malignancies was the object of many more teams in more
places-a race for priority. Yet I must admit that my impression that
there was a priority race is based on the tracks left in publications and in
opposition to the recollections of the researchers themselves.
MASTER NARRATIVE REVISITED: #3 S E G TO
~ MICROTUBULESAND THE "NEW
CLASS OF DRUGS
VLB had been crystallized and used in humans, but its mechanism of
action was still unclear. Who first noticed that it "poisoned the
spindle"? That suggestion was first made, in print at least, by Johnson's
team at Eli Lilly in a paper that was submitted for publication on 7 January 1960.*14Cutts came to a similar conclusion in a paper submitted six
months later, because he found an excess of mitotic figures (cells in
metaphase) in the bone marrows of treated normal rats and mice with
Poisoning the Spindle
173
turn or^."^ But these microscopic observations did not explain how ex-
I
actly the drug was able to arrest mitosis. A key concept was still missing: the tubulin protein of the mitotic spindle had yet to be described. In
other words, to complete "discovery" of periwinkle derivatives as a new
class of chemotherapeutic agents yet another discovery was needed. The
advent of the Vinca alkaloids stimulated researchers to complete that discoveryby the mid 1960s.
Even as scientists studied the effects of periwinkle, one spindle poison had already been well-known and well-used. Its "discovery"
shares many features with that of Vinca: great men, forgotten heroes,
priority questions, independent discoveries, technological imperatives,
and a protracted history.
Colchicine-a substance derived from the auhunn crocus-had been
used in medicine since antiquity and figured in the work of Dioscorides. Its popularity increased in the eighteenth century when Anton
von Storck recommended it as a specific treatment for gout, a rble it continues to play on occasion. It was crystallized in 1884. But coldhicine is
strongly toxic to the gut and can cause severe nausea, diarrhea, and
pain. In 1&89,while studyhg the intestinal lesions induced by colchicine, the Sicilian pathologist Biaggio Pernice noticed a high proportion
of mitotic figures in the damaged gut tissue. His work Was promptly
forgotten. Fifty yews kiter, however, the property of colchicine to arrest
cell division was widely used by scientists interested ift chromosomes
and karyotypes-whether or not they had heard of Pernice.
In 1938, colchicine's spindle-poison effect wag labelled "stathmocin&seUby Brussels pathologist Albert Pierre Dustin. A decade later,
Dustin's son ran across Pernice? reference and awarded him priority
By 1960,when VLB came on the:scene, colchicine was
an estabbhed tool in the work of cell biologists-but how exactly it
poisoned the spindle was still unknown. The technological advantages
provided by radioisotopessharpened the focus slightly.
For more than a century, light microscopistshad reported seeing delicate filaments in dividirlg cells; by the early 1960selectroh microscopists
had gi~fehthese filamerits a name ("rnicrotubules"), dimensions (100 to
120A), and falocation not only in the mitotic spindle-where they were
found in greatest abundance-but also in the dendrites of neurons.'17
While Beer applied tritiated-VLB to studies of VLB rnetaboli~m,"~
Edwin Taylor was applying tritiated colchicine to a study of its mechanism of action and in 1965he confirmed the existence of microtubules,
made of the substancelater named "tub~lin."'~~
Microtubules became a mini-industry in cell biology and they offered
a neat explanation as to why the periwinkle drugs were toxic to nerves
174
JACALYNDUFFIN
as well as to rapidly dividing ~ e 1 l s .Inevitably
l~~
the extracts of periwinkle and crocus were compared.121
Could a discovery of a drug be complete without elucidation of its
mode of action? As noted above, the researchers involved in this discovery claimed to be excited by the recognition that the Vinca alkaloids represented an entirely "new class" of drugs with differing mechanisms of
action, and differing side effects. Yet Vinca's mode of action was unknown even as it was being tested in humans. Its "new class" status as a
spindle poison was only conjecture-conjecture that was not to be settled until 1965, when the pressure brought by the discovery of the Vinca
alkaloids brought to completion yet another discovery in cell biology:
that of the spindle itself.
MASTER NARRATIVE REVISITED:#4 BACK TO VINCA
l
These amplifications to the story still leave us with a number of questions. When exactly did Noble first begin looking at the leaves?For how
long did the London team try to grow and manufacture enough drug
for testing? Who was Miss Farquharson? And above all how did an endocrine team actually think to look at the drug as a potential cancer agent
rather than as a weak source of hormone too toxic to investigate? After
all, n ~ t h i n gin the original protocol should have induced them to measure white blood cells in rats: the technique was cumbersome, time-consuming, and costly. Following yet another speech on his discovery, the
aging Noble was asked, "Why ever did you look at the white cells in the
first place?" He replied that in all honesty, he did not know.122
Seated in the audience for that speech was someone who did know
the answer to the question, but did not have the nerve to speak
Polish-born Halina Czajkowski Robinson (b. 1927) had survived the
camps of Auschwitz and Bergen Belsen and been relocated by the United
Nations and the Red Cross to Sweden in 1945 where she entered university to study chemical engineering. She graduated with high marks eaming herself a place in the Karolinska cancer research laboratory of George
and Eva Klein.124Although her background was in applied basic science, she mastered a number of delicate biological techniques, including the determination of blood sugar and of white cell levels. At the outbreak of the Korean war, many refugees sought to move again and
Halina with her parents (her father had been found after the war) was
relocated to Canada. She hoped to return to engineering and was advised to choose London because it was "central." With irony, Halina
told me how she quickly learned that the London, Ontario of 1951 was
not yet ready for a woman engineer. In May 1951, J. B. Collip gave her
work in his laboratory on the strength of her experience with the Kleins
at the Karolinska. Her supervisor was Robert Noble (Figure2).
175
Poisoning the Spindle
As soon as Halina arrived, Noble showed her periwinkle leaves in a
box and explained that the team was looking for an effect on blood
sugar levels. She was to measure glucose in the blood of rats given oral
extracts. But she did not want to lose the other skills that she had so recently acquired in Sweden. As a result, she performed blood cell counts
too. When the experiments turned to injections on or before 8 September 1952, she observed the decline in white cell counts. At first she
thought it was an error, but the finding occurred on repetition, and she
accumulated and confirmed her results, during the year of 1953. Finally
she showed her results to Noble. He listened to her politely without saying much, and then he sent samples out to the hospital laboratory for
confirmation. She was not offended--she respected his desire for accuracy and she thought that his listening to her at all was a mark of tolerance. Parallel work on autopsies and comparisons with the effects of
cortisone given to animals was carried
Figure 2
Halina Czajkowski (later Robinson)circa 1951,
photograph provided by Halina Robinson.
176
JACALYNDUFFIN
Dr. Vemon Colpitts, cited by Noble as the one who observed the crucial drop in the white cell count, was not involved with the periwinkle
project at all; he had been working on estrogenic effects found in extracts of a different plant, Lithosperm. Halina recommended that the
team perform chromatography to isolate the active component, but that
technique was not applied until the arrival of Charles Beer in 1954.
Halina left Noble's lab in October 1955 to direct the Pediatric Research
Laboratories of War Memorial Children's Hospital in London, Ontario,
where she remained until her retirement in 1976.She gave her notebook
to Collip, but years later, it could not be found.lZ6Misspelling her name
as "Helena," Noble thanked her for her assistance in the acknowledgments of his 1958paper.
Encouraged by Colpitts and the lak Dr. Ken Carroll, Mrs. Robinson
set the record straight in 1991 by publishing what she called an "anecdote" containing some of the foregoing story in the same journal that
had printed Noble's own account the previous year.12' Also choosing
the frame of chance-"another happenstanceu--she explained that her
anecdote provided one more reason why "priority for this discovery remained in Canada." Her own white cell findings she called "fortuitous." Noble seems to have forg~tten
Halina Robinson, just as he forgot
Hertz. When I asked her if it might be because she was a laboratory
technologist and a f e m a l e - s b hesitated at first-and then laughed
saying, "I wouldn't be surprised. I wouldn't be surprised."128
CONCLUSION
I
Noble and Beer moved to Vancouver in 1960 shortly after the Honey
Harbour Conference. They continued to work on the chemistry, uses,
and effects of Vinca alkaloids but both turned to other projects. Archivists at the University of Western Ontario are unable to trace any
record or profits of the vincaleukoblastine patent and neither they nor
their colleagues at the University of British Columbia can locate Noble's
papers or laboratory notebooks. Lilly claims that it took many years to
recover its investment, because the drugs were given away or sold at
cost for a long time in an effort to keep prices down.lZ9One of the early
leukemia investigatorshas written that clinicians associatedwith U.S. National Cancer Institute went in person to appeal to the "Lilly board to produce the drug for humanitarian reasons-the lives of these little children
were at stake."130 Lily archives will not disclose what profits have been
made on the Vinca alkaloids or even what quantities were sold. Warwick
(who signed the royalty cheques for Noble) told Roland that profits were
in the order of a hundred million dollars a year.13'
At the Canadian Medical Hall of Fame, one can read how "Dr. Noble
made his discovery of 'vinblastine,' the first major advance in chemoth-
Poisoning the Spindle
I
177
erapy originating in Canada." You will find the master narrative, including "serendipity," "diabetes," brother Clark, and periwinkle
leaves originating in 1952. And you will read that "working with the Eli
Lilly Co., a small supply of vinblastine was prepared. for clinical trials
the first of which occurred incl959 at the Princess Margaret Hospital in
Toronto with very dramatic results."132Based on the foregoing, it seems
that most of these claims are half-truths, or wrong.
