Gene doping

With the Olympics over, organizations like the World Anti-Doping Agency are turning their attention to Beijing, four years down the road, and asking, “What new ways will athletes find to cheat between now and then?”

The answer they’re coming up with is gene doping: performance enhancement achieved by the direct manipulation of athletes’ genes.

The most recent discovery to raise the specter of genetically modified athletes was announced just last week by a team at the Salk Institute in La Jolla, California, which has produced genetically engineered mice that can run almost twice as far as normal mice.

The researchers are studying the genes involved in obesity and fat metabolism, focusing specifically on a protein called PPARdelta. Increasing the activity of that protein in fat cells encourages a reduction in fat stores, and the greatest user of fat in the human body is slow-twitch muscle tissue–the kind that gives athletes endurance. So, the scientists reasoned, mice genetically engineered to produce extra PPARdelta in muscle tissue should burn more fat than normal mice.

Sure enough, when put on a high-fat diet for 97 days, the genetically engineered mice gained only one third as much weight as normal mice. But the genetic alteration had an unexpected side-effect: it doubled the amount of slow-twitch muscle in the mice, enabling them to run 92 percent longer than normal mice.

Coincidentally, a drug called GW501516, undergoing tests right now as a treatment to lower blood cholesterol and fat, increases PPARdelta production. Farnaz Khadem, a spokesperson for the World Anti-Doping Agency, says she wouldn’t be surprised if athletes try taking GW501516, if it becomes available.

Drugs are usually detectable, but what if an athlete were genetically modified to produce more PPARdelta? Since it is a naturally occurring substance, tests would not reveal the enhancement. And as it happens, there is a way to alter an individual’s muscle tissue genetically: gene therapy.

In gene therapy, a synthetic gene is inserted into a living organism’s tissue via a vector–typically, a harmless virus whose own genetic information has been replaced by the new gene. Viruses reproduce by injecting their genetic information into cells, reprogramming the cells into little viral factories. The modified virus instead injects the new gene.

At the University of Pennsylvania School of Medicine, H. Lee Sweeney is trying to develop gene therapy that could strengthen the muscles of elderly people (whose weak muscles contribute to debilitating falls) and those suffering from degenerative diseases such as muscular dystrophy.

A substance called insulinlike growth factor 1, or IGF-1, promotes the growth of muscle tissue. Sweeney’s team has successfully used gene therapy to boost IGF-1 production in skeletal muscle in mice and rats. In one a recent test, they used gene therapy to boost IGF-1 production in just one leg of lab rats, then put the rats through an eight-week weight-training program (little Nautilus machines?). At the end of training, the injected legs had gained nearly twice as much strength as the uninjected legs–and lost muscle more slowly once training stopped.

While IGF-1 boosts muscle growth, a substance called myostatin inhibits it–which means an alternative way to making bigger muscles is to block the action of myostatin. Myostatin-blocking drugs are already being developed, and Sweeney and his team plan to test a gene therapy method of blocking myostatin production.

Of course, endurance is about more than just muscles; the amount of oxygen reaching those muscles is also important. Eoro Mäntyranta of Finland, who won the cross-country skiing gold medal at the 1964 Winter Olympics, had a mutation in the gene that encodes for erythropoietin, a protein that regulates the production of oxygen-carrying red blood cells; as a result, his muscles got more oxygen than ordinary skiers’ muscles. A synthetic version of erythropoietin, called Epoietin (EPO for short) was developed–and in 1998, a team in the Tour de France was thrown out of the competition for using it. If there had been a way to use gene therapy to program their bodies to over-produce erythropoietin, they would never have been caught.

In fact, gene therapy to enhance erythropoietin production has already been tried. In 1997 and 1998, scientists used gene therapy to cause monkeys and baboons to produce more erythropoietin. The animals’ red-blood counts nearly doubled within 10 weeks–but that resulted in blood so thick it had be regularly diluted to keep their hearts from failing.

Other health risks gene doping might pose to athletes are unknown–but health risks never stopped those athletes determined to win at all costs from misusing medical therapies to gain an advantage.

Bet on hearing more about genetic doping between now and Beijing–a lot more.

P.S. Here’s an excellent, more in-depth article on gene doping from Scientific American.

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