1) Advances in gene therapy have provided concepts and tools that could enable genetic modification to enhance athletic performance, raising ethical issues for both science and sport.
2) Some early experimental studies have demonstrated enhanced muscle function or increased blood production from gene therapy techniques, illustrating the potential for genetic manipulation to dope.
3) As the science progresses, these same genetic methods will likely be applied for non-therapeutic human enhancement, including doping in sport, which some commercial entities have already begun marketing despite ongoing risks.
1) Advances in gene therapy have provided concepts and tools that could enable genetic modification to enhance athletic performance, raising ethical issues for both science and sport.
2) Some early experimental studies have demonstrated enhanced muscle function or increased blood production from gene therapy techniques, illustrating the potential for genetic manipulation to dope.
3) As the science progresses, these same genetic methods will likely be applied for non-therapeutic human enhancement, including doping in sport, which some commercial entities have already begun marketing despite ongoing risks.
1) Advances in gene therapy have provided concepts and tools that could enable genetic modification to enhance athletic performance, raising ethical issues for both science and sport.
2) Some early experimental studies have demonstrated enhanced muscle function or increased blood production from gene therapy techniques, illustrating the potential for genetic manipulation to dope.
3) As the science progresses, these same genetic methods will likely be applied for non-therapeutic human enhancement, including doping in sport, which some commercial entities have already begun marketing despite ongoing risks.
1) Advances in gene therapy have provided concepts and tools that could enable genetic modification to enhance athletic performance, raising ethical issues for both science and sport.
2) Some early experimental studies have demonstrated enhanced muscle function or increased blood production from gene therapy techniques, illustrating the potential for genetic manipulation to dope.
3) As the science progresses, these same genetic methods will likely be applied for non-therapeutic human enhancement, including doping in sport, which some commercial entities have already begun marketing despite ongoing risks.
POLICYFORUM Gene Doping and Sport ETHICS Theodore Friedmann, 1 * Olivier Rabin, 2 Mark S. Frankel 3
W e humans have long sought to enhance ourselves beyond nor- mal through cosmetic surgery and drugs. Science is increasingly becoming humanitys partner and handmaiden in those efforts ( 1) and has added genetic manipulation to our enhancement tool kit. Many forms of human enhancement are becoming more fea- sible, sought-after, and even justiable in the quest for healthier, happier, and longer lives. Around the world, people have been exposed to the notion of human enhancement through sport, as some athletes seek a boost to success, stardom, and nancial reward. In the past, doping and cheating in sport have been enabled by advances in pharmacology and physiology. Recently, the successful develop- ment of gene therapy has provided the con- cepts, tools, opportunity, and, for some, justi- cation for genetic modication of functions that affect normal human traits, including athletic performance. This intersection of sci- ence and sport raises fundamental ethical and policy issues that neither domain can resolve absent a broader societal conversation ( 2). As science progresses and sport and antidoping authorities express increasing concerns, the time is right to look at how advances in genet- ics are affecting sport in ways unexpected just a decade ago. Genetic Manipulation for Doping Some early experimental studies illustrate the potential of gene therapy for treating dis- eases ( 3 8). Although most gene therapy approaches involve gain-of-function expres- sion of exogenous transgenes, other methods for genetic modication have also emerged ( 9 15). A denitive approach to genetic mod- ication for therapy would involve an emerg- ing technology of site-specific sequence correction of disease-causing mutations, as through the use of zinc fingerassociated recombinational methods ( 16). Although highly effective in some mod- els, these gene therapy techniques are imper- fect and still highly risky, as demonstrated by severe adverse events such as treatment-induced leukemia, or even deaths ( 17 19). Nev- ertheless, it is inevitable that, as the science and techniques mature, these same methods and concepts will be applied to broader nontherapeutic