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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 $7,8 m – a quarter of its research budget for 2004-07 – to 21 projects intended to develop ways of
detecting it. Now another $6,5 m 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.
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