Noble and Beer may have found their places in the Canadian Medical
Hall of Fame, but this version of their achievement is world famous
only in Canada. Lilly executive I. S. Johnson knew the team well, had
been to the Honey Harbour conference and to UWO, and had even been
offered a job at Vancouver by Robert N0b1e.l~~
Yet in 1992, Johnson
seemed to overlook Canadian "priority" in the development of these
drugs when he wrote; (quite truthfully) in Science magazine 1992 that he
was "the leader of the group that detected the anti-tumour activity from
the plant at L i l l ~ . " 'He
~ ~acknowledged that "two different groups" had
been working on the plant, To me, he wrote that "this was a classical
case of two groups making similar observations, completely independently of each
As we have seen, a printed record does not
prove ~ r i 0 r i t y . l ~ ~
Indeed, it is difficult to ascertain what credit for this "discovery"
should be Canadian at all. Researchers in Australia had published on
Vinca's lack of effectivenessin diabetes back in the 1920s-was it chance
that Noble was stillvpursuingthe possibility, or simply ignorance? Scientists of the pre-Medline world might be forgiven for not having noticed much earlier papers in foreignjournals.
As for the cancer connection, Lilly scientists were well launched on
Vinca alkaloids in cancer chemotherapy screening, and they had already demonstrated an anti-tumor effect before any Canadian applied
it to the hematologic malignancies for which it is now principally used.
As much as the academic team in Ontario tried to maintain respectable
production, they too came to reIy on the products and generosity of industry for their work.
And if priority is somewhat fuzzy, what is left for chance? Noble's
claim that cancer was "far from our minds" cannot be sustained. Before
1958, he was first or second author on no less than 13 papers on cancer
research; he enjoyed NCK funding, had a collegial relationship with
Hertz based on their interest in hormones in oncology, and was regarded as an expert in turnor growth. He held priority for the important
discovery of the effectsof hormone withdrawal in neoplasms-the reason why Chester Stock had invited him to the New York symposium on
cancer treatment in the first place. In addition, Noble had been deeply
involved in finding a way to foster communication between Canadian
178
I
JACALYN DUFFIN
researchers studying cancer. As a member of the Research Advisory
Group to the NCIC, he was a founder of the biennial Honey Harbour
Conferences on cancer research-conferences which began in 1954-in
the midst of his periwinkle studies.137Furthermore, by his own testimony to Charles Roland, Noble's original goal (thwarted by Macleod)
was cancer research. And in 1960-right after the Honey Harbour conference-Noble left for Vancouver to direct the Cancer Research Centre.
From the beginning to the end of his career, Noble had cancer squarely
in his sights. There was scarcely a time when he was not "thinking of
cancer."
Noble's deep immersion in cancer research was shared by his team.
With his Oxford PhD in chemistry, Beer was familiar with the latest isolation techniques and had spent three years at the Sloan-Kettering Institute for cancer research in New York City. Walina Robinson had just left
a cancer research laboratory at the Karolinska Institute in Sweden
where she had learned white cell counting fm the purposes of assessing
chemotherapy drugs-the technique she later applied in London, Ontario without Noble's direction or knowledge.
At the beginning of this paper I alluded to Noble's connection to the
insulin discovery and to his partisan view of the rivalry. As a child and
again after he became an adult, that story was never far from the surface-whether he was in Aberdeen, dining with the Macleods, or in
Montreal and London, working with his greatly admired mentor, Collip, ever distressed over his own lack of recogniti~n.'~~
With the
unhappy legacy of insulin as a touchstone, laboratory-chief Noble seems
to have played a more successful Macleod to Beer's Collip. In this country
at least, his vetsion of the story "won"4lawsand all.
I think that Noble's invocation of chance may have helped in that victory. In framing his "discovery," he could turn to "chance" because the
leaves had came to him with a diabetes label affixed. On several occasions;however, he later admitted that he'd done so "tongue in cheek,"
because of a more serious matter about the philosophy of the research
enterpri~e.'~~
He told Charles Roland it was to "pull the leg" of the large
pharmaceutical companies and their massive screening programs that
could in timidate researchers at smaller places.
At that time, the United States had a tremendous budget for chemotherapeutic
drugs, and this meeting.. . at the New York Academy of Science. . . was devoted to discussihg the methods of applying this. What tumors should be used
and how much money was being spent? At that time they were screening virtually everything. They'd take.. . thousands of chemicals and, just purely at random, to see ifthey could pick up anything. With my tongue in my cheek, 1 said
this [i.e. his1 was,a serendipitousapproach, rather than this enormous vast budget which was k i n g spent [on the principle that] something might turn up
sometime. I was sort of pulling their leg a bit. Turned out to be true.
Poisoning the Spindle
After that they started to screen plants, I might say. But they just stopped just
the other day.. . . . They all thought that the plant kingdom was full of things.
This was too bad, that the first one was active. They haven't found one ever
since. Depends on how you look at it.140
Noble seems to have been nostalgic for a different kind of science, one
that he knew was on the verge of disappearing only to be replaced by
something bigger, more technical, more crass, and perhaps less pure.14'
To Dr. Roland, he said:
Beer and I went to Lilly's .. .and saw what they were doing, and they came up
to Western, and it was quite obvious that we couldn't compete with their chemistry department, which was an enormous set-up, so we decided to work in collaboration with them. Eli Lilly-it was somewhat like the insulin situation.142
Beer shared Noble's research philosophy when he contrasted the
Canadian team's approach with that of the pharmaceutical company.
True, he may have been making a virtue of fiscal necessity, when he
said:
.
The Lilly approach was somewhat different from ours.. .We would do a quite
elaborate chemical fractionation and then we would test the fractions at that
point by injecting them into experimental animals, into rats and, in our case,
monitoring the white count. We didn't need a pure compound to do that. That
was our back-up. The thread that led us through the jungle, as it were.
But the Eli Lilly Company.. . would probably have enough to isolate, pure,
these compounds.. . We were on a very narrow track. We had a light we
thought we saw at the end of the tunnel and we kept our eye on that biological
activity. That was our approach. It was the only approach we could have done,
but it worked. It probably kept us ahead. We were single-minded, not because
we were more pure-minded, but because we had really no 0pti0n.l~~
.
l
In a sense, the Canadian researchers accepted the "rules" of scientific
competition; to work autonomously, they must "compete"; since the
competition could not be won, they allowed Lilly to become their "pat r ~ n . " 'Emphasis
~~
on "chance" allowed the smaller group to be equal
players and to retain their priority: "Aw shucks! We were just lucky," it
modestly seemed to imply. Contributions of Vinca derivatives were often described as "gifts."145 The patronage relationship was beneficial to
both sides, but the academics worried that it came at what they viewed
as a philosophical cost.
Canadians have an uneasy relationship with fame, priority and
money. Like any good scientist, Noble was attuned to the tremendous
importance of priority-not only for fame, but also for continued funding of research in Canada. His preoccupation with the opportunities for
national science in Canada was shared by the clinicians Whitelaw and
Warwick who, with Noble, tended to feature the Canadian aspects of
180
JACALYN DUFFIN
the discovery in the opening lines of their early p~b1ications.l~~
In his
conversations with Dr. Roland, Ndble referred not only to the priority
matters related to periwinkle but also to the priority he could claim for
his other
For example, he spoke with regret about the lack of
public recognition for the role of the Noble-Collip drum in the "discovery of chlorpromazine" credited to Poullenc F r & r e ~ . * ~ ~
By 1988, Noble was 78 years old and still actively engaged in research.
Harold Warwick thought that he was "bitteru--over loss of NCI support late in his career, and perhaps over not receiving enough credit for
Vinca drugs and his later work on tumors. Again drawing a parallel to
insulin, Warwick told Charles Roland,
He's not winding down graciously. I wish for his sake. ..he'd say "I've had my
day". . . He's an angry older man.. . . I have a feeling that Beer and Cutts had
been left just a ltttle in the background.. that they haven't received the recognition they might have. . . . I've had the feeling that the fellow who really, night
after night, was working there and actually produced the crystalline substance. . . that was a pretty important thing- just as important as Dr. C011ip.l~~
.
