CITIUS – ALTIUS - FORTIUS To become an Olympic athlete choose

Norbert Bachl MD Prof.
EFSMA President
FIMS EC-Member
Department Sports- and Exercise Physiology
University Vienna
Kraków – Teplice – Belgrade
September 2004
LIMITS OF SPORTS PERFORMANCE
CITIUS
–
ALTIUS
-
FORTIUS
To become an
Olympic athlete
choose your parents
well!
!
wellPer-Olaf
Astrand
IT IS MORE
IMPORTANT
PARTICIPATIN
G THAN
WINNING
AND TRAIN WHAT EVER YOUR ORGANISM WILL TOLERATE.
MEDICAL ASSISTANCE
MEN VS. WOMEN
Marathon World Record:
2:15:25 h
marathon
MARATHON
PAULA RADCLIFFE
3.30.00
3.00.00
rec.men
rec.women
2.30.00
19
08
19
35
19
52
19
64
19
67
19
81
19
85
19
99
2.00.00
Men’s first record (1908): 2h.55m.18s.
Men’s last record (1999): 2h.05m.42s.
Diff.: -49m.76s.
Women’s first record (1964): 3h.27m.45s.
Women’s last record (1999) : 2h.20
m.43s.
Diff.: -1.24h
Health
Khalid
Khannouchi
Training
Recovery
Expected World Record 2030: 2:11 h
1
THE OLYMPIC GLORY
Like the Lords of Genesis?!
Gene-Technology and Gene-Ethics
Colin Tudge 1993
SUPPORT TO
IMPROVE ATHLET´S
PERFORMANCE
LIMITS FOR MEDICAL
ASSISTANCE
Gene technology and its consequences are the
challenge of the 21st century. How we will deal with
this challenge will be more important than all our
measures against NUCLEAR POWER, AIDS and
XENOPHOBIA together.
The improved human being!
Î The development of superhuman beings?
Î The development of super-athletes?
Michael Weight
Î Race-related superhuman beings?
Î The evolution of „Einsteins“?
Î Prevention of hereditary diseases?
Î Prevention: Genetic counseling?
Î Gene therapy?
TEMPTATION – ADVANCEMENT - NIGHTMARE!?
When is the application of gene technology
meaningful?
The glass human being
Altering the attributes
Cloning
Artificial life
In which situation does the application of gene
technology seem indispensable?
How should we control the application of gene
technology?
Where do we draw the margin when we manipulate
the genotype and thereby interfere with evolution or
creation?
2
Definition of Gene Therapy as Agreed
by the Expert Panel
Gene Therapy is the
transfer of genetic
material to human
somatic cells for the
treatment or
prevention of diseases
or disorders.
One strategy is a procedure in which target cells are isolated
from the patient, cultivated and genetically modified in vitro,
and the modified cells are then reimplanted back in to the
patient.
This strategy is termed ex
vivo gene therapy.
This ex vivo approach is labour intensive and costly, but safe,
as the target cells are manipulated under controlled in vitro
conditions and no viral particles are injected to the patient.
Moreover, the genetically modified cells can be tested before
reimplantation.
The glass human being
HUGO (Human Genome Project):
Another strategy is a procedure in which the vectors are
introduced directly into the body. This technically simpler
strategy is termed in vivo gene therapy.
Gene cards for various diseases caused by genetic
defects (cystic fibrosis, muscle dystrophy – Duchenne´s
disease, cardiac disease, etc.
Because retroviral vectors integrate randomly into the Genome,
there are concerns about possible insertional mutagenesis
resulting from placement of the transferred genes into sensitive
parts of the host genome.
Î Consequences for the health system/prevention
ÎConsequences for sickness/health insurance (insurance
policies)
Î Consequences with regard to job selection (industries
that pose a health hazard – risk of cancer specific risk
factors for particular field of work)
The potential for abnormal regulation of cell growth and the
subsequent development of malignancy or toxicity associated
with chronic overexpression are possible, although until now
this has never been reported.
Î Consequences for the selection of talent
Î Consequences with regard to the practice of sports
(avoidance of specific types of sports depending on
individual weaknesses, risk factors).
Î Enhancing physical performance
Types of Gene Therapy
Medicines being developed
(Doug Jolly)
clinical trials to date: 2002
Cancer
Genetic Disease
Cardiovascular
Infectious Disease
Autoimmune
Bone disease
Neurological
311
52 (20 CF, 5 Hemoph.)
41
37 (36 HIV)
3
3
3
When will Gene Therapy Medicines
become generally available?
3-5 years away
• First approvals in either HIV, cancer or
hemophilia
• Still not completely defined; safety still an
issue
• Will be employed first in life threatening
disorders
3
Although the application of gene therapy to sports medicine is
in its infancy, it holds much promise as a novel procedure with
which to improve the clinical management of sporting injuries.
