Genetics and Sport (2003, Sept 30, Geneva)


Genes in Sport, Geneva, Sept 30 2003 GATTACA -    crucial point in film where two brothers are swimming against each other and the GM brother says to his brother ‘we cant see the shore, we have to turn back’. This moment is very  interesting because it reveals the relative importance of that contest in comparison to their broader dispute (which was what gave rise to the contest). -    Hero is not merely the ‘natural’ athlete, but also the benevolent and ‘injured’ GM athlete.

Bengt

Bob Goldman (1984) – if take drugs, big success, then death, would you =52% said yes

Lane, T. 2003 Jan A future of jocks, genes and jingoism.  www.theage.com

Veronique L. Bilat Why do Kenyans run so well?

Wolfarth, B. Genes and sports performance: what do we know today, what will we know tomorrow?

GENATHLETE study

ACE and Performance

NOS3 and Performance

Aerobic performance and trainability -    which genes are involved -    what are major intermediate phenotypes for aerobic performance and regulation? -    Poss to predict aerobic performance and trainability levels using genetic markers?

ACEII (not a strong candidate gene) -    cardiac contractility -    cardiac and vascular hypertrophy -    vasoconstriction -    Rigat, B. et al NAR20: 1433, 1992 -    Inertion-/Deletion -    Montgomery, HE Nature (1998) -    ACE in the HERITAGE study o    Cannot support concept that ACE locus plays a contribution to training

No difference between genotypes of trained and untrained athletes, with respect to ACE I/D –polymorphism.

Outside of sport related research (e.g. hypertension), similar findings

ACE I/D also asso with left ventricular hypertrophy -    Landry et al JAMA 1985 254, 1 -    Kupari, 1994, Am J Physio -    Montgomery (1997, Circulation, 96(3) 741-747

Material and Methods LVM (Left ventricular mass)

LVM and LVMI of different ACE I/D genotypes and allele carriers -    any differences between genotypes and carriers? o    No overall association between ACE I/D and LVMI •    But new studies using higher sample o    For carrier status, a small significant difference between I carriers and D carriers •    But I carriers had higher mass (Montgomery concluded that D is responsible for training)

NOS (Nitric oxide synthase) -    REF: McAllister, RM Med Sci sport Exercise, 27 -    Nadaud et al, 1994, -    Nakayama et al 199 – hypertension and left ventric hypertrophy o    Found link between patients with hypertension and left ventric hypertrophy had allele o    Perhaps play a role in endurance o    4 polymorphisms in NOS3 genes analysed o    no different between EEA and SC o    no signif in overall distribution o    but higher proportion for 164 base pair allele •    why? Not sure yet. Might be marker  for variant in surrounding genes, need to screen gene for variants

Perusse, tankinen, Rauramaa, migual rivera, wolfarth, bouchard Human gene map for performance and health related fitness phenotypes: the 2002 update, Med Sci Sport Exercise , Vol 35, no.8

Sandro Rusconi Dept of Medicine, Biochemistry, Uni of Fribourg

Basic understanding of genes -    what is a gene, molecular biology dogma, genetic diseases, environmental factors, ageing

Essential concepts

DNA – RNA - Protein 100000 genes, more than 300000 functions

no such thing as a genetic disease, except for monogenic ones, e.g. muscular dystrophy, where genetic component is dominant

other conditions are significantly environmental and bahvioural -    Familiar breask cncer, poradic breast cancer, lung cancer, obesity, atherosclerosis, alzhiemers, parkinsons, dru abuse, homosexuality

Genes important but cannot define them because they are multi-functional

Science-grade material can be prepared easily Clinical-grade material is more difficult (i.e. GNP prepared vectors for patients) Millilitre of XX is 1franc, for GNP is 10000Francs (safety measures)

Molecular medicine -    prevention, diagnosis, therapy

Four eras of molecular medicine -    eighties: genes as probes (pre-natal diagnosis) -    nineties: genes as factories (isolate gene and put back to work into cells, e.g. yeast, growth factors, pharma products, many of which save lives) -    Y2K: genes as drugs – inject gene into body to correct -    Post-Y2K: post-genomic era

If we live long enough we all get Alzeimers and Cancer! -    these are part of ageing process

Somatic gene transfer

Definition of FT – use of genes as drugs (correcting disorders by somatic gene transfer

Chronic, acute, preventive Hereditary and acquired disorders Loss of function, gain of function

Why somatic? -    somatic gene transfer is a post-natal treatment aiming at somatic cells o    does not led to a hereditary transmission of genetic alteration •    Is not a Genetic selection

Four fundamental questions -    efficiency -    specificity (which kind of tissue to address) -    persistence (acute or rapid treatment) -    toxicity (how toxic is treatment)

Pharmacological considerations

Classical drugs -    synthetically prepared, rapid diffusion,oral delivery poss, cellular delivery, can be delivered as soluble molecules, rapidly reversible treatment

Protein drugs -    e.g EPO -    biggermolecules -    cannot enter into cells -    act exocellary -    if stop using, effect will go away

Nucleic acids -    larger -    biologicall prepared -    slow diffusion -    oral delivery inconceivable -    cellular dlivery: no membrane, no nuclear, no biological import -    must be delvered as complex carrier particles -    slowly or not reversible

therapy with nucleic acids -    reqs particularted -    more complex -    different degrees of reversibility