Beer took a different, more sympathetic view. Attached to the Vinca
research and admiring of Noble's qualities, Beer contentedly followed
his boss to Vancouver. He found Noble not only "pleasant" and "affable," but also "stimulating" and "imaginative,"
full of ideas.. . always watching for something which is a little out of the ordinary and then he'll push it. He may push it a little further than a cautious person would, which is a good thing, but he'$ quite ready to pull back and
change. . . He's deserved the honours that he's got. 1 think in some cases he's
been slow in getting them.'"
.
I
Noble had wanted to publish his 1984 Terry Fox lecture amplifying
on the discovery, but had difficulty finding a place for it. He tried the
medical student journal at Western, but "the dean wasn't very keen on
it."151 A version of the lecture was read again in 1989 and finally published the following year-in the month of his death.152
Like a good historian, Noble strove for evidence, accuracy, and care in
all his endeavors, including the story he told of the discovery. His periwinkle tale might seem to have lacunae to us now, but it contained the
features that mattered to him. He packaged it in a "diabetes/chance"
wrapper because that is how periwinkle first captured his attention.But it
is clear that in looking for A (a source of insulin), Noble himself and his
team were already deeply immersed in a search for B (cancer cures).
Their minds were far more than prepared.
Noble's perspective has much to tell us. When we historians put together a story, we use the sources that are available and decide how
much we can trust them. Noble's accounts are out there in cold hard
Poisoning the Spindle
I
181
print, but his papers cannot be traced and many of the players are now
dead. The Lilly company will not let me into their records, Halina
Robinson's notebook is lost, Noble and Johnston family descendants
cannot trace personal papers, and I'm still looking for Miss Farquharson. To the extent that these accounts can be reconciled, I have relied on
what people recollected for me or for Charles Roland. But memory is a
funny thing. Events fall into structural sequences that seem logical in
retrospect and national and personal egos enter into play. In addition to
whatever personal reasons Noble may have had for wanting to emphasize his priority, he also had a long-standing commitment to the status
of research in this country, and-as Alison Li and Terrie Romano have
shown-an important discovery was the best of all possible ways to
validate continued s ~ p p 0 r t . Doubly
I ~ ~ conflicted both by the pressure
of the reward system in science that demands originality, and by a national characteristic that values modesty, Noble found that invoking
chance as a fellow actor in his discovery allowed him to retain humility,
even as he staked his claim to priority in the face of American big busin e ~ s . ~ ~ ~
To conclude, I doubt that the physiological process of any discovery
can be reconstructed because of the nature of our sources and the traditions of preservation. In the case of the Vinca alkaloids, I think that the
discovery was not solely Canadian but a multiple discovery that took
place in at least two different laboratories and involved the crucial observations of many more people than Noble's paster narrative was able
to recall. Furthermore, the discovery took place at no particular moment because it involved a series of iterative steps, from recognition of
activity, to isolation, purification, clinical testing and manufacture-all
of which were essential for the production of the new cancer drugs.
Notwithstanding the protests of the players, a priority race for isolation,
clinical testing, and the demonstration of positive results did indeed ensue. In fact, the hesitation of the main actors to label it a "race" is a testimony to the ambiance of collegiality and personal good will that they
managed to establish within the confines of their scientific endeavors.
Finally, I remain squarely in the camp that is suspicious of the role ascribed to chance in this or any other discovery. Notwithstanding the
title of that seminal paper of 1958, chance was not a big factor after all.
Or, let us say chance plays a role in every discovery-in the guise of "experience (or experiment)" that brings an event to the observation of an
informed mind. In that sense, its part is banal.
One thing is clear, however: Charles T. Beer devised a method for isolating vincaleukoblastine-the first of the effective Vinca alkaloidsbut only vincaleukoblastine. The isolation and develapment of the 60
other alkaloids and the more frequently used drug, vincristine, belongs
182
JACALYN DUFFIN
entirely to the Eli Lilly company. "Were there celebrations?" Chuck
Roland asked Beer back in 1987. "No not particularly" came the reply.
"My main feeling was one of relief. "Thank God that's over,"' Beer
said.155
ACKNOWLEDGMENTS
I am especially grateful to the many people contacted during this project, all of whom responded to my questions with enthusiasm. They are
Dr. Charles Beer, Dr. Donald Christian, Alison Li, Halina Robinson, Dr.
0.
Harold Warwick, Dr. Ruth Alison, Rosemary Grant, Dr. M. E. Hodes,
Dr. Roy Hertz, Dr. Irving S. Johnson, Dr. Charles G. Roland, Mrs. Mary
Heighington, the vast, interconnected Farquharson clan, and the descendants of Dr. and Mrs. C. D, Joknston in Jamaica and Canada. I
thank Adrian F. ailson, Robert David Wolfe, Chelrilyn Yalin, and an
anonymous reader for comments on earlier versions of this paper.
NOTES
I
1 See ~anadian'Medical Hall of Fame, London, Ontario, website at http://johns.
largnet.uwo.ca/shine/cmhf/.
2 Y. S. Ahn, J. J. Burnes, W. J. Warrington, M. L. Cayer, D. S. Smith, D. E. Brunskill, and
L. M. Pall, "The Treatmentof IdiopathicThrornbocytapenia with Vinblastine-Loaded
Platelets," New England Journal of Medrcine, 298 (1978):1101-7.
3 Noble, R. L., C. T. Beer and J. H. Cutts, "Role of Chance Observations in Chemotherapy: Vinca Rosea," AnnaEs of the New York Academy of Sciences 76 (19%): 882-94, especially 882.
4 A. C. Crombie, "Introduction," in A. C. Crombie, ad., Scientific Change: Historical
Studies in the Intellectual, Soctal and Technical Conditions for Scientific Discovery and
Technical Inventlon,from Antiqirtty to the Present. Symposium on the History of Science,
Oxford, 9-15 July 1961 (London; Heinemam, 1963),p. 1-11; Mrko Drazen Grmek, "A
Plea for Freeing the History of Scientific Piscoveries from Myth," in Mrko Drazen
Grmek, Robert S. Cohen and Guido C i M ? eds., On Scientific Discovey.fThe Ertce
Lectures, 1977, translated by Margaret Roussel (Dordrecht: D. Reidel, 1980), p. 9-42;
and Ren6 Taton, Reason nnd Chance rn Scierltific Discovery (London:Hutchinson Scientific and Technical, 1957).
S In an effort to locate consensus on individual discoverers, Lindahl et 41. have suggested the use of citation indices. Admitting that discoveries can be multiple yet with
an inexplicable deference to the "need" to find the firsts (e.g., the Nobel prize or the
Lasker prize), they contend thet citation patterns reflect the ~onsensusof the scientific community. Using the discovery of HIV and citation practices as an example,
they awarded priority to the team of Montagnier at the Pastep Institute. It remains
for someone to find an example of erroneous consensus.B. I. B. Lindahl, Aant Elzinga
and Alfred Welljams-Dorof, "Credit for Discoveries: Citation Data as a Basis for History of Science Analyses," The&etrcal Medime, 19 (1998):609-20.
6 For a general discussion of the problem of sources and present-centred history, see
Adrian Wison and T. G.Ashplant, "Whig History and Prespnt-Centered History,"
The Htstortcal Journal 31 (1988):1-16; T. G. Ashplant and Adrian Wilson, "PresentCentered HStoty and the Problem of Historical Knowledge," The Histort&l Journal
31 (1988):253-74.
Poisoning the Spindlr
I
183
7 WiEliam F. Ogburn and Dorothy Thomas, "Are Inventions Inevitable?" Polrtrcal Scrence Quarterly, 37 (1922):83-98; Robert K. Merton, "Multiple Discoveriesas Strategic
Research Site [1963]," and "Singletons and Multiples in Science (19611," in Robert
Theoretrcal and Emprrrcal Investtgatrons (Chicago
K. Merton, The Socrology of Sc~~nce:
and London: University of Chicago Press, 1973),p. 371-82and p. 343-70, respectively.
8 Merton, "Priorities in Scientific Discovery [1957]," in Merton, Soczology of Scrence,
p. 286-324, especially 317-21.See also Warren 0.Hagstrom, The Sclentlfrc Communrty
(New York: Basic Books, 1965),p. 85-98; Tatan, Reason and Chance, p. 131;and George
Windholz and P. A. Lamal, "Vagaries of Science; Priority, Independent Discovery,
and the Quest for Recognition," Psychological Record, 43 (1993),339-50. For analysisof
various specific disputes over scientific discoveries, see Paul Cranefield, The Way In
and the Way Out (Mount Kisco, New York: Eutwa, 1974), p. 44-54; John Farley and
Gerald Geison, "Science, Politics, and Spontaneous Generation in Nineteenth-Century France," Bulletm of the Hrstoy of Medicine, 48 (1974): 161-98; Mirko D. Grmek,
Histoy of AIDS, translated by Russell C. Maulitz and JacalynDuffin (Princeton, N.J.:
Princeton University Press, 1990), p. 60-77; David Harley', "Honour and Property:
The Structure of Professional Disputes in Eighteenth-CenturyEn&h Medicine," in
Andrew Cunningham and Roger French, eds., The Medzcal Enlrghtenment of the
Eighteenth Century (Cambridge:Cambridge University Press, 1990), p. 13&64; and
Elizabeth Labrousse and Alfred Soman, "La querelle de l'antirnoine. Guy Patin sur la
sellette," Htstorre, Cconomie et socrCtb, 5 (1986):3145.
