192 LEADER

Genetic doping that may be seen following hard training ...... or . MGF is made in muscle tissue and does not circulate in the blood. This Super athletes or cheats? means its effects are localised but more importantly in athletics, blood or urine P McCrory screening for such agents is unlikely to ...... be useful in detecting use of such agents. One research group from London re- The threat of gene transfer technology to elite sport ported a 20% increase in muscle bulk over a two week period in mice when using MGF gene transfer. IGF-1 itself is he International Olympic Com- states such as for treating the anaemia made in the liver as well as muscle and mittee (IOC) recently released its seen in chronic renal failure. Athletes has similar anabolic effects with Tnew list of banned substances and were quick to exploit the drug, especially Sweeney et al showing a 15% increase in methods. This list will be effective from 1 in professional cycling, where the scan- muscle bulk in mice injected with the January 2003 and replaces the 1 Septem- dal at the 1998 Tour de France high- gene. This was in the absence of any spe- ber 2001 list. Amongst the important lighted this issue when a team employee cial exercise programme.5 Such gene changes, the category of genetic doping was caught with a carload of perform- therapy is likely to be relatively safe as a banned method is listed for the first ance enhancing agents, including EPO. given that the effects seem to be localised time. The current list can be easily This problem may increase if athletes to the targeted muscle and is likely that accessed on both the IOC and World can insert a gene that results in a similar human trials will be relatively soon. It is Anti-Doping Agency (WADA) websites effect to that which naturally occurred in speculated that combining IGF-1 or (www.wada-ama.org or www.olympi- Mäntyranta. This can be done by cou- MGF with other growth factors or with c.org) pling the relevant to a delivery strength based training programmes The use of gene doping or gene trans- vector such as an adeno or adeno- may lead to even greater responses in fer technology to improve athletic per- associated virus. In 1997, Leiden et al muscle growth. formance heralds a significant threat to used an adenovirus to deliver the EPO the integrity of anti-doping initiatives. gene in mice and monkeys. This boosted CAN GENE DOPING BE This approach has the potential to the haematocrit from 49 to 81% in the DETECTED? improve sporting performance far be- mice and from 40 to 70% in the monkeys. Detecting such abuse will not be easy. yond “traditional” pharmacological The effects lasted for over a year in the Engineered genes are likely to look iden- means and in ways that make detection mice and for approximately 12 weeks in tical with endogenous genes products. of use extremely difficult if not impossi- the monkeys.3 Similar findings have Perhaps detection of associated viral par- ble at the present time. It sounds like the been reported in other primate models.4 ticles may be of use but this would ultimate sporting nightmare come true. Clearly there are significant safety involve muscle biopsies. It would be like There is also another side to gene issues not least from excessive haemat- looking for the proverbial needle in the transfer technology which is a more dif- ocrit levels causing thrombosis as well as haystack and would be unlikely to ficult ethical issue, namely the use of some disturbing early reports of unex- garner much enthusiasm from athletes gene mapping in talent identification plained deaths in liver failure patients given the invasive nature of the biopsies. and the use of tissue engineering in the treated with . The fine line Many of the muscle based gene recovery from injury, such as muscle of performance and health is highlighted technologies are unlikely to be detected atrophy following cruciate ligament in- by the fact that in families with EPO by urine or blood testing as is currently jury. Once such gene therapy is clinically gene mutations, early death from stroke done in elite athletes. Even with EPO available then can we deny its benefits to and myocardial infarction is often the gene transfer, finding a high haematocrit athletes? rule. There is also a theoretical concern may be suggestive but separating it from that the effect of repeated injections may a naturally occurring gene mutation will HOW MAY GENE DOPING BE be less effective because of the immune not be easily and in any case, cyclists USED? response against the viral delivery vector. have shown that even with injectable We have known for decades that genetic Once these problems are more fully EPO use, close medical monitoring en- differences between athletes can result understood, clinical trials of EPO gene sures that red blood cell parameters can in markedly improved performance.1 At transfer in humans will not be far off. be contained within set levels making it the 1964 Winter Olympics in Innsbruck, If EPO gene therapy can boost aerobic difficult to even be suspicious that illicit a Finnish competitor Eero Mäntyranta, performance, what about muscle gene doping may have occurred. won two gold medals in cross country strength? A number of groups around The labelling of gene transfer products skiing. Though his training programme the world are currently working on gene with genetic “bar codes” as has been wasn’t radically different from his rivals, transfer therapy for a variety of chronic suggested with GM modified agricul- Mäntyranta had a distinct advantage. He muscle diseases as well as for specific tural produce may be another option was born with a genetic mutation that problems such as muscle atrophy. To however this would require the complete increased the oxygen carrying capacity adapt this technology for athletic tissue cooperation of scientists, ethicists, ath- of his red blood cells by 25–50%. Mänty- engineering will be a relatively simple letes, sports authorities, medical practi- ranta had a mutation in the gene coding matter. tioners, professional societies, pharma- for the erythropoeitin (EPO) receptor One of the targets of this research is ceutical, and biotech industries, and which prevented the normal feedback the insulin-like growth factor 1 public authorities (including govern- control of red blood cell mass.2 This (IGF-1) and one of its isoforms, ments) to avert misuse. An unlikely genetic mutation is exceedingly rare mechano-growth factor (MGF) that is scenario! however anyone can boost his or her red turned on by mechanical signals such as In 2002, WADA held the “Genetic blood cells simply by taking exogenous stretch or exercise overload. The protein Enhancement of Athletic Performance” EPO. EPO has been commercially avail- is also important in muscle repair conference, at the Banbury Center of the able since 1989 principally for disease mechanisms such as the muscle damage Cold Spring Harbor Laboratory on Long