3 classes of physio gene delivery -    exvivo (bone marrow, liver cells, skin cells) -    invivo (topical delivery) e.g. brain, muscle, eye, joints, tumours) -    invivo (systemic delivery) intravenous,inttra arterial, intra peritoneal o    bigger implications

2 classes of gene transfer -    non viral transfer (transfection) Nuclear envelope barrier, see Nature Biotech, Dec 2001 -    Viral gene transfer (infection)

Popular vectors -    Adenovirus o    No persistence o    Limimited packaging toxicity -    adeno-associated Very -    retrovirus (include. Hiv) o    limited package, random insertion,

Gene Therapy in Clinic -    cancers main

A of Sept 2002, 599 registered protocols, 4000 treated patients -    86% phase I -    13% phase II -    1% phase III

Genetic milestone -    gives overview of recent science -    all experimental

(Road runner cartoon, cayote on drugs)

currently, side effects would and should ethically limit science

3 levels of doping

possible treatments -    Before the competition anabolic enhancers -    During competition – performance enhancers -    After competition – repair enhancers

Anti-TNF factor, BMPs

Current limitations Viral gene transfer (immune problems, limited readmin, gen toxicity Nonviral (inefficient Strategy-indep (laborious, long term different to control, irreversible

Side effects -    short – mid term, autoimmunity, hyperimmunity, toxic shock -    long term: fibrosis cancer, inaccessibility to other interventions

Intrinsic to reckless apliaction (problem biggest danger) -    malpractice (unsuitable vector administration route) -    non-clinical grade material (pathogens or allergens)

Detection -    antibody detection (viral antigens) -    r-nucleic acids

Anatomoically difficult to detect

Need muscle biopsy -    before permit, need strong suspician!

Gene based doping versus drug or protein based doping -    drug protein is most possible -    gene doping detection is difficult or impossible

odds speak against adoption of gene-based doping -    b tu this applies to common-sense clinical practice and this aspect is not guaranteed in doping field

entire  sector of sport where doping is not rigorously controlled

major risk is with premature application

5-10 yrs before effects has been a lot of bad science and Stock market crash has got rid of bad scientist -    follow this up!

Alex Mauron Gene Doping

Ethics of human gene manipulation Convention vs gene doping, ethical differences? Doping and ethics of sport Doping and ethics of human enhancement

Gene therapy: initial ethical debate 1980s -    somatic, and therapeutic OK -    germ-line and enhancement, NOT OK

enhancement is called doping -    not correct: non-medical therapy is characterised as enhancement. That’s all.

1990s many clinical trials of somatic gene therapy, often for polygenic diseases few successes ‘normalisation’ of somatic gene therapy, that is increasingly felt to be similar to any innoivative chemotherapy (paradigm of DNA medicine – A. Kahn) normal doesn’t mean harmless (the Gelsinger case)

Gelsinger case largely misunderstood -    reaction was ‘gene therapy is dangerous’ -    actually, clinical research is dangerous, not just genetics! (whenever system of ethical process breaks down, then it becomes dangerous)

still, messing with genes of humans remains highly controversial. Why?

Genomic metaphysics -    genome represents ontological hardcore of organism, determining both its individuality and species identity -    Mauron, Genomic metaphysics J Mol Biol, 219, 2002 -    Mauron, Is t genome t secular equivalent of soul, science, 2001, 291:831-832

Gene therapy debate concludes that somatic gene therapy is ethically similar to pharma therapy

Same relationship to gene doping and pharma doping

Therefore gene doping would be objectionable on same grounds as doping -    ME: not true: doping is typically associated with anti-social behaviours and a negative sporting culture. Gene doping doesn’t have that context, but if we make it illegal, then we imbue it with that framework

Back to therapy./enhanement distinction

In gene therapy, ethics just as in sport ethics, therapy ok, enhancement is not.

Standard ethics of sport -    let best win -    to bethe best, ought to result from virtuous combintion of innate talent of personal meirt and effort, plus some degree of luck -    chemistry or genetics represent moral shortcuts that substitute undeserved facility where there should be meritorious effort and excellece -    doping disturbs the ‘level playingfield’  need for a fair competition

doping is immemorial -    ME: this is reason to question the moral discourse running through it

Be it through genetics, drugs, or divine intervention, sports has always attracted cheating

Notion of level playing field may be an illusion -    talent: includes genetic differences -    first order capacities (muscultaion potential, bone structure, lung capacity, etc) -    second order capacities (somatopsychic, insentitivity to pain, endurance etc) -    such capacities are unequally distributed almost by definition real reason of prohibition has little to do with fairness, actually has to do with the threat to health of athletes (threatens it more severely than intensive sports training does) -    ME: how do we make this conclusion? -    Well I agree, but this is a partial reading of the situation. Anti-doping is poltically more entrenched than the health issue

What is the merit in sport?

What is merit in scientific training? -    ME: hmmm, it is not easy, as our first presentation indicated

Difference between sports and other competitive human activities -    ME: not sufficient

Our concepts of fairness and merits have been honed by other human activities, and have been applied to sports in appropriately

Conclusion

Enjoy the freaks, Mark Lawson, The Guardian, June 7, 2003.