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.

Trying out Slideshare

[slideshare id=372085&doc=miah200612hastings2-1209129492787872-8&w=425]

IOC hopes to crack down on 'gene doping' in 2010 (2008, Jan 6)

IOC hopes to crack down on 'gene doping' in 2010Updated Sun. Jan. 6 2008 9:01 PM ET

CTV.ca News Staff

The International Olympic Committee is hoping a test will be available to expose the next generation of athletes who engage in gene doping.

"Gene therapy--molecular based medicine--is advancing very, very quickly and it is quite possible that there could be breakthroughs in the next couple of years that could be applied to sports by 2010," Jim Rupert, assistant professor at the University of British Columbia's School of Human Kinetics told CTV News.

However, the IOC hopes new testing methods will catch those who misuse gene-based medical treatments.

"As we go forward, they are more and more confident that they will have a non-invasive test that will allow us to determine whether or not there has been artificial manipulation," said Dick Pound, IOC member and former head of the World Anti-Doping Agency (WADA).

Gene therapy has been around for years, but remains largely untested. It involves inserting new DNA into the body's cells to correct genetic flaws that cause disease.

To increase performance, it is believed that dopers are trying to develop a method for increasing levels of a naturally occurring hormone through genetic manipulation.

"People will be pushing the envelope and looking for an edge, and if you can get a 15 or 30 per cent muscle increase in sports that require explosive strength... it's clearly something that people will think about," said Pound.

To ensure athletes end up on the podium fair and square, WADA awarded Jim Rupert a $325,000 grant to come up with a prototype test that will tell the difference between real hormones and those created by gene therapy. Rupert admits this will be difficult.

"Detecting something that's not supposed to be there is relatively easy. Detecting higher or lower levels of something that's naturally there is somewhat more challenging," he said.

Gene therapy revisited (2007, Dec 13)

Gene Therapy, RevisitedBy GRETCHEN REYNOLDS Published: December 13, 2007 In decisions followed closely by experts in performance-enhancing drugs, the Food and Drug Administration and the National Institutes of Health both ruled in the past two weeks that the death of an Illinois woman receiving gene therapy to treat her rheumatoid arthritis was not related to the therapy itself. The woman had developed a life-threatening infection that the regulators decided was due to other drugs she was taking.

As PLAY reported in June, gene doping -- or the attempt to alter athletes' genetic code to make them stronger, faster, bigger, more durable or otherwise inhumanly good -- piggybacks on legitimate gene therapy for ideas. Although there are no known cases of gene doping, many drug experts believe that dopers are squirreled away right now in underground labs, consulting published data about gene therapy to create their own home-brewed versions.

Which is why, in theory, the F.D.A.'s findings about the gene trial in Illinois are heartening. Gene therapy, in this case, didn't kill. Christopher Evans, a professor at Harvard Medical School, who's preparing his own gene therapy trial for osteoarthritis, speculates that dopers would have been less interested in the women's death than the promising early results from the trial. "Everything I've learned about the psychology of high-performance athletes is that they'll try anything to get an edge," he says. Last month, Evans's gene therapy human trial was pushed back by at least a year, to allow for more safety studies in animals. Gene dopers aren't likely to be so scrupulous. "Safety," Evans says dryly, "is not their main concern."

The Illinois gene therapy trial is expected to resume soon.

Engineering a win (2007 Oct)

Engineering a winIssue 17 of Cosmos, October 2007 <http://www.cosmosmagazine.com/issues/2007/17/> by Dominic Cadden <http://www.cosmosmagazine.com/node/1669> Sporting prowess at the flick of a gene? In the race to be the best, some athletes are even prepared to toy with their DNA.

Doping in sport is big business. Fierce competition drives athletes to extreme measures to improve their performance, while sports institutions employ ever more comprehensive tests to screen for the most commonly abused steroids and drugs.

