Outlaw DNA (2007, June 2)

Outlaw DNABy GRETCHEN REYNOLDS It was a single line from a longer e-mail message. But when read into the record by prosecutors at the drug trial last year of the German track coach Thomas Springstein, it caused a sensation. “The new Repoxygen is hard to get,” Springstein had written. “Please give me new instructions soon so that I can order the product before Christmas.”

Until that day in the courtroom, Repoxygen was an obscure gene-therapy drug developed at a pharmaceutical lab in Oxford, England, to fight anemia. The lab shelved the product when it seemed unlikely to be profitable. Once it was mentioned in court in January 2006, however, Repoxygen vaulted to celebrity-drug status in Europe. Newspapers and Web sites ran dozens of stories about the imminent danger of the therapy. “The moment that e-mail was presented in open court,” a columnist wrote in the weekend paper Scotland on Sunday, was when the “era of genetic doping . . . arrived.”

Repoxygen works by worming a specialized gene into its host’s DNA. In the right circumstances, the gene directs cells to start making extra erythropoietin (EPO), a hormone that drives the production of red blood cells. More red blood cells means more oxygen transported to muscles, which is why athletes have been known to inject themselves with synthetic EPO. By insinuating itself into an athlete’s genetic code, Repoxygen would theoretically produce a natural stream of the stuff.

That presumably was its allure for Thomas Springstein, who in all likelihood had heard the rumors that a single dose of Repoxygen was not only undetectable but also had the capacity to alter an athlete’s DNA. Once a coach for several top German track-and-field athletes, Springstein was tried last year for giving performance-enhancing drugs to unwitting young runners, including one of Germany’s best female hurdlers, Anne-Kathrin Elbe, who was 16 at the time.

“I was taken aback and speechless,” Elbe told me in an e-mail message. “He said that they were vitamins.”

It’s unlikely that Springstein ever got hold of Repoxygen; none was found during a 2004 raid of his home. It’s even harder to say that the “era of genetic doping” is unequivocally upon us. What is clear, and what the Springstein case reminds us, is just how impatient some coaches and athletes are to find new and ingenious ways to cheat. First it was steroids, then EPO, then human growth hormone — and now the illicit grail seems to be gene therapy. Researchers have been hounded with requests for gene therapy from sports teams as well as individual athletes; many scientists also believe that would-be dopers troll the Internet, searching for just the right gene-therapy study to try to duplicate on their own. The formula for Repoxygen itself is publicly accessible, and a few Web sites even claim to have it for sale.

“We filed a patent,” says Alan Kingsman, the chief executive of Oxford BioMedica, the lab that developed Repoxygen. “We published our data. It’s all available to anyone who has the training to understand it.”

So far, there have been no confirmed cases of gene doping in the United States or anywhere else, though that could change during the 2008 Summer Olympics in Beijing, which is when some speculate that gene doping will make its debut. The World Anti-Doping Agency (WADA), which preemptively banned gene doping in 2003, has been funding research at laboratories around the world to develop a reliable blood or urine test to use at the Games. “They’ll freeze samples,” says Theodore Friedmann, a geneticist at the University of California <http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_california/index.html?inline=nyt-org> , San Diego, who also is head of a gene-doping advisory panel for WADA. “If gene doping is happening in Beijing, I believe we will be able to tell — if not during the competition, then later.”

Friedmann can’t say just how close WADA is to producing its gene-doping test, and won’t speculate about how foolproof it would be. At present, gene doping is detectable only through biopsies of affected muscle tissue. Cheaters can only hope this remains the case indefinitely.

“We all know people who’ll take anything — anything — to make the Olympic team,” says Darren De Reuck, a running coach in Boulder, Colo., whose athletes include his wife, Colleen, the 2004 United States Women’s Olympic Trials marathon champion. “It doesn’t matter how weird and wacky it sounds. Playing around with genes is about as out-there as anything I’ve ever heard of. So I’m sure some people will think it would be a great thing to try.”

In the United States, the first news media reports of gene doping appeared in the late 1990s, when word got out that “Schwarzenegger mice” were being produced in the lab of H. Lee Sweeney, a molecular physiologist at the University of Pennsylvania <http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_pennsylvania/index.html?inline=nyt-org> . Sweeney, who had been searching for treatments for muscle-wasting diseases, focused his research on a gene that produces a protein called IGF-1, which helps regulate growth. His experiments worked. The mice that had been injected with an extra copy of the IGF-1 gene packed on muscle and became as much as 30 percent stronger than before.

