POLICYFORUM ETHICS Advances in gene therapy set the stage for the Gene Doping and Sport next generation of illegal doping, and doping detection, in sport. Theodore Friedmann, 1* Olivier Rabin, 2 Mark S. Frankel 3† e humans have long sought to severe adverse events such as lar identifi cation of foreign erythropoietin, enhance ourselves beyond nor- treatment-induced leukemia, and detection of abnormally high erythro- Wmal through cosmetic surgery or even deaths ( 17– 19). Nev- cyte production following exogenous eryth- and drugs. Science is increasingly becoming ertheless, it is inevitable that, ropoietin exposure). Although this is the humanity’s partner and handmaiden in those as the science and techniques most direct approach, new assays are con- efforts ( 1) and has added genetic manipulation mature, these same methods stantly needed to respond to chemical modi- to our enhancement tool kit. Many forms of and concepts will be applied fi cations that make some drugs more diffi - human enhancement are becoming more fea- to broader nontherapeutic cult to detect, and therefore more prone to sible, sought-after, and even justifi able in the uses, including gene-based doping abuse. quest for healthier, happier, and longer lives. “enhancement” of human A potentially more powerful detection Around the world, people have been traits linked to sport. method has emerged, based on the concept exposed to the notion of human enhancement Toward that end, genetic methods have that chemical, biological, or genetic dop- through sport, as some athletes seek a boost to been used, for instance, to demonstrate ing agents are likely to produce broad meta- success, stardom, and fi nancial reward. In the enhanced muscle function from the insulin- bolic, genetic, and proteomic changes. These past, doping and cheating in sport have been like growth factor (IGF-1) or follistatin trans- changes are now detectable by techniques enabled by advances in pharmacology and genes ( 20, 21) and stably increased, regulat- such as microarray- or sequence-based tran- physiology. Recently, the successful develop- able, erythropoietin-enhanced blood pro- scriptional profiling and proteomic and ment of gene therapy has provided the con- duction in primates ( 22). One of the most metabolomic analyses that can defi ne molec- on June 17, 2013 cepts, tools, opportunity, and, for some, justi- widely discussed transcriptional modula- ular “signatures” of exposure to specifi c dop- fi cation for genetic modifi cation of functions tion approaches has involved small molecule ing agents, or families of drugs, or methods. that affect normal human traits, including modulators of peroxisomal proliferator-acti- Such signatures may be used to identify per- athletic performance. This intersection of sci- vated receptor delta (PPAR-δ), which regu- turbed physiological systems, even in the ence and sport raises fundamental ethical and lates expression of genes involved in lipid absence of knowledge of, or assays for, spe- policy issues that neither domain can resolve metabolism, energy utilization, and insulin cifi c doping agents. This approach is similar absent a broader societal conversation ( 2). As action and that increases the production of to that commonly used in searches for molec- science progresses and sport and antidoping slow twitch oxidative energy-effi cient mus- ular signatures of oncogenesis, developmen- www.sciencemag.org authorities express increasing concerns, the cle fi bers. These effects have important impli- tal disorders, and so on ( 26, 27). time is right to look at how advances in genet- cations for therapy of diabetes, obesity, and Highly concerned by the risk of gene dop- ics are affecting sport in ways unexpected just muscle disease. Furthermore, mice overex- ing, the World Anti-Doping Agency (WADA) a decade ago. pressing a PPAR-δ transgene or treated with ( 28), which has retained gene doping in its list a PPAR-δ agonist show enhanced endurance of prohibited substances and methods since Genetic Manipulation for Doping performance ( 23). 2004, has sponsored international research Some early experimental studies illustrate Not surprisingly, these scientific teams with early results providing growing the potential of gene therapy for treating dis- approaches are known in sport communities credence to the utility of molecular signatures Downloaded from eases ( 3– 8). Although most gene therapy and are coming temptingly close to human in doping detection. For instance, exposure of approaches involve gain-of-function expres- doping. A German athletic coach was found murine myoblasts to IGF-1 has been shown to sion of exogenous transgenes, other methods attempting to obtain Repoxygen, a gene- induce transcriptional and proteomic changes for genetic modifi cation have also emerged transfer vector that induces expression of the that may eventually constitute a “signature” ( 9– 15). A defi nitive approach to genetic mod- erythropoietin gene ( 24). A Chinese genet- specifi c for exogenous IGF-1 exposure ( 29, ifi cation for therapy would involve an emerg- ics laboratory reportedly offered gene-based 