The next paradigm in doping for those who can afford (and stomach) it may lay in illicitly manipulating their own DNA for a range of benefits, from increased stamina and reduced fat to larger muscles. 'Gene doping' exploits the ability to splice or 'cut and paste' useful genes resulting in athletic benefits ˆ and unknown side effects ˆ that last a lifetime.

A substance linked to gene doping was first detected at the 2006 Winter Olympics and there's now concern the practice could be used in the 2008 Beijing Olympics.

Gene doping is a spin-off from gene therapy, which is being investigated to treat hereditary disorders such as cystic fibrosis by replacing a patient's faulty genes with functional ones. Doctors have had some success with transferring genes into harmless viruses, which are injected into the body. With luck, these viruses replicate within target cells and copy themselves into the body's strands of DNA.

"The skills involved aren't that difficult," says Daniel Eichner, scientific manager for the Australian Sports Anti-Doping Authority in Canberra. "There are scientists who are willing to do anything for money, and a lot of athletes are willing to put their body on the line, no matter what the danger."

Even in medical gene therapy, however, two major dangers exist. The first is the risk that a manipulated gene can't be controlled or turned off. The second is that gene therapy could trigger cancer. One seemingly successful French trial for treating severe combined immunodeficiency disorder was halted in 2002 when some of the 11 patients developed leukaemia. However, despite the risks, the temptations will be hard to resist.

Since the full publication of the human genome in 2004, a handful of the 25,000-odd genes detected so far have been found to have some role in athletic performance. One example is the IGF-1 or insulin growth factor gene, says geneticist Damien Abarno of the University of South Australia in Adelaide. Scientists have already had some success getting this gene to 'take' in animals and, unlike steroids, "it increases the number of muscle cells, not just the size of them," he says.

And there are many more genes that could be useful to athletes. Boosting the expression of the gene for MGF, or mechano-growth factor, could limit fatigue and improve muscle repair. The AMPK gene affects how muscles accumulate glycogen, and therefore impacts endurance. The ACE-1, or angiotensin-converting enzyme gene, can be deleted for increased strength or inserted for greater endurance, and has an effect on blood pressure and how muscles use oxygen.

Only a few of these genes have been extensively tested for side effects. However, animal trials with one gene called HCP have highlighted some of the potential risks. One common method of improving performance is increasing red blood cell numbers, which boosts the transport of oxygen from the lungs to the muscles, improving stamina and performance. The conventional method of boosting red blood cell count is with the hormone erythropoietin (EPO), although this is now easily screened for in athletes. Similar effects can be gained by inhibiting the function of the gene HCP, which itself regulates blood cell distribution. However, trials in monkeys were unsuccessful, and often fatal, says Albarno. "The problem was that the [red blood cell count] increased rapidly up to levels where it turned the blood to jelly."

This side-effect was avoided with a different gene therapy treatment, for anaemia. Tested in 2002, but never produced commercially, Repoxygen works by increasing levels of the body's own EPO. This, in turn, boosts red blood cell production, but only in response to very low levels of oxygen that might be experienced with anaemia or during intensive exercise.

It was Repoxygen that German athletics coach Thomas Springstein was accused of attempting to obtain prior to the 2006 Winter Olympics in Turin, Italy. Springstein and another trainer in Germany are under investigation by the World Anti-Doping Authority (WADA), which outlawed gene doping in 2003. The WADA is now working with geneticists to find effective screening techniques.

"Close to US$8 million has been spent in the WADA research program for gene doping, representing a significant portion of the entire budget," says geneticist Theodore Friedmann at the University of California in San Diego, USA, and chair of WADA's gene doping panel.

One proposal has been to genetically map athletes and then periodically re-screen them to detect changes, says Robin Parisotto, a Canberra-based consultant to Sport Knowledge Australia, who helped establish a test for blood doping with EPO. "But when do you do that? Before they become elite athletes, as a child, or soon after birth?" Parisotto asks.