It is our view that gene therapy will be particularly useful in
initiating and accelerating the repair of cartilage, meniscus,
tendon and ligament.
The effectiveness of growth factors in wound healing has been
demonstrated in animal models. However, the specifics of
healing process for many types of connective tissues have not
been studied throughly.
Ch. Lamsam, 1997
Many studies have demonstrated that several growth factors
including platelet-derived growth factors (PDGF), fibroblast
growth factor (FGF), epidermal growth factor (EGF), and
transforming growth factor-β2 (TGF- β2) each have the
potential for enhancing wound healing.
Ch. Lamsam, 1997
Meniscal fibrochondrocytes are
capable of cell proliferation and
matrix production in cell
culture. TGF-β1 has been shown
to stimulate proliferation of
fibrochondrocytes and
proteoglycan synthesis in cell
and explant culture of meniscus.
Fibroblasts from the anterior cruciate ligaments also
respond to EGF, PDGF and insulin-like growth factor-1
(IGF-1). The results of such investigations encourage
the notion that growth factors have potential as
clinically useful agents of tissue repair.
Ch. Lamsam, 1997
Ch. Lamsam, 1997
Heritability of these phenotypes is generally low (about 25 %
or less) and rarely exceeds 50 %.
Is the application of Gene Therapy in Sports during the
rehabilitation correct?
Or is it „gene doping“ because the athlete´s come back time is shortened?!
Individuals with the same genotype respond more similarly
to training than those with different genotypes.
The search for genetic markers of trainability status will
likely be more productive than the investigation of
molecular markers of the performance phenotype in the
untrained state. C.Bouchard et al, 1997
4
GENOMIC SCAN AND VO2max
TRAINING RESPONSE RESULTS
Performance
Olympic Champions?
High Responder
Low Responder
Fast Responder
Slow Responder
Amount of Training
C.Bouchard, 2000
C.Bouchard, 2000
It is likely that probes will be eventually used to
identify the carriers of DNA sequence variations
desirable for sports performance, particularly if a
certain number of genes are found to have a
substantial influence.
It can been suggested that nothing will prevent
parents, sport leaders, coaches, or entrepreneurs
from using genetic probes in children and then in
infants for the purpose of identifying potentially
talented individuals. C.Bouchard et al, 1997
Targeted Intervention into oocytes and/or sperms,
fertilized oocyte:
Germline Therapy
T.Schultz et al, F.I.T. 1/98
Approaches for Gene-Doping:
Erythropoietin (EPO)
Is this DOPING?
Is it possible to classify this as doping?
Not in the classical approach?
But in a new approach?!
Do we need new approaches?
z Recombinant EPO is used in the therapy of different
diseases
High costs, needs regular in - patient and out - patient
control
z
New approach: Insert the EPO-Gene into cells which
can be transplanted/injected subcutaneous inhaled and
produce EPO-themselves!
Is there a fair chance to establish proof of this targeted
intervention?
5
Approaches for Gene Doping
Human Growth Hormon (HGH)
HGH producing genes are placed in myoblasts or
fibroblasts and are able to express HGH
in vivo transfection: special HGH producing genes placed
into a special protein-construct
Ð
In vitro transfection:
Myoblasts/fibroblasts then are injected into the muscle
than, they can be used as a spray to inhale into the
bronchial system
Ð
Ð
Ð
Approaches for Gene-Doping
The cells integrate into muscle structure and produce
HGH over a certain time range.
Ð
Longer lasting effects, successful!
than they can be injected into the vessels/blood system
(lipofection)
HGH Production increased
Approaches for Gene Doping
HGH loaded myoblasts:
Approaches for Gene-Doping
placed into skeletal muscle
Ð
ÐÐ
Ð
Animal model:
When these cells were injected into the muscles, the blood
HGH-concentration was more than 8-fold increased over
more than 3 months (the mice blood HGH concentration
was higher than respective blood concentration of adult
men).
Clinical trial: (Phase 1 trial) is running at the moment
First experiments on patients with muscle dystrophy
Duchenne are running (in these patients the missing
Dystrophin gene was placed into the myoblasts and
injected into their muscles)
GROWTH FACTORS
GDF-8 (Myostatin)
IGF-1
MGF
Successful !!
Approaches for Gene-Doping:
Approaches for Gene-Doping:
Ð Myostatin-Gene
• Myostatin (GDF-8) is one representative of the
transforming growth factors
• it is responsible for the differentiation of the skeletal
muscles
• it is down regulating the muscle growths
(hypertrophy)
• In special cattle (Belgium blue) this gene is not
working due to different mutations.