9 Augustine Brannigan, The Social Basis of Scient$c Discoverres (Cambridge: Cambridge University Press, 1981),p. 59-78. For a similar perspective that explores the social forces behind decisions to continueor end &esearchpathways (usingthe example
of physics), see Pater Galison, How Experiments End (Chicago: University of Chicago
Press, 1987).
10 David Lamb, Discovery, Creativity, and Problem-Solving (Aldershot, Hants. UK: Avebury, 1991), p. 31-42; and Marx W. Wartofsky, "Scientific Judgement: Creativity and
Discovery," in Thomas Nickles, ed., Scient+c Drscovey: Case Studies (Dordrecht:
D. Reidel, 1980),p. 1-16.
11 See for example two collection of essays:Medicine and Change:Historical and Sociological Studies of Medical Innovatron. Colloque INSERM Vol. 220,Ilana Ltiwy, Olga Amsterdaltlska, JohnPickstone, and Patrice Pinell, eds. (Paris:John Libbey Euyotext, 1993);
and Medical Innovattons in Hlstorlcal Perspective, John V .Pickstone, ed., (Basingstoke,
Hampshire.Macmillan, 19921,
12 A Medline search in July 1999 combining "serendipity" and "discovery" produced
31 hits. Comroe provided 24 capsule histories of discoveriesin medicine that wereattributed to chance and Ronald E. Rossman provided 61. Julius J. Cornroe, "Retrospectoscope: Roast Pig and Scientific Discovery. Part I and 11," American Revrew of Respiratory Diseases, 115(1977):853-60 and 1035-44;and Ronald E. Rossman, "The History and Significanceof Serendipity in.Medital Discovery," Transactions and Studies
of the College of Physicians, 33 (1965): 104-20.SWlarly, some attributethe exploitation
of discoveries to chance. See for example, William H. Schneider, "Chance and Social
Settingin the Application of the Discovery of Blood Groups," Bulletrn of the History of
Medicine 57 (1983),545-62.
13 Chance is not mentioned in several key works. See for example, Karin Knorr-Cetina
and Michael Mulkay, "Introduction," in Karin Knorr-Cetlna and Michael Mulkay,
eds. Science Observed: Perspectives op the Social Study of Scrence, (London, Beverly
Hills, New Delhi: Sage, 1983), 1-IT; Susan E. Cozzens and Thomas F. Gieryn, "Introduction: Putting Science back in Society," in Susan E. Cozzens and Thomas F.
Gieryn, eds. Theories of Scrence in Society, (Bloomingtonand Indianapolis:University
of Indiana Press, 1990),p. 1-15;and Peter Galison and David J. Stump, eds. The Disunity of Science: Boundartes, Contexts and Power (Stanford, CA; Stanford University
Press, 1996). In recent literature on philosophy of science index entries on "justifica-
184
JACALYNDUFFIN
tion," "method," "practice," "relativism," and "realism" are far more numerous
than the entries on "discovery," "chance," or "accident."
Cornroe, "Roast Pig and ScientificDiscovery," p. 1043;and Ronald E. Rossman, "Serendipity in Medical Discovery," Strrgey, Gynecology, and Obstetrics, 124 (1967):
837-38.
In a speech read at Lille in 18w, Louis Pasteur is said to have remarked: "in the fields
of observation, chance favors only the mind that is prepared." RenC Vallery-Radot,
Life of Pasteur, translated by R. I. Devonshire, (GardenCity: Garden City Publishing,
1927,~:76. On uses of this famous quote, see for example, Cornroe, "Roast Pig and
Scienhhc Discovery," p. 854; Rossman, "Serendipity in Medical Discovery" (1965);
Dillip V. Jeste, J. Cristian Gillin and Richard Jed Wyatt, "Serendipity in Biological
Psychiatry-A Myth?Archtves of General Psychlaty, 36 (1979): 1173-78; and Peter
Medawar, "Can Scientific Discovery be Premeditated?" in Peter Medawar, The Ltmtts of Science, (NewYork: Harper and Row, 1984),p.45-54.
Ahron Kantorovich,SctentlficDtscovey: Logic and Tinkerrng (Albany:State University
of New York 1995), p. 157; Taton, Reason avd Chance, p. 90; and Rossman, "Serendipity in Medical Discovery" (1965),especiallyp. 104-5.
Kantorovich, ScientiftcDtscovey; Jeste et al. "Serendipity in Biological Psyrhiatry";
Comroe, "Roast Pig and ScientificDiscowry Part 11," p. 1035-44.
For example, Jesteet al. "Serendipity in BiologicalPsychiatry."
Brannigan,Social Basis ofSctentifzcDiscoveries,p, 11.
Kanbrovich, ScientificDiscovery, p. 169. Comroe expressed similar desires without
the rules. Comroe, "Roast Pig and ScientificDiscovery Part 11," especially p. 1044.
For more on the status of topics in science studies, see David J. Stump, "Afterword:
New Directions in the PhUosophy of Science Studies," in Peter Galison and David
J. Stump, eds., The Disuntty of Science: Boundaries, Contexts and Power (Stanford,Calif.:
Stanford University Press, 1996), p. 443-50. See also Simon Schaffer, "Scientific
Discoveries and the End of Natural Philosophy," Social Studies of Sctence, 16 (1986):
387-420.
One notable exception is John Patrick Swann, Academic Scienttsts and the Pharmaceutical Industry: Cooperative Research in the bentieth Centuy (Baltimore:JohnsHopkins
University Press, 1988).
For example, Gerhard Domagk who worked for Bayer and won the 1939Nobel prize
for the first sulfa drug; Gertrude Elion and George Hitchings of BurroughsWellcome
who shared the 1988 Nobel prize with James Black of SmitWine and French, for
their multiple discoveriesof "rational derivatives."
Robert L. Noble,Intemiew with Charles G. Roland, 31 January 1986, "Experiences in
Research, Particularly with Respect to Vinblastine, 1950s;' HCM 2-86, p. 2. Noble
continued "Macleod was just the opposite that evetythingand everybody's written
about him, except Michael Bliss" (p. 4). The coin toss had first been reported by Banting. Citing both Best and Noble, Stevenson suggested that the toss never happened.
Lloyd G. Stevenson, Sir Frederick &Wing (London: Heinemam Medical Books, 1946,
1 9 4 7 , ~78,79n.
.
Blissdescribed it twice:in 1982,he wrote that no evidencesupported
the legend that Best had "lost"; in 1984 he wrote, "Best wonr'-which is certainly
true from the sense of posterity. Michael Bliss, The Discowy of Insultn (T~ronto:
McClelland and Stewart, 1982), p. 57-58; and Michael Bliss, Banttng. A Biography
(Toronto:McClellandand Stewart, 1984),p. 59.
"It's intriguing for me to hear about the pminsulin days. The family was sort of
bound up by it, so I've been hearing about it since I was a little boy." Robert L. Noble,
in his Interview of Walter Campbell, undated ca. 1970, p. 10. "[Charles Best] and my
brother worked out of Georgetown where they were students.. . and Charly and
Margaret were engaged, and I used to know them as a small boy. I've known them
for many, many years. They've changed considerably." Robert L. Noble in his interview of Hamld Ettinger, undated ca. 1970, p. 14 . When Ettinger opined that the
"meat advertisement of Charlv is bv his wife rather than bv Charlv," Noble revlied
Poisoning the Spindle
26
27
28
29
30
31
32
33
34
35
36
37
38
185
"Yes. I think she is pretty rabid on the whole thing." (p. 14). On the legacy of Charles
Best, see Michael Bliss, "Rewriting medical history: Charles Best and the Banting and
Best myth," journal of the H~storyof Medrcine and Allied Sciences, 48 (1993): 253-74.
"At that time, I'd read somewhere or other that [Lumsden] . .. at Guy's Hospitalpublished that he was curing, he thought he could cure, cancer. If you took one strain of
tumour, one strain of rat or mouse [himour] and transplanted it into another, it
would be rejected. This, not knowing anything about it, excited me and I wrote Professor Macleod, and Macleod's letter was very guarded. I didn't know what he
thought of Lumsden. Anyway I didn't go to Lumsden." Robert L. Noble, Interview
with C. G. Roland, 31 January 1986, p. 5. Macleod may well have had an opinion of
Thomas Lumsden, since the latter's degree was from Aberdeen according to hisLancet publication. The articles Noble had seen seem to be the following, although the
work originated from London Hospital not Guy's: T. Lumsden, T. Macrae and E.