Friedmann says that scientists working under the WADA banner have studied a number of the side effects that occur with changes to genes and to metabolism. If researchers can put these together to create a 'signature', eventually it may be possible to detect this signature in saliva samples, he says. "In exactly the same way that DNA technology has added so much in forensic science and crime detection, it will add very powerful new tools to detect doping."

With the 2008 Beijing Olympics looming, the clock is ticking to find tests capable of detecting the practice.

"Realistically, it will be very difficult to have a test up and running before Beijing", says ASADA's Eichner. But this doesn't mean GM cheaters will manage to remain undetected ˆ WADA rules allow samples to be tested for up to eight years after an event. 

Dominic Cadden is a freelance science and physiology writer based in Sydney, Australia.

Gene doping could replace performance-enhancing drugs, experts predict (2007, Oct 23)

Gene doping could replace performance-enhancing drugs, experts predict

By Morgan Ashenfelter

(AXcess News) Washington - Performance-enhancing drugs are nothing new in professional sports, as recent scandals with Major League Baseball, the Tour de France and Marion Jones attest. But members of medical and policy making communities are worried about a new technology called gene doping, which modifies genes regulating specific traits.

"The sports industry is a small window into an entire realm of non-medical testing that we need to consider how to regulate," said Mark Rothstein, director of the Institute for Bioethics, Health Policy and Law at the University of Louisville School of Medicine. He and three other members of a panel spoke on Monday.

The focus of the panel, put on by the Hastings Center and the American Association for the Advancement of Science, was the effects gene doping and genetic testing could have on athletes and how it should be regulated.

"The science is inevitable," said Dr. Theodore Friedmann, professor of pediatrics at the University of California, San Diego. "The time is not too early to think about policy and ethical issues."

In the sports world, gene doping would be the use of genes instead of drugs to enhance performance. Scientists have identified genes that control blood production, muscle growth and fast and slow twitch fibers, which determine muscles' ability to work at a high intensity or steady endurance. If an athlete has a lower amount of a certain gene in his or her body, a doctor could inject the athlete with more of that specific gene.

Genes are also affected by environment and development over time, meaning scientists may not be able to modify the genes that could enhance an athlete's performance.

But that's a risk most professional athletes are willing to take, said John Feinstein, National Public Radio sports commentator and the author of several sports books.

"The pressures on athletes, the fact that there's always someone right behind you and the amount of money encourages them to take the risk," Feinstein said. "To athletes, succeeding at their sport is worth the risk to their health, to be labeled as a cheater and of being caught."

Thomas Murray, president of the Hastings Center, a bioethics research institute, said in the short run, education is the most important.

"In the next several years, it is much more likely athletes will hurt themselves because no one knows exactly how to regulate certain genes," Murray said. "In the long run, sports bodies will have to do the most in terms of policy, but there will be some room for Congress."

Genes, which are made up of DNA, can be likened to instructions that contain a person's physical and functional traits. When a problem exists within DNA, a mutation occurs in the gene, which affects whichever trait it controls.

Through gene therapy, doctors can target specific, problematic genes by injecting a virus into the person's body. The virus has been stripped of its disease-causing materials and instead carries a human gene that is mutilated or missing in that person. When the virus multiplies, the new, healthy gene will have different traits than the one it replaced.

In athletes, the injections could add traits that didn't exist before or reinforce existing traits.

Because the technology is so new, risks are high. Many patients who undergo gene therapy to cure life-threatening diseases die from contracting other diseases, such as leukemia. Friedmann encourages the use of gene therapy only for patients with life-threatening mutations, not for healthy athletes.

"Gene therapy is an immature technique, still," Friedmann said. "It's experimental medicine."

Murray said that one protection would be to discourage gene testing, at least on children.

Gene testing analyzes a person's DNA to look for a number of specific traits, such as cognitive ability, addiction, sexuality and coordination. What Rothstein is concerned about is parents using genetic testing to place children on a certain life path, including sports. He cited Genetic Technologies, an Australian company, which offers such tests.

"It is an incorrect notion, genetic determinism, to think that genes are immutable," Rothstein said.

