[tt] Economist: Gene doping: Genetically Modified Olympians?

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Genetically Modified Olympians?
http://www.economist.com/science/PrinterFriendly.cfm?story_id=11839246
[Thanks to Steve for this.]
8.7.31

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.