T 199 - Performance Enhancements

Genetically Modified Olympians?
Jul 31st 2008From The Economist print edition
On the eve of the Beijing Olympics, we examine the prospect of athletes using gene therapy to enhance their performance—and of catching them if they try
FOR as long as people have vied for sporting glory, they have also sought shortcuts to the champion’s rostrum. Often, those shortcuts have relied on the assistance of doctors. After all, most doping involves little more than applying existing therapies to healthy bodies. These days, however, the competition is so intense that existing therapies are not enough. Now, athletes in search of the physiological enhancement they need to take them a stride ahead of their opponents are scanning medicine’s future, as well as its present. In particular, they are interested in a field known as gene therapy.
Gene therapy works by inserting extra copies of particular genes into the body. These extra copies, known as “transgenes”, may cover for a broken gene or regulate gene activity. Though gene therapy has yet to yield a reliable medical treatment, more than 1,300 clinical trials are now under way. As that number suggests, the field is reckoned to be full of promise.

As far as sport is concerned, the top transgene on the list, according to Jim Rupert, an anti-doping expert at the University of British Columbia, is the gene for erythropoietin. EPO, as it is known for short, is a hormone that regulates the production of red blood cells. It is already available as a drug (it was one of the first products of biotechnology companies in the late 1980s), and it has been used widely in endurance sports such as long-distance cycling. But if an athlete’s body could be stimulated to make more of it that would—from the athlete’s point of view—be better than taking it in drug form.

No dopes
The reason is that EPO, like most performance-enhancing drugs, is banned. However, bans work only when they are enforced, and that requires a test which can distinguish synthetic EPO from the natural hormone made by an athlete’s body. At the moment, this is possible. The EPO from a biotechnology company’s vats has a slightly different chemical structure from the natural sort. But the evidence suggests that EPO produced as a result of gene therapy will be far harder to distinguish.
In fact, EPO doping may already have happened. In 2006, during the trial of Thomas Springstein, a German coach accused of doping his underage charges, it transpired that Repoxygen, an experimental gene-therapy product containing the gene for EPO, was already making the rounds on the black market. Repoxygen causes a controlled release of EPO, but only when the body senses a lack of oxygen. Or at least it does so in mice.
Whether black-market Repoxygen has won any races is unknown. But several other genetic therapies being tested in mice also look as if they may interest the sort of men and women who feel their athletic performance needs a little boost.
Like EPO, vascular endothelial growth factor spurs red-blood-cell formation and thus helps to supply tissues with oxygen. The gene that encodes this protein is the subject of several medical studies, and is thus a prime candidate for sporting use.
IGF-1 is also a growth factor—though it promotes brawniness in muscle rather than the production of blood cells. Inject the gene that encodes it into a particular muscle and you can affect that muscle and no other. Such specificity might be of interest to people like tennis players and javelin throwers. Meanwhile, a gene called MSTN encodes a protein called myostatin, which limits rather than enhances muscle development. In this case, therefore, the doping is designed to switch the gene off. The result is what have been nicknamed “Schwarzenegger” mice.
Once brawny muscles have been acquired, whether licitly or illicitly, other genes might then be used to tune their activity. Tweaking PPAR-delta, for instance, alters the way muscles obtain their energy. The individual fibres that comprise a muscle can run in one of two modes. In slow-twitch mode they burn fat, and are less prone to fatigue. In fast-twitch mode they burn sugar. That makes them prone to fatigue, but is useful for delivering short bursts of power. Both modes are valuable to athletes, but in different types of event. The ability to make muscle fibres specialise in one mode or the other would thus be of great benefit to unscrupulous coaches. PPAR-delta controls the switch.
Finally, animal studies on the genes for natural pain-killers called endorphins suggest that these could be used to limit the perception of pain—another desirable trait for athletes. That might consign the adage “no pain, no gain” to the history books.
There is thus a lot of potential. And although—the Springstein incident aside—there is no evidence that any of these techniques have made their way into real athletes, the authorities are taking no chances.
The World Anti-Doping Agency (WADA), sensed several years ago which way the wind was blowing. In 2003 it issued a proclamation banning “the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance”. It followed this by putting its money where its mouth was. Since much of gene doping’s allure derives from its alleged undetectability, WADA committed $7.8m—a quarter of its research budget for 2004-07—to 21 projects intended to develop ways of detecting it. Now another $6.5m is up for grabs.
Broadly, there are two ways of spending this money usefully. The direct approach focuses on improving ways of detecting differences between truly natural and “therapeutically enhanced” proteins or, failing that, on detecting the “vector” used to inject the transgenes into the places where they will operate. Such vectors are often particular sorts of virus.
The indirect approach seeks second-hand signs of the transgene or its vector. Viruses, for example, may produce a characteristic immune response that can be detected. Meanwhile the transgenes themselves may alter the body’s proteome (the set of proteins active in it at any given time) or its metabolome (a list of all the by-products of the chemical reactions that go on in each cell). Changes to either of these “-omes” can, in principle, be detected in blood or urine. What is needed are points of comparison. This requires working out the typical “biosignatures” of elite sportsmen as a group, or indeed of each individual, as a baseline.
Testing times
Whether gene doping will make its debut in Beijing remains to be seen—or perhaps not, if it is as hard to detect as its protagonists hope. Theodore Friedmann of the University of California, San Diego, who heads WADA’s Gene Doping Panel, reckons it probably won’t happen this time. He does not think there is, yet, a form of gene therapy that could easily be used to enhance performance. As for Dr Rupert, he says, “I would be surprised. But I have been surprised before.” It would be ironic if the first successful application of gene therapy were to people who are among the fittest on the planet. But it is possible.