Skipper, "A Note on Certain Effects of Tumour-Immune Rat Sera Revealed by
Cinematography," journal of Pathology and Bactertology, 40 (1935): 418-19; Thomas
Lumsden, T. F. Macrae, and Eric Skipper, "The Direct Demonstration of Anticancer
Bodies in the Serum of Animals Immune to a Homologous Tumour," Journal of Pathology and Bactertology, 39 (1934): 595-607; and T. Lumsden, T. Macrae and E. Skipper, "The Mechanism of HomologousTumour Immunity," Lancet, 1(1934): 731-32.
Noble, et al. "Role of Chance Observations," p. 882.
A. B. Corkill and A. Doutch, "An Investigation into the Alleged Therapeutic Properties of Vincn rosea in the Treatment of Diabetes," Medical Journal of Australta, 1(1930):
213-15; L. J. Jarvis Nye and Mdrgaret E. Fikgerald, "Vinca Treatment of Diabetes,"
Medtcal journal of Australia, 2 (1928): 626-28. Noble's team may not have known of the
Australian articles until they saw them cited in P. Hugh-Jones, "Diabetes in
Jamaica," Lancet 2 (1955): 891-97. For more on periwinkle and other Jamaican folk
remedies see, John Crellin, ed., Traditional Maroon Med~crnein Jama~ca:
An lntroduct~on
to Health and Community Care ik Accompong (St John's, Nfld.: Faculty of Medicine,
Memorial Univesity of Newfoundland, 1998).
Noble, et al. "Role of Chance Observations," p. 883.
Noble, et al. "Role of Chance Observations," p. 883.
sh
Cancer Campaign 33rd Annual Report, (1955): 487; J. H. Cutts,
C. T. Beer, in B r ~ t ~ Emptre
C. T. Beer and R. L. Noble, "Effectson Hematopoeisisin rats of Extracts of Vica Rosea,"
Revue Cmddtenne de Btologie, 16(1957): 476 (reprintsupplied by Dr. Beer).
Noble, et al. "Role of Chance Obervations," p. 893.
Noble, et al. "Role of Chance Observations," p. 882.
Noel Vietmeyer, "Robert Noble and the Puzzle of Periwinkle," Redder's Digest,
(1987): 101-5; Ken W. MacTaggart, "Western U. MDs Hope Plant May Aid Cancer
Fight," Toronto Telegram, 12 April 1958,p. 1,3; and R. L. Noble, "Vincaleukoblastine,"
Modern Medmne, 15(1960): np (reprint provided by Dr. C. T. Beer).
In particular, Cutts was to read a version of the paper in April 1938in Philadelphia and
the TorontoTelegram of 12April 1958indicated that the team was on the verge of finding a
cancer cure. "Well Cutts was nervous anyway and he saw this and he had a fit." Robert
Laing Noble, Interview with Charles G. Roland, 1February 1986, "Experiences in Research, Particularly with Respect to Vinblastine, 19505,'' HCM 2,86, p. 32-33.
Robert L. Noble, "The Discovery of the %ca Alkaloids-Chemotherapeutic Agents
against Cancer." The Terry Fox Lecture, BCMA Meeting, Vancouver, 1984, photocopy typescript (gift of Dr. Charles T. Beer). A similar lecture was given at the fourth
Biennial Rossiter Research Conference in 1989. Both formed the basis of an article
published the following year: Robert L. Noble, "The Discovery of the Vinca Alkaloids-Chemotherap@uticAgent$ against Cancer," Btochem~styand Cell Bzology, 68
(1990,12): 1344-51:
Noble, "Discovery of the Vinca Akaloids" (199O),p. 1345.
C. D. Johnston, Medical Faculty, McGdl Un~versityYearbook, 1914. McGill University
Archives.
186
JACALYN DUFFIN
39 "Dr. C. D. Johnston, Physician and Dairy Farmer Dies at 83," Gleaner (Kingston,
Jamaica),16October 1968-includes text of citation read at his retirementin 1949;and
Mymelle Mclntosh Uohnston's daughter now deceased], "Nostalgia: Bush Medicine
and Modern Science," Sunday Glmnw (Kingston,Jamaica), 1998; and Mymelle McIntosh, "Nostalgia: Practising Medicine in the Early 20th Century," Sunday Gleaner
(Kingston, Jamaica),16 July 1995. These articles were kindly provided by Johnston's
granddaughter,Sandy McIntosh of KingstonJamaica, via e-mailand telephoneinterview, 7 October 1999.Other informationcame from Dr. Donald Christianof Kingston
lamaica, tele~hone
interview. l Qctober 1999.
40 sandy ~ c l n i o s hremembers'her grandmother "drying masses of periwinkle plants
on the back verandah of her house in Black River;' personal communication, 8 October 1999. Charles Beer remembered at "small pac'kage" of a few leaves arriving
"every month 012 so." Charles T. Beer, Interview with Charles G. Roland, "Experiences in Research, Particularly in Regard to Vincoleucoblastine [sic]," 2 February
1987, HCM 3-86, p. 16.
41 Noble, "Discovery of the Vinca Allcaloids" (1990), p. 1344; and Noble, 1986, Interviews with C. G. Roland, 31January 1986, p. 37, and 1February 1986,p. 5-7.
42 I am especially grateful to Clark Noble's daughter,
Mary Heighmgton, for looking into this matter for me.
43 Noble, "Discovery of the Vinca Alkaloids" (WO),p. 1348.
44 Noble, "Discovery pf the Vinca Alkaloids" (1990),p. 1346.
45 Noble, "Discovety of the Vinca Alkaloids" (1990),p. 1345.
46 Hans Selye, "The Influence of STH, ACTH, and Cortisone upon Resistance to Mection," Canadtan Med~calAssociation Journal, 66 (1951):489-94. Selye had worked with
Noble and Collip at McGill and made use of their inyention, a drum for inducing
stress in animals. See also, Hans Selye, "Stress and the General Adaptation Syndrome," Brlttsh Medlcal Journal, 1(1950): 1383-92; and Hans Selye, Stress (Montreal:
Acta Medical Publishm, 1950),p. 64-73, especiaUy p. 65 (Collip-Nobledrum).
47 Halina Robinson, personal laboratorynotes /random notes used in preparation of the
formal laboratory book and written in several languages: Polish, English, and Swedish], property of the author, translated &ad cited by Halina Robinsan in letter to
J. Duffin, 8 October 1999.
48 Beer, Interview with C. G. Roland, 2 February 1987,p. 6,7-11.
49 See S. Hosztafi, "The Discovery of Alkaloids,"Phannazie, 52 (1997):546-50.
50 I. S. Johnson,Interview with J. Duffii, l 5 May 19%.
51 Beer, Interview with C. G. Roland, 2 February 1987,p 11.
52 I. S. Johnson,letter to J. Duffin, l8 May 1999.
53 I. S. Johnson,letter to J. Duffin, 18May 1999.
54 I. S. Johnson,Interview with J. Duffin, 15May 1999.
55 I. S. Johnson, H. F. Wdglrt, and G. Svoboda, "Experimental Basis for Clinical Evaluation of Antiturnor Principles Derived from Vinca Rosea Linn. [abstract no. 721. Proceedings of the 32nd Annual Meeting," J o u m l a f ofbratoy and Cltnical Mediclne, 54
(1959):830; and 1. S. J ~ b o nH.
, F. Wright, and G. Svobada, "Antitwnor Principles
Derived from V m a R a w Linn. [abstractno. 126of p4per read at Atlantic City, 10-12
April 19591," ProCeedt)lgsofthe American Assoctgtionjor Cancer Research, 3 (1959):122.
56 Gordm ;H.Svoboda, Norberthleuss and Marvin Gorman, "Alkaloids of Vinca Rosea
Llnn (Catharanthus m e u s G. Dpn). V. Prepqration and Charactertation of Alkaloids,'' Journal of the American Pkannaceutical Assoctatim, Scientlfrc Editlon, 48 (1959):
659-66.
57 Leurosine eventually became Vinleurosine. Svoboda extended his filial homage to
names for other isolates, but the nomenclature committees did not retain his preferences, e.g., Vinleurosidine (Vinrosidine);Leurocristine (Vincristine).
58 The manuscript of the fifst report was receivetj by the journal on 29 September 1958.
Here and in several other reports, Svoboda implied that his isolation had predated
that of Beer. In the first report, he stated that physical properties show the isolates to
m.