30). Of course, the application of these kinds ing technology of site-specific sequence manipulations before the 2008 Olympic of global assays would require rigorous vali- correction of disease-causing mutations, as Games in Beijing ( 25). It is not clear whether dation of a connection with specifi c doping through the use of zinc finger–associated these or other similar attempts reached the agents or methods. recombinational methods ( 16). stage of actual use in human athletes, but Although highly effective in some mod- there seem to be few technical barriers stand- Marketing Gene Doping els, these gene therapy techniques are imper- ing in the way. The challenges posed to sports organizations fect and still highly risky, as demonstrated by concerned with gene doping are compounded Genetic Tools for Doping Detection by the ubiquity of the Internet, relatively 1University of California at San Diego, La Jolla, CA 92093, Traditional approaches to detection of dop- unconstrained by geographical boundaries, 2 USA. World Anti-Doping Agency (WADA), Montreal, Que- ing in sport have been based on chemical or which, when fueled with private commer- bec H4Z 1B7, Canada. 3American Association for the Advancement of Science, Washington, DC 20005, USA. molecular detection of the doping agent or of cial interests, creates a powerful marketing markers refl ecting the physiological or met- tool for promotion and distribution of per- *T.F. is chair of WADA’s Gene Doping Expert Group and has performed research sponsored by WADA. abolic effect(s) of the agent (e.g., chemical formance-enhancing agents. An industry has CREDIT: ADAPTED FROM ISTOCKPHOTO.COM CREDIT: †Author for correspondence. E-mail: [email protected] assays for steroids and stimulants, molecu- emerged to cater to the desire of athletes and www.sciencemag.org SCIENCE VOL 327 5 FEBRUARY 2010 647 Published by AAAS POLICYFORUM their coaches to fi nd a competitive edge. cal research. They also must be aware that 20. S. Lee, E. R. Barton, H. L. Sweeney, R. P. Farrar, Viral expression of insulin-like growth factor-I enhances Athletes are an especially vulnerable some athletes and coaches will be tempted, muscle hypertrophy in resistance-trained rats. J. Appl. population in the marketing of performance prematurely and unwisely, to take advantage Physiol. 96, 1097 (2004). enhancement ( 31). Reputable athletes or of results packaged by some as performance 21. J. Kota et al, Sci. Transl. Med. 1, 6ra15 (2009). coaches with little knowledge of genetics are at enhancement “breakthroughs,” even if they 22. V. M. Rivera et al., Long-term pharmacologically regu- lated expression of erythropoietin in primates following a disadvantage in assessing “scientifi c” claims are untested in humans and the only “break- AAV-mediated gene transfer. Blood 105, 1424 (2005). that appear in advertisements. Marketing is through” is faster or stronger mice ( 40, 41). 23. V. A. Narkar et al., AMPK and PPARdelta agonists are particularly worrisome when the science is exercise mimetics. Cell 134, 405 (2008). 24. DW-World, Deutsche-Welle, www.dw-world.de/dw/ still a work in progress, when a person’s health References and Notes article/0,2144,1890782,00.html can be adversely affected, and when consumer 1. E. A. Williams, Good, Better, Best: The Human Quest 25. Associated Press, 23 July 2009, www.msnbc.msn.com/ knowledge about genetics is low. Although for Enhancement, Washington, DC, 1 and 2 June 2006 id/25816605/. (Workshop summary report, AAAS, Washington, DC, 26. F. J. Rauscher, 3rd, The year ahead. Cancer Res. 69, 1 advertisements promoting products that prom- 2007); www.aaas.org/spp/sfrl/projects/human_enhance- (2009). ise to enhance athletic performance have per- ment/pdfs/HESummaryReport.pdf. 27. A. Anguiano et al., Gene expression profi les of tumor vaded the Internet for many years, recently it 2. There have long been divergent views of sport doping biology provide a novel approach to prognosis and may has become home for advertisements that pro- and the value of antidoping regulation ( 41). Some com- guide the selection of therapeutic targets in multiple mentators have addressed how the use of performance- myeloma. J. Clin. Oncol. 27, 4197 (2009). mote products to “alter muscle genes…by acti- enhancing drugs in sports and their regulation have 28. Established in 1999, WADA has been the principal agency vating your genetic machinery” ( 32), or that adversely affected fair competition ( 42). Others have responsible for antidoping activities in sport. Responsive state “your genetic limitations are a thing of the suggested that drug- or gene-based doping causes little to initiatives and requests from various stakeholders, 33 or no harm to athletes, sport, and public policy and that WADA establishes global antidoping rules following past!” ( ) or “Finally, every bodybuilder can the controversies surrounding doping could readily be extensive consultation processes with international sports be genetically gifted!” ( 34). obviated by simply carrying out doping under medical federations, and governments of the world. More than supervision ( 43).