After his work was publicized, Sweeney was inundated with calls from athletes volunteering themselves as human test subjects. One high-school football coach offered up his entire team. “I was quite surprised, I must admit,” Sweeney says. “People would try to entice me, saying things like, ‘It’ll help advance your research.’ Some offered to pay me.”

To this day, Sweeney receives overtures from would-be guinea pigs. “Every time there’s a story about our research or any research similar to ours, we get more calls,” he says. Patiently he’ll explain to the caller that, even when his therapy is ready for human testing — Sweeney says it will be years — there will be risks of infection, rejection, organ failure, possibly death. The callers will listen, he says, and then reply, “O.K., when can we start?”

Other gene-therapy advances are closer to fruition. At Harvard Medical School, Chris Evans, a professor of orthopedic surgery, has located a gene that may treat and prevent osteoarthritis; he and his colleagues have tested it successfully in lame horses and plan to switch to human subjects later this year.

“I’ve had lots of people volunteer,” he says. “Some of them are my friends, middle-aged weekend athletes whose knees are shot.” But he’s anticipating that he’ll eventually get requests from coaches and trainers as well. When I ask how his therapy could affect healthy young athletes, he replies: “It is possible they could create stronger joints. They could train harder without risking joint injury. But that’s not the point of our research. We’re trying to treat disease.”

The search for effective gene therapies was a primary motivation behind the Human Genome Project, which, between 1990 and 2003, identified the 20,000-plus genes that make up human DNA. Each of these genes expresses a protein that, in turn, regulates cellular functions. If, for instance, you have a defective gene for producing the muscle protein dystrophin, your muscles won’t repair themselves correctly. That’s the cause of muscular dystrophy. By fixing glitches in a person’s genome, gene therapy would, in theory, cure any number of devastating genetic diseases.

The science is quite simple: typically, the requisite gene is introduced into a virus that is then injected into a patient. The virus can enter the nuclei of host cells, changing their DNA. When the cells replicate, they pass on the new DNA as well.

But the results have been largely disappointing. Hundreds of gene-therapy trials have been performed on humans and animals over the past two decades. A handful of therapies have shown moderate success, but most have done absolutely nothing, good or bad. Some have had unintended, even disastrous consequences. In one 1998 study, baboons were injected with a genetic compound similar to Repoxygen designed to alter EPO production. The new gene did, indeed, produce extra EPO — at an unchecked pace. The baboons’ circulatory systems became so clogged with red blood cells that the animals had to be drained of excess blood. In another study, healthy primates had an unexpected immune reaction to the virus used to carry the EPO gene. Their bodies lost the ability to produce red blood cells. Stricken with anemia, several of the animals had to be euthanized.

Repoxygen is not so capricious. Unlike most experimental EPO gene therapies, Repoxygen has a built-in gauge that recognizes when red-blood-cell counts have fallen below a healthy level. Only then will the gene crank up EPO production. Once normal red-blood-cell counts have been reached, the gene turns itself off. Since athletes presumably have optimum red-blood-cell levels, Repoxygen would likely do nothing for them, except possibly set off an immune reaction to the virus.

Nonetheless, dopers want it, as is apparent by underground Web sites that advertise gene therapies for sale. In the interest of research, Olivier Rabin, the science director of WADA, ordered some samples. “What came was just versions of synthetic EPO,” he says, not gene-therapy drugs. But fraudulent advertising doesn’t seem to be a deterrent to sales.

The Web sites are, Rabin believes, quite popular: “No one ever said the people willing to use gene doping will be great minds or careful scientists.”

The unsettling dystopian aura surrounding gene doping also obscures the fact that this isn’t fantasy science: gene doping is not eugenics. It can’t create superathletes. None of the substances with which dopers will likely experiment would completely rewrite a person’s DNA; nor could dopers pass on their altered genes to future generations. And genetic changes wouldn’t necessarily be permanent.

If successful, gene therapy would affect performance by fractions of seconds. But, of course, gold medals and multimillion-dollar sponsorship deals rest on such knife-edged differences, so the dopers are sure to keep trying.

As for Thomas Springstein, he received a 16-month suspended sentence for supplying an illegal substance to a minor. He has been banned from the German Track and Field Federation but is otherwise free to coach. The word is, he’s been getting offers. .