Genetic Technologies' test analyzes a person for disease susceptibility, identity and sports performance, specifically ACTN3, which controls fast twitch fibers.

"This won't affect the 2008 Olympic Games," Murray said. "But companies will soon be peddling gene doping, and there will be willing and eager athletes as customers."

Source: Scripps Howard Foundation Wire

The Future (2007, August)

The futureNatasha Woods

GENE DOPING is defined by the World Anti-Doping Agency as "the non-therapeutic use of cells, genes, genetic elements, or of the modulation of gene expression, having the capacity to improve athletic performance".

An example of gene doping would involve the non-therapeutic use of gene therapies used to treat muscle-wasting disorders and which will soon be entering human clinical trials.

The chemicals are indistinguishable from their natural counterparts and are only generated locally in the affected tissue. Nothing unusual enters the bloodstream, so officials will have nothing to detect in a blood or urine test.

The first product to be associated with genetic doping emerged in the build-up to the Torino 2006 Olympic Winter Games, where Repoxygen was discussed as a possible substance in use at the Games.

A German court hearing evidence in the trial of a running coach accused of giving performance-enhancing drugs to young athletes was told that a search of his email inbox turned up references to a product called Repoxygen.

The substance, developed by UK firm Oxford Biomedica, delivers the gene for erythropoietin (EPO) to muscle cells. In one email, according to German news service Deutsche Welle, the coach Thomas Springstein wrote that "new Repoxygen is hard to get" and "please give me new instructions soon so that I can order the product before Christmas".

Outlaw DNA (2007, June 2)

Outlaw DNABy GRETCHEN REYNOLDS It was a single line from a longer e-mail message. But when read into the record by prosecutors at the drug trial last year of the German track coach Thomas Springstein, it caused a sensation. “The new Repoxygen is hard to get,” Springstein had written. “Please give me new instructions soon so that I can order the product before Christmas.”

Until that day in the courtroom, Repoxygen was an obscure gene-therapy drug developed at a pharmaceutical lab in Oxford, England, to fight anemia. The lab shelved the product when it seemed unlikely to be profitable. Once it was mentioned in court in January 2006, however, Repoxygen vaulted to celebrity-drug status in Europe. Newspapers and Web sites ran dozens of stories about the imminent danger of the therapy. “The moment that e-mail was presented in open court,” a columnist wrote in the weekend paper Scotland on Sunday, was when the “era of genetic doping . . . arrived.”

Repoxygen works by worming a specialized gene into its host’s DNA. In the right circumstances, the gene directs cells to start making extra erythropoietin (EPO), a hormone that drives the production of red blood cells. More red blood cells means more oxygen transported to muscles, which is why athletes have been known to inject themselves with synthetic EPO. By insinuating itself into an athlete’s genetic code, Repoxygen would theoretically produce a natural stream of the stuff.

That presumably was its allure for Thomas Springstein, who in all likelihood had heard the rumors that a single dose of Repoxygen was not only undetectable but also had the capacity to alter an athlete’s DNA. Once a coach for several top German track-and-field athletes, Springstein was tried last year for giving performance-enhancing drugs to unwitting young runners, including one of Germany’s best female hurdlers, Anne-Kathrin Elbe, who was 16 at the time.

“I was taken aback and speechless,” Elbe told me in an e-mail message. “He said that they were vitamins.”

It’s unlikely that Springstein ever got hold of Repoxygen; none was found during a 2004 raid of his home. It’s even harder to say that the “era of genetic doping” is unequivocally upon us. What is clear, and what the Springstein case reminds us, is just how impatient some coaches and athletes are to find new and ingenious ways to cheat. First it was steroids, then EPO, then human growth hormone — and now the illicit grail seems to be gene therapy. Researchers have been hounded with requests for gene therapy from sports teams as well as individual athletes; many scientists also believe that would-be dopers troll the Internet, searching for just the right gene-therapy study to try to duplicate on their own. The formula for Repoxygen itself is publicly accessible, and a few Web sites even claim to have it for sale.