I
Poisoning fhr Spindle
59
60
61
62
63
64
65
66
67
68
69
I
70
71
72
73
74
75
76
77
bedifferent compounds; by November 1959 however, he implied that they were the
same substance, independently isolated. Gordon H. Svoboda, "A Note on Several
New Alkaloids from Vinca rosea Linn. I. Leurosine, Virosine, Pervine," journal of the
American Pharmaceufical Associafron, 47 (1958):834.; M. Gorman, N. Neuss, G. H. Svoboda, A. J. Jr. Bames and N,J. Cone, "A Note on the Alkaloids of Vrnca rosea Linn
(Catharanthusrosea G. Don) II. Catharanthine, Lochnericine, Vindolinine, and Vindoline," Journal of the American Pharmaceutical Association, Scient$c Edition, 48 (1959):
256-57; N. Neuss, M. Gorman, G. H. Svodoba, G. Maciak and C. T. Beer, "Vinca Alkaloids 111. Characterization of Leuroslne and VincalNkoblastine,new Alkaloids from
Vinca Rosea Linn. [letterj,"1otirnal of the American Chemical Society, 81 (1959):4754-55;
Mantin Gorman, Norbert Neuss, and Gordon H. Svoboda, Wnca Alkaloids TV.
Structural Features of Leurosine and V&@aleukoblastine,Reoresentatives of a New
Types of Indole-IndolineAlkaloids [letter]," Journal of the hic can Chemrcal Society,
81 (1959):4745-46; andG. H. Svoboda, et al., ""Alkkloidsof Vinca rosea" (1959):659-66.
Noble, Interview with C. G. Roland, 31January 1986,~.35; and 1 February 1986,p. 25.
Irving S. Johnson, Howard F. Wright, Gordon H. Swoboda, and Janet Vlantis, "Antiturnor Principles Derived from Vinca rosea Linn. LVincaleukoblastine and Leurosine,"Tancer Research, 20 (1960):1016-17.
R. Hertz, "Suppressiorr of Human Choriocarcinoma Maintained in the Hamster
Cheek-Pouch by Extracts and Alkaloids of Vinca Rosea," Proceedings of the Societyfor
Experimental Biology artd Medicine, 105(1960):281-82.
I. S. Johnson,letter to J. Duffin, 18May 1999.
Noble. Interview with C. G. Roland. 31 lanuarv 1986,v. 35.
Beer; 1987, Interview with C. G. ~oland,p. 12:~or&apparently similar spectra, see
Gordon H. Svoboda, Norbert Neuss, and Marvin Gormhn, "Alkaloids of Vinca rosea
Linn. (Catharanthusroseus G. Don). V, Preparation and Characterization of Alkaloids," Journal of the American Pharmaceutical Association, Scient+c Edition, 48 (1959):
659-66, especially 662-63.
Beer, 1987, Interview withC. G. Roland, p. 12.
Beer, 1987, Interview with C. G. Roland, p. 14-15.
Noble, Interview with C. G. Roland, 1February 1986,p. 30.
0.H. Warwick,J. M. M. Darte, aad T. C. Brown, "Some BiologicalEffects of Vincaleukoblastine, an Alkaloid in Vinca rosea L h in Patients with bialignant Disease," Cancer Research, 20 (1960): 1032-40,especially p. 1033n.
Canada Patent no. 653005 "Vincal&oblastine and Salt$ Thereof." Inventors:
Charles T. Beer, James H. Cutts, and Robert L. Noble. Owners: Canada Patents and
Development Ltd 1961, filed, 2 December 1959, priority date issued 2 December 1958,
granted 27 November 1962, expired 27 November 1979. Also British Patent 870,723,
1%1;USA patent 3,097,137,1961.
Noble, Interview with C. G. Roland, 1February 1986, p. 22.
Noble, Interview with C. C. Roland, 1February 1986, p. 22.
0. Harold Warwick, 1988, Intewiew by Charles G. Roland, 21 January 1988, HCM
2-88, p. 16. Unfortunately, the University of Western Ontario no longer has any
record of these transactions, nor does it have a record of the income derived from the
patent which expired 20 yeam ago. I am gratefulto archivistTheresa Regnier for looking into this matter forme.
Noble, "The Discovery of the Vinca Alkaloids" (1990).p. 1349.
Noble, Interview with C. G. Roland, 1February 1986,p. 23; Noble, "The Discovery of
the Vinca Alkaloids" (1990),p. 1349.
The results were read at the Royal Society of Medicine in 1947.0. Harold Warwick,
Interview with J. Duffin, 12September 1998.
0.Harold Warwick, InterviewwithC. C. Rohnd, 21January1988,HCM2-88, p. 6,17;
Warwick, Interview with J. Duffin, 12September 1998.
Warwick, Interview with C. G. Roland, 21 January 1988, p. 17; Warwick, Interview
with J. Wuffin, 12September 1998.
188
JACALYN DUFFIN
78 Warwick et al., "Some Biological Effects of Vincaleukoblastine," p. 1035.The patient
was identified in ihterviews with C. G. Roland and the author as patient no. 9 in a series published in 1960.Warwick, Interview with C. G. Roland, 21 January 1988,p. ll;
Warwick, Interview with J. Duffin, 12September 1998.
79 Gastrointestina1bleeding is not a recognized side effect of the drug. At autopsy, the
young lawyer was found to have a peptic ulcer unrelated to either his disease or his
r
treatment.
80 "An odd behavior pattern unaccompanied by abnormalneurologicalsignswas a feature in three cases. One patient seemed u e l e to understand spoken questions and
walked along the corridor undressed. Anather wandered about aimlesslyand on two
madons urinated OSL his neighbour's bed. Disorientation land agitated depression
occurred in an elderly man in association with infection and fever." Warwick et al.,
"Some Biological Effects of VinealeukobIaatine," v. 1033.Hertz also reported on "severe" and &explained men281 depression. Roy ~ e r and
k R. H. MO);, 'Therapy of
Methotrexate-Resistant Chorfbcaxinotria in Women with Vicaleukoblastine [ a b
stract no. 108 of paper read at Atlantic City, 10-12April 19591," Proceedings of the
American Assocutionfor Cancer Research, 3 (1959):118.
81 Warwick, Interview by J. Duffin, 12 September 1998.Warwick made the same pbservation to C. G.Roland, Interview-21 January 1988,p. 21.Warwick may be right that
he would have found the problem ir,his large series if had he looked; however his patients had no symptoms and his t e had~ yet ta devise protocols. Although neurotoxicity is more frequent with the later isolate, VincrisMe, the American team had
documented paresthesias and the absence of deep tendon reflexes early in the VLB
work. In other words, Warwick would have learned of his wersight while his research was in progress, Roy Herk, M. B. Lipsett, and R. H., Moy, "Effect of Vincaleukoblastine a n Metastic Choriocascinoma and Related Trophoblastic Tumors in
Women," Cancer Research, 20(1960):1050.53.
82 Rosemary Grant, Interview with J. Duffin, 21 April 1999.
83 Rosemary Grant, Interview with J. Duffin, 21 April 1999.
84 0.H. Warwick, R. E. Alison, and J. M. M. Darte. "Clinical Experience with Vinblastine Sulfate," Canadian Medical 14asociation Journal,85 (1961):578-83.
85 Dr. Ruth Alison, Interview with J. Duffin, l3January 1999.
86 Warwick, Interview with C. G. Roland, 21 January 1988,p. 6;Warwick, Interview
with J. Duffin, 12September 1998.
87 M. E. Hodes, R. J. Rohn, and WUam
"Effects of a Plant Alkaloid,Vincaleukoblastine, in Human Beings [abstract no. 671.Proceedings of the 32nd Annual Meeting," Journal of Laboratory and Clinical Medicine, 54 (1959):826-27.The meeting was
held 5-6November 1959.None of Hodes' early reporb included dates when treatment began. I have been unable to determine the date of submissionfor this abstract.
By the time the paper was read, Hodes' sample had grown to 32 patients, but it was
not until January that dnnlysis was available for 27 of these patients. M. E. Hodes,
Robert J. Rohn, and Willirm H. Bond, "Vincaleukoblastine. I. Preliminary Clinical
Studies," Cancerb e a r c h , 20(1960):1041-49.
88 M. E. Hodes, e-mail letter to J. Duffin, 11 January 1999.The results of these clinical
tests appeared in abstracts: MfE. Hode$, R. J. Rohn, W. H. Bond, and J. Yardley,
"Clinical Trials with Leurosine Methidine, an Alkal&d $mm Vinca Rosea, h.,"
Cancer Chemotherapy Repor& 28,(1963):53-55,
89 See for example, Roy Hertz, Delbert M. Bergenstal, Mortimer Q.Lipsett, Edward B.
Price, and Theodore F. Hilbish, "Chemotherapy of Ghoriwarcinoma and Related
Trophoblastic Tumors in Women," Journal of the American Medical Association, 168
(1958):845-54.
90 Hertz and Moy, "Therapy of Methotrexatct-ResistantCh&xa&noma"; Roy Hertz
et al., "Effect of Vincaleukoblastineon Metastatic Chariocarcinoma and Related TrophoblasticTumors," p. 1053(thanks Modes);Roy Herk, J. L. Lewis andM. B. Lipsett,
"Five Years Experience with Chemotherapy of Metastatic Cboriocadnoma and re-
m,
I
Poisoning the Spindle
l
lated TrophoblasticDisease [abstractno. 1271," Proceedzngs of the American Association
for Cancer Research, 3 (1960); Roy Hertz, "Suppression of Human Choriocarcinoma
Maintained in the Hamster Cheek-Pouch by Extracts and Alkaloid6 of Vinca Rosea,"
Proceedzngs of the Soczetyfor Experimental Bzology and Medzcme, 105(1960), 281-82.