uses, including gene-based enhancement of human traits linked to sport. Toward that end, genetic methods have been used, for instance, to demonstrate enhanced muscle function from the insulin- like growth factor (IGF-1) or follistatin trans- genes ( 20, 21) and stably increased, regulat- able, erythropoietin-enhanced blood pro- duction in primates ( 22). One of the most widely discussed transcriptional modula- tion approaches has involved small molecule modulators of peroxisomal proliferator-acti- vated receptor delta (PPAR-), which regu- lates expression of genes involved in lipid metabolism, energy utilization, and insulin action and that increases the production of slow twitch oxidative energy-efcient mus- cle bers. These effects have important impli- cations for therapy of diabetes, obesity, and muscle disease. Furthermore, mice overex- pressing a PPAR- transgene or treated with a PPAR- agonist show enhanced endurance performance ( 23). Not surprisingly, these scientif ic approaches are known in sport communities and are coming temptingly close to human doping. A German athletic coach was found attempting to obtain Repoxygen, a gene- transfer vector that induces expression of the erythropoietin gene ( 24). A Chinese genet- ics laboratory reportedly offered gene-based manipulations before the 2008 Olympic Games in Beijing ( 25). It is not clear whether these or other similar attempts reached the stage of actual use in human athletes, but there seem to be few technical barriers stand- ing in the way. Genetic Tools for Doping Detection Traditional approaches to detection of dop- ing in sport have been based on chemical or molecular detection of the doping agent or of markers reecting the physiological or met- abolic effect(s) of the agent (e.g., chemical assays for steroids and stimulants, molecu- lar identication of foreign erythropoietin, and detection of abnormally high erythro- cyte production following exogenous eryth- ropoietin exposure). Although this is the most direct approach, new assays are con- stantly needed to respond to chemical modi- cations that make some drugs more dif- cult to detect, and therefore more prone to doping abuse. A potentially more powerful detection method has emerged, based on the concept that chemical, biological, or genetic dop- ing agents are likely to produce broad meta- bolic, genetic, and proteomic changes. These changes are now detectable by techniques such as microarray- or sequence-based tran- scriptional profiling and proteomic and metabolomic analyses that can dene molec- ular signatures of exposure to specic dop- ing agents, or families of drugs, or methods. Such signatures may be used to identify per- turbed physiological systems, even in the absence of knowledge of, or assays for, spe- cic doping agents. This approach is similar to that commonly used in searches for molec- ular signatures of oncogenesis, developmen- tal disorders, and so on ( 26, 27). Highly concerned by the risk of gene dop- ing, the World Anti-Doping Agency (WADA) ( 28), which has retained gene doping in its list of prohibited substances and methods since 2004, has sponsored international research teams with early results providing growing credence to the utility of molecular signatures in doping detection. For instance, exposure of murine myoblasts to IGF-1 has been shown to induce transcriptional and proteomic changes that may eventually constitute a signature specic for exogenous IGF-1 exposure ( 29, 30). Of course, the application of these kinds of global assays would require rigorous vali- dation of a connection with specic doping agents or methods. Marketing Gene Doping The challenges posed to sports organizations concerned with gene doping are compounded by the ubiquity of the Internet, relatively unconstrained by geographical boundaries, which, when fueled with private commer- cial interests, creates a powerful marketing tool for promotion and distribution of per- formance-enhancing agents. An industry has emerged to cater to the desire of athletes and C R E D I T :
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I S T O C K P H O T O . C O M *T.F. is chair of WADAs Gene Doping Expert Group and has performed research sponsored by WADA. Author for correspondence. E-mail: [email protected] 1 University of California at San Diego, La Jolla, CA 92093, USA. 2 World Anti-Doping Agency (WADA), Montreal, Que- bec H4Z 1B7, Canada. 3 American Association for the Advancement of Science, Washington, DC 20005, USA. Advances in gene therapy set the stage for the next generation of illegal doping, and doping detection, in sport. Published by AAAS