www.bjsportmed.com LEADER 193

Island. This meeting brought together ultimate performance will be in the elite tissue-engineered supermen and super- international experts and leaders in range. Whilst few people would have a women. biology and genetics, sports medicine, problem with this approach, what if the Br J Sports Med 2003;37:192–193 policy makers, legal experts, representa- same potential can be detected using a tives of the Olympic Movement, and ath- genetic blood test instead of a tape letes to explore the science, technology, measure? ...... and ethical issues facing the sports com- The physical performance phenotypes Author’s affiliation munity as a consequence of gene trans- for which genetic data are currently P McCrory, Centre for Sports Medicine fer technology. The outcome from this available include cardio-respiratory en- Research and Education and the Brain Research conference was that a combination of durance, elite endurance athlete status, Institute, University of Melbourne, Melbourne, regulation, education, and research was muscle strength, other muscle perform- Australia thought to be the best current method ance traits, training response, and exer- Correspondence to: Dr McCrory, PO Box 93, for addressing the prospect of gene dop- cise intolerance to varying degrees. The Shoreham, Victoria 3916, Australia; ing in sport from becoming a reality. phenotypes for health related fitness [email protected] include exercise heart rate, blood pres- THE OTHER SIDE OF THE COIN sure, heart morphology, exercise related REFERENCES Although gene doping and the use of cardiac arrhythmias, anthropometry, gene transfer technologies are of major 1 Nazarov I, Woods D, Montgomery H. The body composition, insulin and concern in sport, much of this work is angiotensin coverting enzyme I/D metabolism and blood, lipoprotein, and polymorphism in Russian athletes. EurJHum ultimately based on our more complete haemostatic factors. Although this Genetics 2001;9:797–801. understanding of the human genome. As 2 Aschwanden C. Gene cheats. New Scientist seems a wide variety of exercise pheno- a human map of performance related 15 January 2000:24–9. types, the human fitness and perform- 3 Svensson E, Black H, Dugger D, et al. Long genes and health related fitness pheno- ance gene map is still in its infancy. With term erythropoeitin expression in rodents and types is drawn up so our understanding non-human primates following intramuscular of the role of various genes in targeting advances in technology such as genome- injestion of a replication-defective adenoviral wide scans followed by intensive posi- vector. Hum Gene Ther 1997;8:1797–806. athletic performance increases and also 4 Zhou S, Murphy J, Escobedo J, et al. the potential targets for gene doping tional cloning, new candidate genes will Adeno-associated virus-mediated delivery of 6 similarly expands.67 Currently there are be rapidly identified. leads to sustained elevation of As described above, as more and more haematocrit in non-human primates. Gene over 100 chromosomal loci, including Ther 1998;5:665–70. nuclear and mitochondrial DNA, in- candidate genes are identified so the 5 Barton-Davis E, Shoturma D, Musaro A, et volved in human performance with more potential problems with gene doping will al. Viral mediated expression of insulin like increase. With more potential gene tar- growth factor 1 blocks the ageing-related loss genes discovered each year. of function. Proc Nat Acad Sci For many years, most countries have gets available, once the gene transfer 1998;95:15603–7. had talent identification programmes of technology is safe for human use, then a 6 Rankinen T, Perusse L, Rauramaa R, et al. one sort or another. Typically these Pandora’s box of applicable uses in The human gene map for performance and health-related fitness phenotypes: the 2001 involve sports such as rowing, where sporting performance will be available. update. Med Sci Sports Exerc young athletes are identified on the basis Unless innovative, non-invasive, and as 2002;34:1219–33. of anthromorphic characteristics and yet unknown means of detecting gene 7 Rankinen T, Perusse L, Rauramaa R, et al. The human gene map for performance and subjected to intensive training pro- transfer use are developed then the health- related fitness phenotypes. Med Sci grammes with the expectation that their future of elite sport may be a race of Sports Exerc 2001;33:855–67.

New BASEM office

BASEM is pleased to announce that it has now opened an administrative office in Leeds. It is open on weekdays from 1.00pm to 5.00pm. Contact may be by telephone: +44 (0)113 263 5014; email: [email protected] or by Royal Mail at PO Box 148, Chelsea Close, Amberley Road, Leeds LS12 4WW, UK. It will be run by Sobia Rafiq, who will redirect all queries to the relevant Executive Member.

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