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Sports, Gene Doping, and WADA

By: Leslie A. Pray, Ph.D. © 2008 Nature Education 
Citation: Pray, L. (2008) Sports, gene doping, and WADA. Nature Education 1(1):77
Gene doping could stretch the physical limits of human strength and endurance. What are the consequences of gene therapy in sports competition, and more, importantly, is it safe?
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An illustration shows two disembodied hands in a cupped position, with the open palms of each hand facing upward. The hands are grey against a light blue background, and are cupping a yellow, simplified DNA molecule rising out of them. The DNA molecule is composed of two parallel strands coiled together to form a double-helix. Horizontal lines are arranged in parallel from the top of the molecule to the bottom, connecting the two strands, and resemble rungs on a ladder.
Gene doping.
© 2003 Nature Publishing Group Murray, T. An Olympic tail? Nature Reviews Genetics 4, 494 (2003). All rights reserved. View Terms of Use
Gene doping is an outgrowth of gene therapy. However, instead of injecting DNA into a person's body for the purpose of restoring some function related to a damaged or missing gene, as in gene therapy, gene doping involves inserting DNA for the purpose of enhancing athletic performance. The World Anti-Doping Agency (WADA), an international organization created in 1999 to "promote, coordinate, and monitor the fight against doping in sport in all its forms," defines gene doping as the "nontherapeutic use of cells, genes, genetic elements, or modulation of gene expression, having the capacity to enhance performance" (World Anti-Doping Agency, 2008).

One of the first issues that comes up when considering whether, when, and how results from genetic studies will be exploited for gene doping purposes is whether gene doping is "right." While many people agree with WADA's position that gene doping threatens the integrity of sports competition, others think differently. For example, Julian Savulescu, professor of ethics at the University of Oxford, England, argues that "[g]enetic enhancement is not against the spirit of sport; it is the spirit of sport" (Skipper, 2004). Whether or not it is right to use DNA for enhanced athletic performance will likely be a subject of fiery debate for years to come.

The Science Behind Gene Doping

While gene doping has yet to become a reality, H. Lee Sweeney, a professor of physiology at the University of Pennsylvania School of Medicine and one of the leading researchers in the field of gene therapy, has already been inundated with requests for such doping from professional weight lifters and numerous other athletes, according to an article in Science News (Brownlee, 2004). Sweeney has garnered this attention because of his discovery of a way to potentially reverse muscle degeneration caused by diseases like Duchenne muscular dystrophy (DMD), a sex-linked genetic disorder. In patients with DMD, a critical muscle protein called dystrophin gradually becomes dysfunctional over the first few years of an affected person's life, leading to a loss of muscle fiber, an increase in fibrosis, and eventually complete loss of muscle function. Working with a mouse breed that had a mutation in the dystrophin gene and thus displayed a DMD-like phenotype (mdx mice), Sweeney and his colleagues observed that when a protein called insulin-like growth factor 1 (IGF-1) interacted with the cells on the outside of muscle fibers, it caused the cells to grow. In addition, the research team determined that inserting the gene that encodes IGF-1 into muscle cells produced the same effect.

Sweeney and his colleagues further found that when the muscle fibers of mdx mice were exposed to IGF-1, not only did fibrosis decrease as the mice aged, but muscle mass actually increased by about 40% (Barton et al., 2002). Sweeney told Science News that when the mice became the equivalent of senior citizens (which for mice is about 20 months of age), they were still as strong and fast as they had been when they were young. After these and subsequent studies, the IGF-1-endowed mice became known as "Schwarzenegger mice." While groundbreaking, Sweeney's research is still experimental, and the findings have yet to be tested on DMD patients or other humans.

Meanwhile, a group of scientists headed by Ronald Evans of the Salk Institute in La Jolla, California, demonstrated that injecting mice with the gene that encodes a fat-burning protein called PPAR-δ enabled the animals to run up to twice the distance of their wild-type littermates (Wang et al., 2004). Although genetic engineering of these so-called "marathon mice" could potentially be exploited to enhance athletic performance (in long-distance runners or swimmers, for example), Evans's reason for pursuing this line of research was to see whether it might have therapeutic value. Specifically, he wanted to test whether increasing PPAR-δ expression would transform muscle fibers in a way that might protect against obesity and type II diabetes, as previous studies had shown that many obese and type II diabetic patients have fewer type 1 muscle fibers. Evans and his team thus determined that increasing PPAR-δ expression effectively increased the number of type 1 muscle fibers in mice.

Would Gene Doping Be Safe?

More important than the ethical implications of gene doping, some experts say, is the fact that gene doping could be dangerous, and perhaps even fatal. Consider the protein erythropoietin (EPO), a hormone that plays a key role in red blood cell production. EPO is often administered (as a hormone, not via gene therapy) to patients suffering from anemia as a result of kidney failure or chemotherapy. Scientists are hopeful that they can someday develop a gene therapy method of delivering the gene for EPO instead of administering the protein itself. The hormone EPO is also used as a highly controversial performance-enhancing substance by athletes as a way to optimize oxygen delivery to muscle cells (by increasing the number of red blood cells). Like IGF-1 and PPAR-δ, the EPO gene is considered by some experts to be a potential candidate for gene doping (Azzazy et al., 2005).

But scientists still have much work to accomplish before EPO gene delivery, whether for the purpose of gene therapy or the more controversial purpose of gene doping, is considered safe. In the aforementioned Science News article, the reporter relays a story by Jim Wilson, a professor of medicine at the University of Pennsylvania and a leading researcher in the field of gene therapy. When Wilson and colleagues injected macaque monkeys with viral vectors carrying the EPO gene, the host cells ended up producing so many red blood cells that the macaques' blood initially thickened into a deadly sludge. The scientists had to draw blood at regular intervals to keep the animals alive. Over time, as the animals' immune systems kicked in, the situation reversed and the animals became severely anemic (Rivera et al., 2005).

The field of gene therapy, and by extension, gene doping, is full of unpredictable and dangerous results like this, which is why Sweeney, Evans, and other researchers who have identified DNA targets that could potentially be exploited for gene doping are the first to emphasize that the research is still at only an experimental stage. The therapies need to be proven safe in some of the larger animal models, not just mice, before they can even be tested in humans, let alone used for therapy or, as Savulescu says, "in the spirit of sport."

References and Recommended Reading

Azzazy, H. M. E., et al. Doping in the recombinant era: Strategies and counterstrategies. Clinical Biochemistry 38, 959–965 (2005)

Barton, E. R., et al. Muscle-specific expression of insulin-like growth factor 1 counters muscle decline in mdx mice. Journal of Cell Biology 157, 137–148 (2002)

Brownlee, C. Gene doping: Will athletes go for the ultimate high? Science News 166, 280 (2004)

Murray, T. An Olympic tail? Nature Review Genetics 4, 494 (2003) doi:10.1038/nrg1135 (link to article)

Rivera, V. M., et al. Long-term pharmacologically regulated expression of erythropoietin in patients following AAV-mediated gene transfer. Blood 105, 1424–1430 (2005)

Skipper, M. Gene doping: A new threat for the Olympics? Nature Reviews Genetics 5, 720 (2004) doi:10.1038/nrg1461 (link to article)

Wang, Y. X., et al. Regulation of muscle fiber type and running endurance by PPAR-δ. PLoS Biology 2, e294 (2004) (link to article)

World Anti-Doping Agency Home Page. (accessed June 27, 2008).


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