91 Roy Hertz, letters to J.Duffin, undated (May 1999)and (29July 1999).
92 M. E. Hodes, e-mail to J. Duffin, l2 January 1999.
93 M. E. Hodes, e-mail to J. Duffin, 13 and 19 January 1999. On the Krebiozen controversy, see Patricia Spain Ward, "'Who Will Bell the Catf: Andrew C. Ivy and Krebiozen," Bulletin of the History ofMedicine, 58 (1984):28-52.
94 In October 1963, the N.C.I. of the United States announced that it was seeking40 previously untreated patients with Hodgkin's disease of a combination chemotherapy
trial in which vincristine was one of the agents. See "Hodgkin's Disease to Get
4-Drug Test," New Mrk Tzmes, 4 October 1963, p. 71, cols. 4-5. One month later, the
public read reports of how the "combined approach (radiotherapy and chemotherapy) had produced "cures" of m u s e leukemia. "Leukernia Reported Cured in
Mice Tests," New York Times, 22 November 1963,p. 33, col. 7.
95 M. E. Hodes,e-mail to J. Duffin, 12January 1999.
96 M. E. Hodes, e-mail to J. Duffin, 11January 1999.
97 M. E. Hodes, e-mail to J. Duffin, l2 January 1999.
98 Roy Hertz,undated letter to J. Duffin, (May 1999).
99 Roy Herk,letter to J. Duffin, 29 July 1999.
100 Roy Hertz, Chdrzocarcinoma and Related Gestatronal Trophoblastic Tumors in Women
(New York: Raven, 1979),p. 103.
101 "He told me that he tried to interest some people here [London, ON] but he couldn't
arouse any interest." Warwick, Interview with J. Duffin, 12 September 1998.Like NOble, Warwick was surprised that his early positive results could not interest his colleages. He wonders if he received no reply to his letter to David Kamofsky of the
Sloan Kettering Institute in New York City because of Kamofsky's own premature
and terminal iftness with bronchogenic cancer. Warwick, Interview withJ. Duffin, 12
September 1998.
102 Warwick et al., "Some Biological Effects of Vincaleukoblastine"; Irving S. Johnson,
Howard E. Wright, Gordon H. Svoboda and Janet Vlantis, "Antitumor Principles Derived from Vinca rosea Linn. 1.Vincaleukoblastine and Leurosine," Cancer Research,
20 (1960): 1016-17; M. E. Hodes, Robert J. Rohn and William H. Bond, "Vincaleukoblastine. I. Preliminary Clinical Studies," Cancer Research, 20 (1960): 1041-49;
J. H. Cutts, C. T. Beer and R. L. Noble, "Biological Properties of Vincaleukoblastine,
an Alkaloid in Vznca Rosea Linn. with Reference to Its Antitumor Action," Cancer Research, 20 (1960):1023-31;and Roy Hertz, M. B. Lipsett and Moy. K. H., "Effect of Vmcaleukoblastine on Metastatic Choriocarcinoma and Related TrophoblasticTumors in
Women," Cancer Research, 20 (1960): 1050-53.
103 Robert L. Noble, "Symposium on Vincaleukoblastine (VLB), Honey Harbour, Ontario, June 12-16,1960," Canadian Cancer Conference,4 (1961),333-38.The proceedings
were published in the same volume, pages 339-88. C. G. Palrner, D. Livengood,
A. K. Warren, P. J. Simpson and I. S. Johnson, "The Action of Vincaleukoblastineon
Mitosiszn Vztro," Experimental Cell Research, 20 (1960):198.265.
104 "Lilly Stock," New York Times, 4 March 1961, p. 28, col. 3.
105 "Fight againstcancer," Financ~alPost, l0 June 1961,p. 63, cols. 1-8.
106 One other source states that four isolates were tested clinically. William L. Laurence,
"Science: Cancer Research New York Tzmes, 15 December 1963, IV,p. 7, col. 7-8. The
four substances would have been Vinblastine, Vincristine, Leurosine (Vinleurosine),
and Leurosidine (Vinrosidine).
107 I. S. Johnson, Interview with J. Duffin, 15 May 1999, and letter to J. Duffin, 18 May
1999.The most active drug was Vm-leumsidine.
108 G. H, Svoboda, "Alkaloids of Vinca rosea Linn. (Catharanthus rosea). IX: Extraction
and characterization of leurosidineand leurocristine," Lloydza, 24 (1961):173-78.
190
I
JACALYN DUFFIN
109 R. J. Rohn and M. E. Hodes, "Some effects of intravenously given Leurocristine [abstract no. 2231," Proceedings of the Amencan Assocratron for Cancer Research, 3 (1962):
355; Harold M. Schmeck, Jr. "New Drug Tested in Blood Cancers," New York Trmes, 15
April 1962, p. 79, col. 1.
110 "Jamaican Periwinkle Plant Tested as Cure for Cancer," Fznancial Post, 9 June 1962,
p. 62.
111 Myron R. Karon, Emil J. Freireich, and Emil Frei 111, "A Preliminary Report on Vincristine: A New Active Agent for the Treatment of Acute teukemia," Pedtatrics, 30
(1962): 791-96; and John Martin and Nigel Compston, "Vincristine Sulphate in the
Treatment of Lymphoma and Leukemia," Lancet, 2 (1963):1080-83.
112 "Science Notes: Cancer Drug," New York Ttmes, 28 July 1963, IV, p. 7, col. 6-8.
113 Irving S. Johnson, "The Cain Memorial Award Lecture: Rational Drug Screening:Serendipity to Selectivity," [extended abstract] Proceedtngs of the American Assoctationfor
Cancer Research, 27 (1986):433-35.
114 C. G. Paher, D. Livengood, A. K. Warren, P. J. Simpson and I. S. Johnson, "The Action of Vincaleukoblastine on Mitosis In Vitro," Experimental Cell Research, 20 (1960);
198-265.
115 J. Harry Cutts, "The Effect of Vincaleukoblastine on Dividing Cells rn Vivo," Cancer
Research, 21 (1961): 168-72. See also J. Harry Cutts, "Changes in Ascites Tumors and
Normal Bone Marrow Induced by Vincaleukoblastinern Vrvo," Canadian Cancer Conference, 4 (1961): 363-72.
116 0.J. Eigsti, P. Dustin and N. Gay-Winn, "On the Discovery of the Action of Colchicine on Mitosis in 1889," Science, 110 (1949): 692. P. Dustin, "Sur le centenaire d e la
dCouverte des proprGt4s antimitotiques de la colchicine," h u e midical de Bruxelles,
10(1989): 385-90.
117 David B. Slautterback, "Cytoplasmic Microtubules," journal of Cell Biology, l 8 (1963):
367-88.
118 C. T. Beer, M. L. Wilson and J. Bell, "A Preliminary Investigation of the Fate of Tritiated Vinblastine in Rats," Canadran Journal of Physiology and Pharmacology, 42 (1964):
368-73;C. T. Beer and J. F. Richards, "The Metabolism of Vinca Alkaloids. Part U. the
Fate of Tritiated Vinblastine in Rats," Lloydia, 27 (1964): 352-60; and C. J. Secret,
J. R. Hadfield and C. T. Beer, "5tudies on the Binding of [H3]Vinblastineby Rat Blood
Plateletsin Vitro," Biochemical Pharmacology, 21 (1972): 1609-24.
119 Edwin W. Taylor, "The Mechanism of Colchicine Inhibition of Mitosis. I. The Kinetics
of Inhibition and the Binding of H~-Colchicine,"Journal of Cell Biology, 25 (1965):
145-60.
120 The anti-mitotic effects of Vincristine were published soon after its isolation:
Giuseppe Cardinali, Giuliana Cardinali and Mostafa Abdoul Enein, "Studies on the
Antimitotic Activity of Leurocristine (Vicristine)," Blood, 21 (1963): 102-10. For more
on microtubules, see K. Roberts and J. S. Hyams, Mtcrotubules (London, New York,
Toronto, Sydney, San Francisco: Academic Press, 1979); and Pierre Dustin, Mrcrotubules 2d ed. (Berlin, Heidelberg, New York, Tokyo: Springer-Verlag,1984).
121 C. J. Secret, J. R. Hadfield a d C. T. Beer, "Studies on the Binding of [~~Ivinblastine
by Rat Blood Platelets in Vitm: Effects of Colchicineand Vincristine" Biochemical Pharmacology 21 (1972): 1609-24; and Roberts and Hyams,Mrcrotubules (1979), 102-4.
