Genetically Modified Olympians? (2008, July 31)


Genetically Modified Olympians?Jul 31st 2008 From 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.

Copyright © 2008 The Economist Newspaper and The Economist Group. All rights reserved.

Fairly safe Jul 31st 2008 From The Economist print edition

What athletes may or may not do ought to be decided on grounds of safety, not fairness

ANOTHER Olympics, another doping debate. And this time it is a fervent one, as recent advances in medical science have had the side-effect of providing athletes with new ways of enhancing performance, and thus of putting an even greater strain on people’s ethical sensibilities.

This is especially true of gene therapy. Replacing defective genes holds out great promise for people suffering from diseases such as muscular dystrophy and cancer. But administered to sprightly sportsmen, the treatment may allow them to heave greater weights, swim faster and jump farther (see article). And that would be cheating, wouldn’t it?

Two notions are advanced against doping in sport: safety and fairness. The first makes sense, the second less so—particularly when it comes to gene therapy. For instance, some people have innate genetic mutations which give them exactly the same sort of edge. Eero Mantyranta, a Finn, was a double Olympic champion in cross-country skiing. His body has a mutation that causes it to produce far more of a hormone called EPO than a normal person would. This hormone stimulates the production of red blood cells. A synthetic version of it is the (banned) drug of choice for endurance athletes.

Mr Mantyranta was allowed to compete because his advantage was held to be a “natural” gift. Yet the question of what is natural is no less vexed than that of what is fair. What is natural about electric muscle stimulation? Or nibbling on nutrients that have been cooked up by chemists? Or sprinting in special shoes made of springy carbon fibre? Statistically speaking, today’s athletes are unlikely to be any more naturally gifted than their forebears, but records continue to fall. Nature is clearly getting a boost from somewhere.

Given that so much unnatural tampering takes place, the onus is surely on those who want to ban doping (genetic or otherwise) to prove that it is unusually unfair. Some point out, for instance, that it would help big, rich countries that have better access to the technology. But that already happens: just compare the training facilities available to the minuscule Solomon Islands squad alongside those of mighty Team America. In druggy sports it may narrow the gap. One condition of greater freedom would be to enforce transparency: athletes should disclose all the pills they take, just as they register the other forms of equipment they use, so that others can catch up.

The gene genie is already out of the bottle From this perspective, the sole concern when it comes to enhancing athletic performance should be: is it safe for the athletes? Safety is easier to measure than fairness: doctors and scientists adjudicate on such matters all the time. If gene doping proves dangerous, it can be banned. But even then, care should be exercised before a judgment is reached.

Many athletes seem perfectly willing to bear the risks of long-term effects on their health as a result of their vocations. Aged Muhammad Ali’s trembling hands, for example, are a direct result of a condition tellingly named dementia pugilistica. Sport has always been about sacrifice and commitment. People do not admire Mr Mantyranta because he had the luck of the genetic draw. They admire him for what he achieved with his luck. Why should others be denied the chance to remedy that deficiency?