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5 FEBRUARY 2010 VOL 327 SCIENCE www.sciencemag.org 648 POLICYFORUM their coaches to nd a competitive edge. Athletes are an especially vulnerable population in the marketing of performance enhancement ( 31). Reputable athletes or coaches with little knowledge of genetics are at a disadvantage in assessing scientic claims that appear in advertisements. Marketing is particularly worrisome when the science is still a work in progress, when a persons health can be adversely affected, and when consumer knowledge about genetics is low. Although advertisements promoting products that prom- ise to enhance athletic performance have per- vaded the Internet for many years, recently it has become home for advertisements that pro- mote products to alter muscle genesby acti- vating your genetic machinery ( 32), or that state your genetic limitations are a thing of the past! ( 33) or Finally, every bodybuilder can be genetically gifted! ( 34). Conclusion The stakes are high in competitive sport. Enter the science of genetics and the increas- ing ability to modify genes for medical and performance enhancement purposes. As a result, the former chairman of WADA pro- claimed that You would have to be blind not to see that the next generation of doping will be genetic ( 35). As others have observed, What is clear is just how impatient some coaches and athletes are to nd new and inge- nious ways to cheat. First it was steroids, then EPO [erythropoietin], then human growth hormoneand now the illicit grail seems to be gene therapy ( 36). The global market- place is ready to meet the demand in ways that will inevitably include untested, and per- haps unregulated, products and exaggerated claims. Although commercial Web sites may be biased, and unreliable by rigorous sci- entic standards, they are a principal source of information for many athletes and should be monitored when looking for evidence of developing trends in doping ( 37). Accompanying those developments is the emergence of a community that alleges short- comings in the testing process and blames the antidoping effort for stimulating an arms race between regulators and the cheats ( 38). Others question why certain enhancement technologies are banned while others remain legal and argue that athletes should be free to use virtually any enhancing agents that sci- ence makes available to them ( 39). Scientists are not mere bystanders in these matters. The 2010 Winter Olympic Games and other major sport events present good opportunities for researchers to reafrm their responsibilities to conduct and report their work by means con- sistent with international ethics codes of clini- cal research. They also must be aware that some athletes and coaches will be tempted, prematurely and unwisely, to take advantage of results packaged by some as performance enhancement breakthroughs, even if they are untested in humans and the only break- through is faster or stronger mice ( 40, 41). References and Notes 1. E. A. Williams, Good, Better, Best: The Human Quest for Enhancement, Washington, DC, 1 and 2 June 2006 (Workshop summary report, AAAS, Washington, DC, 2007); www.aaas.org/spp/sfrl/projects/human_enhance- ment/pdfs/HESummaryReport.pdf. 2. There have long been divergent views of sport doping and the value of antidoping regulation ( 41). Some com- mentators have addressed how the use of performance- enhancing drugs in sports and their regulation have adversely affected fair competition ( 42). 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Responsive to initiatives and requests from various stakeholders, WADA establishes global antidoping rules following extensive consultation processes with international sports federations, and governments of the world. More than 600 international sport organizations, including all 33 Olympic federations, have demonstrated their strong sup- port of antidoping policies by adopting the World Anti- Doping Code and the related International Standards. Many active and former elite athletes are members of the consultative commissions or take part in the work of the executive boards of international sports federations, and the nal rules and guidelines issued by WADA reect both their input and support. 29. C. R. Bhasker, T. Friedmann, Insulin-like growth factor-1 coordinately induces the expression of fatty acid and cho- lesterol biosynthetic genes in murine C2C12 myoblasts. BMC Genomics 9, 535 (2008). 30. C. C. King, K. Bouic, T. 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(Advances in Genetics 51) Jeffery C. Hall, Jay C. Dunlap, Theodore Friedmann, and Veronica van Heyningen (Eds.) - Gene Doping in Sports_ The Science and Ethics of Genetically Modified Athletes-Elsevie (1).pdf