“We filed a patent,” says Alan Kingsman, the chief executive of Oxford BioMedica, the lab that developed Repoxygen. “We published our data. It’s all available to anyone who has the training to understand it.”

So far, there have been no confirmed cases of gene doping in the United States or anywhere else, though that could change during the 2008 Summer Olympics in Beijing, which is when some speculate that gene doping will make its debut. The World Anti-Doping Agency (WADA), which preemptively banned gene doping in 2003, has been funding research at laboratories around the world to develop a reliable blood or urine test to use at the Games. “They’ll freeze samples,” says Theodore Friedmann, a geneticist at the University of California <http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_california/index.html?inline=nyt-org> , San Diego, who also is head of a gene-doping advisory panel for WADA. “If gene doping is happening in Beijing, I believe we will be able to tell — if not during the competition, then later.”

Friedmann can’t say just how close WADA is to producing its gene-doping test, and won’t speculate about how foolproof it would be. At present, gene doping is detectable only through biopsies of affected muscle tissue. Cheaters can only hope this remains the case indefinitely.

“We all know people who’ll take anything — anything — to make the Olympic team,” says Darren De Reuck, a running coach in Boulder, Colo., whose athletes include his wife, Colleen, the 2004 United States Women’s Olympic Trials marathon champion. “It doesn’t matter how weird and wacky it sounds. Playing around with genes is about as out-there as anything I’ve ever heard of. So I’m sure some people will think it would be a great thing to try.”

In the United States, the first news media reports of gene doping appeared in the late 1990s, when word got out that “Schwarzenegger mice” were being produced in the lab of H. Lee Sweeney, a molecular physiologist at the University of Pennsylvania <http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_pennsylvania/index.html?inline=nyt-org> . Sweeney, who had been searching for treatments for muscle-wasting diseases, focused his research on a gene that produces a protein called IGF-1, which helps regulate growth. His experiments worked. The mice that had been injected with an extra copy of the IGF-1 gene packed on muscle and became as much as 30 percent stronger than before.

After his work was publicized, Sweeney was inundated with calls from athletes volunteering themselves as human test subjects. One high-school football coach offered up his entire team. “I was quite surprised, I must admit,” Sweeney says. “People would try to entice me, saying things like, ‘It’ll help advance your research.’ Some offered to pay me.”

To this day, Sweeney receives overtures from would-be guinea pigs. “Every time there’s a story about our research or any research similar to ours, we get more calls,” he says. Patiently he’ll explain to the caller that, even when his therapy is ready for human testing — Sweeney says it will be years — there will be risks of infection, rejection, organ failure, possibly death. The callers will listen, he says, and then reply, “O.K., when can we start?”

Other gene-therapy advances are closer to fruition. At Harvard Medical School, Chris Evans, a professor of orthopedic surgery, has located a gene that may treat and prevent osteoarthritis; he and his colleagues have tested it successfully in lame horses and plan to switch to human subjects later this year.

“I’ve had lots of people volunteer,” he says. “Some of them are my friends, middle-aged weekend athletes whose knees are shot.” But he’s anticipating that he’ll eventually get requests from coaches and trainers as well. When I ask how his therapy could affect healthy young athletes, he replies: “It is possible they could create stronger joints. They could train harder without risking joint injury. But that’s not the point of our research. We’re trying to treat disease.”

The search for effective gene therapies was a primary motivation behind the Human Genome Project, which, between 1990 and 2003, identified the 20,000-plus genes that make up human DNA. Each of these genes expresses a protein that, in turn, regulates cellular functions. If, for instance, you have a defective gene for producing the muscle protein dystrophin, your muscles won’t repair themselves correctly. That’s the cause of muscular dystrophy. By fixing glitches in a person’s genome, gene therapy would, in theory, cure any number of devastating genetic diseases.