Ð
Myostatin-Gene
* If this gene is switched off in mice (knock
out mices) –> abnormal muscle hypertrophy
T.Schultz et al, F.I.T. 1/98
Ð Doubled muscle mass
T. Hertrampf et al, FIT 1/2004
6
BIOTEST MYOSTAT (BT-Myostat) (80 Capsules)
MYOSTATIN – INHIBITOR
CSP3, Alga: Cystoseira carnariensis
Approaches for Gene-Doping:
z Insulin like Growth Factor I (IGF-I)
IGF-I: important growth factor for development,
maintainance and regeneration of neuromuscular tissues.
z Animal Model:
Special Offer!
(Inc. V.A.T.) £66.99
Suggested Retail Price:
(Inc. V.A.T.) £84.99
Our Regular Price:
(Inc. V.A.T.) £84.99
„… Biotest Myostat Supplement helps promote muscle
growth, company claims.“
Why do athletes dope ?
After a intramuscular injection of a plasmid with a special
gene for human IFG-1, this IGF-1 was expressed in the
muscles.
Æ Strength increase!
Æ Deleterious side effects? (these growth factors regulate
also the growth of hormon dependent tumors)
Æ Lack of detection in blood and urine
Æ Detection in the muscles with PCR
(Polymerasechainreaction) – muscle biopsy necessary!!
New Approaches for Gene-Doping
Goldspink et al, 2000, had detected two new growth factors, that
are expressed by muscle it is subjected to activity which are derived
from the insulin like growth factor (1) (IGF-1) gene by alternative
splicing.
Æ One isoform: Muscle L. IGF-1 (similar to the lever type of IGF-1)
Æ Mechano growth factor (MGF): detected only when the muscle is
exercised or stretched
* MGF appears to be designed for local action out does not enter the
blood stream in any quantity
Bamberger & Yaeger, Sports Illustrated 1997
New Approaches for Gene-Doping MGF
Growth Factor producing genes are placed in stem cells
(muscular stem cells) and than in vivo transfected.
This growth factor appears to be involved in protecting
heart as well as skeletal muscle by inducing local repair and
preventing apoptosis.
There is also evidence that MGF involved in maintaining
nervous tissue, as IGF-1 is known to be transported within
neurons.
effects?
side effects?
* if MGF is placed in an engineered gene and injected into
muscles of a laboratory mouse: 20 % increase in muscle
mass in 2 weeks
* When liver type IGF-1 is introduced into muscles with a
similar approach, the increase of muscle mass is also 20 %,
but only after 4 months!
7
GENE –TECHNOLOGY Æ
Detection of different Methods used as
gene-engineering
Obviously: yes!
The vectors for inserting artificial genes into a cell are
an „artificial protein“ which is not present in the
normal Genome
Æ those artificial DNA can be analysed by a special
method:
Æ Theoretically: A single DNA molecule is detectible
Æ ... If a artificial gene is inserted into the muscle cell
or fibroblasts ..... The material for detection/control
must be part of this tissue: f.e. muscle biopsy!
Alticus - Citius - fortius
Æ GENE – ETHICS
Gene Therapies that could be abused
Gene Therapies that could be abused
(IOC-MC)
- Systemic protein: EPO, Growth Hormone,
Growth Factor
- Wound or injury healing: PDGF, KGF, bone
repair factors
- Increase muscle mass: angiogenic factors to
skeletal and heart muscle
- Blood vessel growth: FGF-1, 2, 4 or 5;
vascular endothelial growth factors, VEGF
- Pain relief: (endorphins, enkephalins,
other analgesic peptides)
- Neurological: hormones/growth factors
Pituitary/hypothalamic i.e. GHRF,
cognition/memory enhancers; mood
altering
The improved athlete!
The improved athlete!
Approaches for Gene Doping:
Approaches for Gene Doping:
GENE-ENGINEERING WITH GROWTH
FACTORS, HORMONS, ENZYMES...
FACTS
FICTION
*
Selection of talent
*
Detection of deficits
*
Reinforcing different attributes
*
Altering the attributes
FACTS
FICTION
8
The improved athlete!
OUTLOOK - NIGHTMARE
Approaches for Gene Doping:
Î The development of super athletes,
depending on the structure of the discipline?
Î Race-related super athletes? „THE EAST
AFRICIAN RUNNERS..“
Î The evolution of „Klammers“, „Dählies“
„Armstrong´s“?
Î Germline therapy: targeted intervention into
oocytes and/or sperms or the fertilized oocyte.
FACTS
Î Superstar – Altering the
attributes - Cloning
Î Persistence of superstars
through generations
Î Spare-part depots after
accidents, injuries,
overloading
Î Superbreeding Degeneration
FICTION
The Sword of Damocles over Olympia
THANK YOU FOR YOUR ATTENTION !
20 positive Doping control tests in Athens 2004.
(29 August 2004)
How many in Bejing 2008?
MIRACLES OF THIS WORLD
9