122 Halina Robinson, interview with J. Duffin, 15 May 1999.
123 Halina Robinson, interview with J. Duffin, 15May 1999.
124 From their microbiology and turnor laboratories at the Karolinska Institute, the
Kleiw established distinguished research careers and continue to publish in leading
journals, including Cancer and Nature.
125 Halina Robinson, personal laboratory notes [random notes used in preparation of the
formal laboratory book and written in several languages: Polish, English, and Swedish], property of the author, translatedand cited in letter to J. Duffin, 8October 1999.
126 Halina Robinson, interview with J. Duffin, 15May 1999.
Poisoning thr Spindle
191
127 Halina Robinson, "Vinca revisted-Another Happenstance in the Discovery of Vinblastine," Btochem~sty and Cell B~ology,69 (1991),581-82.
128 Halina Robinson, interview with J. Duffin, 15 May 1999.
129 According to the New York Trmes report of Lilly's decision to market the periwinkle
products at cost, an ounce of vincristine was derived from 10 to 15 tons of leaves; a
pound of VLB required 5000 pounds of leaves. William L. Laurence, "Science: Cancer
Research New York Tunes, 15 December 1963, IV,p. 7, col. 7-8.
130 Emil J. Freireich and Noreen Lemak,Mllestones rn Leukemla Research and Therapy (Baltimore, MD. JohnsHopkins University Press, 1991), p. 58.
131 Warwick, Interview with C. G. Roland, 21 January1988, p. 9,14.
132 See http://johns.largnet.uwo.ca/shine/crnhf/~.
133 I. S. Johnsonand R. L. Noble got along very well. Johnsonwent to Vancouver to consider Noble's offer, but eventually declined because he thought his resources for research were "not as good" as those at Eli Lilly. I. S. Johnson, Interview with J. Duffin,
15 May 1999.
134 Irving S. Johnson, "Drugs from Third World Plants [letter]," Scrence, 257 (1992):860.
In fairness I should add that this letter was in response to an ill-informed editorial
complainingthat Lilly had enjoyed "easy pickings" on the Madagascar periwinklewhich actually had been grown in Jamaica, Philippines,Ontario, and Texael'without ever paying Madagascar a dime"! Richard Stone, "The Biodiversity Treaty: Pandora's Box or Fair Deal?" Science, 256 (1992):1624.
135 Irving S. Johnson,letter to J. Duffin, 18 May 1999.
136 Since the conventionsestablishedby the 17th-century deliberationsof the Royal Society of London, dilemmas over priority have been settled by date of publication. Due
to lag time from submission to printing, leading journals have taken to indicating the
date of submission and acceptance on every article. The practice itself seems to provide more evidence for the claim that discoveries are the inevitable product of zeitge~stand that chance is of little consequence. Leslie Roberts, "The Rush to Publish,"
Saence, 251 (1991): 260-63; B. I. B. Lindahl, Aant Elzinga and Alfred Welljams-Dorof,
"Credit for Discoveries: Citation Data as a Basis for History of Science Analyses,"
Theoretrcal Medicine, 19 (1998):609-20.
137 Noble, Interview with C. G. Roland, 1 Pebruary 1986, p. 61-66. "There was a need to
stimulate interest in research in Canada." On the commitment of the NCI to Canadian
scienceand scientists,see "Dedicated Medicos," Saturday Night, 24 April 1951, p. 21.
138 "Macleod was just about the opposite that everything and everybody's written about
him, except Michael Bliss. He was very gentlemanly,very quiet-mannered, a Scotchman with a verv auiet sense of humour. He verv seldom showed anv exveression of
anger. . . . He W&; very delightful person. He k d a great respect f& ~drrnanscientists. He read German. ... in all the years, after all this sauabble over insulin, I never
heard him say anything at all derogkory about either ~ e sort Banting. The only thing
he did say, he said, if he'd stayed in Toronto, he would have had to take Banting to
court, and he didn't want to do this." Noble, Interviews with C. G. Roland, 31 January 1986, p. 6, and 1 February 1986, p. 19-20.This same view is evident in the undated
interviews Noble conducted with Harold Ettinger and Walter Campbell ca. 1970 in
preparation for a planned biography of Collip. In the interview with Ettinger espe
cially, disappointment, hurt, bitterness, and jealousies felt by others come up often. I
am grateful to Alison Li for provding me with copies of these fascinatingdocuments
in which the interviewer spoke as often as his subjects.
139 Noble, "The Discovery of the Vinca Alkaloids," Terry Fox Lecture, 1984, p. 9; and Noble, "The Discovery of the Vinca Alkaloids" (1990):1349.
140 Noble, Interview with C. G. Roland, 1 February 1986, p. 19-20. In the published revision of the Terry Fox lecture, Noble contended that the discovery of the Vinca alkaloids became the basis for a large-scale screening of plants for anti-cancer properties.
Noble, "The Discovery of the Vinca Alkaloids-Chemotherapeutic Agents against
Cancer" (1990):1349.
192
JACALYN DUFFIN
141 For more on the philosophicalchangesin laboratory research at the interface between
science and technology and its implications for history (using examples from physics),see Peter Galison, "Three Laboratories," Journal of Philosophy, 64 (1997):112555.
142 Noble, Interview withC. G. Roland, 1 February 1986,~.20.
143 Beer, Interview with C. G. Roland, 2 Februarv 1987, D. 14-15.
On patronage in science, see Susan E. ~ozzeks
and ?horns F. Gieryn, "Introduction:
Putting Science back in Society," in Theories of Scrence rn Soclety, Susan E. Cozzens
and Thomas F. Gieryn, eds. (Bloomington and Indianapolis. University of Indiana
Press, 1990), p. 1-15; and Susan E. Cozzens, "Autonomy and Power in Science," in
Susan E. Cozzensand Thomas F. Gieryn, eds, Theories of Science tn Soclety (Bloomington and Indianapolis:University of Indiana Press, 1990),p. 164-84.
See for example, H. F. Greenius, R. W. McIntyre and C. T. Beer, "The Preparation of
Vinblastine-4-acetyl-tand Its Distribution in the Blood of Rats," Journal of Medrcrnal
Chemlsty, 11 (1968): 254-57;-and J. F. Richards, R. G. W. Jones and C. T. Beer,
"Biochemical Studies with the Vinca Alkaloids. I. Effect on Nucleic Acid Formation
by Isolated Cell Suspensions," Cancer Research, 26 (1966):876-87. On @giving as an
organizingprinciple in science, see Warren 0.
Hagstrom, "Gift-Giving as an Organizing Principle in Science [1965]," in Barry Barnes and David Edge, eds. Science In Context; Readrngs rn the Sociology of Science (Cambridge, Mass.: MIT Press, 1982),p. 21-34.
Warwick et al., "Clinical Experience with Vinblastine Sulfate"; Whitelaw and Teasdale, "Vincaleukoblastine in the Treatment of Malignant Disease"; Warwick et al.,
"Some BiologicalEffects of Vincaleukoblastine."
For example; Noble betrays the sentiment of priority race when speaking of his
1940-41work on breast tumor regression following the removal of estrogen and on
the isolation of an anti-thyroid substance in rutabaga: "we just missed out on that
one." Noble, Interview with C. G. Roland, 1February 1986, p. 28-30. For the original
references to these projects, see R. L. Noble, C. S. McEuen and J. B. Collip, "Mammary
Tumours Produced in Rats by the Adion of &&one Tablets," Canadian Medical Association Journal,42 (1940):413; R. L. Noble, C. S. McEuen and J. B. Collip, "Mammary
Tumours followingTreatment with OestroneTablets in Female Rats," Canadian Medlcal Assoc~at~on
Journal,44 (1941):82-83; and R. L. Noble and J. B. Collip, "The Production of Mammary Tumours in the Rat Following Oral Administration of Diethylstilboestrol over Prolonged Periods," Proc. Soc. Can. Physiol, (October l94l), np (item#43
of Robert Nob1e'sC.V.).
Noble, Interview with C. G. Roland, 31 January 1986, p. 24. He claimed that he dare
not work with his own invention (the drum) again for fear of anti-vivisectionist attacks. Noble expressed the same regret in his interview of Harold Ettinger, undated
(ca. 1970), p. 33-34. In the same interview, Noble said, "My better ideas in the war
were all turned down by the NRC" (p, 37).
Warwick, Interview with C. G. Roland, 21January1988, p. 17-19.
Beer, Interview with C. G. Roland, 2 February 1987,p. 19,2940.
Warwick, Interview with C. G. Roland, 21January 1988,p. 1415.
Noble, "The Discovery of the Vinfa Alkaloids" (1990).
Alison Li and Terrie Romano, "Insulin's Long Shadow: The Politics of Medical Research in Canada" paper read at the annual meeting of the American Association for
the Historv of Mkdicine, Toronto, 1998.
The impa& of the rise in the funding of research by pharmaceutical firms is a topic
that has yet to be explored by historians of medicine.
Beer, Inkrview wi& C. G. bland, 2 February 1987,p. 17-18.