The science is quite simple: typically, the requisite gene is introduced into a virus that is then injected into a patient. The virus can enter the nuclei of host cells, changing their DNA. When the cells replicate, they pass on the new DNA as well.

But the results have been largely disappointing. Hundreds of gene-therapy trials have been performed on humans and animals over the past two decades. A handful of therapies have shown moderate success, but most have done absolutely nothing, good or bad. Some have had unintended, even disastrous consequences. In one 1998 study, baboons were injected with a genetic compound similar to Repoxygen designed to alter EPO production. The new gene did, indeed, produce extra EPO — at an unchecked pace. The baboons’ circulatory systems became so clogged with red blood cells that the animals had to be drained of excess blood. In another study, healthy primates had an unexpected immune reaction to the virus used to carry the EPO gene. Their bodies lost the ability to produce red blood cells. Stricken with anemia, several of the animals had to be euthanized.

Repoxygen is not so capricious. Unlike most experimental EPO gene therapies, Repoxygen has a built-in gauge that recognizes when red-blood-cell counts have fallen below a healthy level. Only then will the gene crank up EPO production. Once normal red-blood-cell counts have been reached, the gene turns itself off. Since athletes presumably have optimum red-blood-cell levels, Repoxygen would likely do nothing for them, except possibly set off an immune reaction to the virus.

Nonetheless, dopers want it, as is apparent by underground Web sites that advertise gene therapies for sale. In the interest of research, Olivier Rabin, the science director of WADA, ordered some samples. “What came was just versions of synthetic EPO,” he says, not gene-therapy drugs. But fraudulent advertising doesn’t seem to be a deterrent to sales.

The Web sites are, Rabin believes, quite popular: “No one ever said the people willing to use gene doping will be great minds or careful scientists.”

The unsettling dystopian aura surrounding gene doping also obscures the fact that this isn’t fantasy science: gene doping is not eugenics. It can’t create superathletes. None of the substances with which dopers will likely experiment would completely rewrite a person’s DNA; nor could dopers pass on their altered genes to future generations. And genetic changes wouldn’t necessarily be permanent.

If successful, gene therapy would affect performance by fractions of seconds. But, of course, gold medals and multimillion-dollar sponsorship deals rest on such knife-edged differences, so the dopers are sure to keep trying.

As for Thomas Springstein, he received a 16-month suspended sentence for supplying an illegal substance to a minor. He has been banned from the German Track and Field Federation but is otherwise free to coach. The word is, he’s been getting offers. .

Ethics to guide gene quest for sport stars (2007, May 19)

Ethics to guide gene quest for sport starsJacquelin Magnay May 19, 2007 GENETICS has long been touted as the next big thing in sport - the "big" being the potential abuse of gene manipulation to enhance sporting performance.

But Australian authorities are keen to use genetics in an ethical way to identify the next big thing: the next great sporting hero.

In the past two days the bio-ethicists at the Hastings Centre in New York have grappled with their final position statement, using input from the Australian Institute of Sport's director, Peter Fricker, to clarify research issues affecting genes and sport.

Fricker is planning to submit the Hastings Centre framework to the World Anti-Doping Agency and seek permission from the Federal Government to restart athlete genetic research which was put on hold in 2004.

"We had to make sure we got the guidelines in place because it is such an important issue," he said. "But the research will be to see if genetic screening is worth doing in the first place. Is it worth making it part of the battery of current testing like heart rate∑ or do we find 99 per cent of an athlete's ability is because of coaching, physiological aspects or training and the DNA is only a small part?"

Scientists could, for example, take a sample of tissue, analyse the DNA and work out which sport an athlete is best suited to. And if the athlete had the "boxer" gene, indicating a predisposition to injury, or more serious diseases like Alzheimer's and heart disease, they could be spared long stints on the sideline with prevention programs.

The think tank's initial ideas for ethical guidelines include a requirement that athletes be at least 12 years old before being involved in research, and that the need of sports organisations who cared for athletes to know genetic information should prevail over an athlete's not wanting to know.

Gene doping may give athletes edge (2007, April 28)

Gene doping may give athletes edgeTinkering with mutations would be much harder to detect than the substance doping some use today By Greg Lavine The Salt Lake Tribune Salt Lake Tribune Article Last Updated:04/28/2007 01:28:04 AM MDT

Performance-enhancing drugs can be tough enough to detect in athletes, but the future of cheating - gene doping - may be even harder to notice. And it could be happening now, said Utah genetics expert Marc Williams. Most illegal sports drugs are designed to enhance the body's production of natural substances, such as testosterone or steroids. But gene manipulation could alter an athlete's genetic makeup to bump up the amount of certain substances. There are no proven cases of gene doping, yet the International Olympic Committee and the World Anti-Doping Agency have already banned the practice. Gene doping was one of several topics discussed by Williams, director of the Intermountain Clinical Genetics Institute at LDS Hospital, and other doctors this week in Murray during a seminar on the growing link between genomics and athletics. Part of the problem, the experts agreed, is there is no sure way to prove someone has been gene doping. "It's gonna be tough to detect this stuff," said Eric Heiden, an Olympic gold medalist in speed skating who is an orthopedic surgeon at TOSH, The Orthopedic Specialty Hospital, in Murray, "and it's gonna work." An area of potential concern is genetic ways to alter an athlete's blood. The traditional cheat involves the drug erythropoietin, or EPO, which is used to increase hemoglobin levels in the body. Williams said hemoglobin can be thought of as buckets carrying oxygen to vital tissues. Increasing hemoglobin levels means more buckets are available to distribute oxygen. Drugs that mess with hemoglobin levels can leave telltale signs that can be found in drug testing. If a gene has been altered to increase EPO levels, it may leave behind no sign of foul play. This raises the question of genetically-gifted athletes who happen to have beneficial mutations. A champion Nordic skier from Finland, Eero M`ntyranta, in the 1960s had a genetic mutation that helped his body to produce higher levels of EPO, and this likely gave him an edge over competitors, Williams said. Genetic researchers may be able to detect abnormally high levels of certain substances, but there might be no way to prove who has been gene doped and who is genetically gifted, Williams said. Gene doping has already taken place in lab animals, including mice and monkeys, but there is no evidence the practice has made the leap to humans, he said. To alter an athlete's genetics, a modified virus cell could be used to carry a new gene into a person's DNA, he said. Just as drugs can have negative side effects, gene doping may also have unforeseen long-term consequences on other bodily functions. These concerns may apply more to the possibility of creating genetically altered superathletes from birth. Williams said parents might one day have the option of picking genetic traits in their offspring, such as bulkier body for football or a taller frame for basketball. "Where is the child's choice?" asked Williams. The doctor also wondered what happens after a genetically-altered athletes pass their physical peak, and are no longer good at what they were designed to do. glavine@sltrib.com

Scientists racing to catch athletes who manipulate genes to boost performance (17 Dec, 2006)

Maria Cheng, Canadian Press

http://www.canada.com/edmontonjournal/news/story.html?id=dcdfdf6d-3d05-4ccc-8d5b-7d7a42482a59&k=36249

Published: Sunday, December 17, 2006

LONDON (AP) - Scientists are racing to develop a test to catch athletes who try to boost their performance by manipulating their own genes.

Though there is no proof that gene doping is already occurring, researchers say they would like to be ready ahead of the 2008 Beijing Olympics. Gene doping is an illegal spin-off of gene therapy, which typically alters a person's DNA to fight diseases like muscular dystrophy and cystic fibrosis.

....

Gene Doping Test?

Yesterday, it was announced by Ted Friedmann that a new tool to detect gene doping has been discovered. I haven't yet seen whose lab has developed this test, but I might be seeing Ted today in New York at the Hastings Center. Perhaps some further light can be shed on this. In the press coverage i've seen so far, Ted does mention that there is a long way to go with the test and it has indicated that the test is for 'foreign DNA'. The question remains as to whether this would reveal all forms of gene doping. On that, the coverage is also less clear. The important quote from my perspective is the following:  "It is very early in the development of the technology, and we are encouraged that it is proving possible to find evidence of foreign genes being introduced into a body," says Friedmann, director of the Center for Molecular Genetics at the University of California-San Diego School of Medicine. "The problem is not only to develop a test but to validate it to the point where you can take it to an arbitration or court and prove that's the only explanation for the finding that you made. That's very difficult, and that's going to take a lot more work."

BBC Five Live (3 Oct, 2006, 9-10pm)

I took part in a debate with Matthew Syed and Ted Friedmann about the prospects of Gene Doping

International Performance in Sport Conference (Newcastle, 26 Sept, 2006)

I've already written a few things about this meeting. It was great to see a number of friends again at this meeting and it was particularly interesting to hear concerns from within the medical community over the conflict of interests they face when treating athletes. My paper was titled 'Gene Doping: The Politics and Ethics of Enhancement'

Genes and Juice (11 Aug, 2006)

TCS Daily - Washington,DC,USA... future. Gene doping, the modification of the body's own cells to produce various substances, has been much discussed recently. The ...

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Miah, A. (July, 2004)Genetically Modified Athletes: Biomedical Ethics, Gene Doping, and Sport London and New York: Routledge ISBNs: hb: 0415298792; pb: 0415298806.

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Book Contents of Genetically Modified Athletes

Foreword by Thomas H. Murray Editors' Preface

Author's Preface

INTRODUCTION: ANTI-DOPING AND PERFORMANCE ENHANCEMENT Why genetics now?: An Introduction I: Why Not Dope?…It’s Still About the Health II: Forget Drugs & the Ideology of Harmonisation

CONCEPTUALISING GENETICS IN SPORT III: What is Possible? Imminent Applications for the GM athlete IV: Interests, Politics, & Ways of Reasoning

THE ETHICAL STATUS OF GM IN SPORT V: Humanness, Dignity, and Autonomy VI: Personhood, Identity, & the Ethics of Authenticity VII: Virus, Disease, Illness, Health, Well-Being…and Enhancement VIII: Unfair Advantages & Other Harms

GENETICALLY MODIFIED ATHLETES IX: Enhancing, Altering, or Manipulating People? X: Sport Needs Genetic Modification XI: Conclusions & Implications

Genetic doping in sports causes concern

Genetic doping in sports causes concernThe World Today - Thursday, 27 July , 2006  12:46:00 Reporter: Michael Edwards ELEANOR HALL: Some scientists are predicting that if genetic doping is allowed to continue unchecked, athletes will soon be running 100 metres in eight seconds and clearing three-metre high jumps.

But a conference in Sydney is being told that this brave new world could be extremely dangerous.

Genetic doping uses DNA fragments to change a person's genetic structure. It's already widespread particularly in endurance events like cycling.

Michael Edwards was at the conference in Sydney and filed this report.

Scientist finds the speed genes

Scientist finds the speed genes DNA analysis can take the guesswork out of the ancient art of producing a champion, says geneticist

Greg Wood Tuesday March 21, 2006 The Guardian <http://www.guardian.co.uk>  

A British scientist yesterday claimed to have made a "historic breakthrough" in the study of thoroughbred genetics, after a six-year research project produced the first proof of a relationship between specific genes and the individual performances of racehorses.

The results of the study by Dr Stephen Harrison, whose company Thoroughbred Genetics is based in Kent, will be published next month in the peer- reviewed journal Mitochondrian....

Genetic doping cheats could find that it's all downhill after Turin

Genetic doping cheats could find that it's all downhill after Turin MICHAEL BUTCHER , Scotland on Sunday

IF SALT Lake is remembered among drug-busters as the Darbepoetin Olympics, Turin is likely to be its Repoxygen equivalent. The difference is that, since Repoxygen is a genetic doping product, there is less likelihood that anyone will be caught using it.