Huard says “we have absolutely no clue” about side effects, but he and others are worried about an immunologic reaction to the virus that serves as a carrier. That is what killed 18-year-old Jesse Gelsinger, who had a rare liver disease and was participating in gene therapy research at the University of Pennsylvania. The Food and Drug Administration immediately terminated all gene therapy trials at Penn, and the incident prompted federal regulators to establish new rules for human gene therapy research. Another concern is that the vector virus might run amok. Scientists believe that’s what happened during a 1999 French gene therapy trial on a group of 10 infants with X-SCID, an immune deficiency disorder known as boy-in-the-bubble syndrome. Researchers engineered a virus to carry a replacement gene to repair the immune systems of the sick children. The technique cured nine of the children, and scientists deemed the trial an overwhelming success. Nearly three years later, however, doctors diagnosed two boys in the study with T-cell leukemia. Somehow the virus carrier—not the replacement gene—had managed to touch off the blood disease. In future tests doctors will either modify or change the carrier.
Photograph by Jennifer Tzar
Like all mammals, including humans, mice lose up to a third of their muscle mass and power as they get older. But gene therapy can arrest this loss. The aging mouse on the right increased its body strength by 27 percent after injections of the IGF-I gene, which fosters muscle growth and repair. The smaller mouse on the left is a control.
Those two incidents sparked widespread condemnation that stifled nascent research initiatives. Today some clinical gene therapy trials on humans are under way with tighter safeguards, but most experiments are confined to rodents. Despite the medical and regulatory setbacks, the largest roadblock to commercializing the technology is money. “We’ve been struggling with getting dog studies [under way] because of the cost,” says Sweeney. But once he gets funding, he’s ready to go. His team has already made a version of the IGF-I vector to test on dogs with muscular dystrophy. If successful, he’ll begin trials on children with muscular dystrophy sometime before the end of the decade. Sweeney keeps a list of telephone numbers from desperate parents who’ve contacted him.
Meanwhile, amateur athletics is trying to come to grips with gene doping. In March 2002, Theodore Friedmann, who directs the program in human gene therapy at the University of California at San Diego and has advised the National Institutes of Health and congressional leaders on gene-related issues, organized a three-day workshop for the world agency. Scientists, regulatory officials, and athletes gathered in Cold Spring Harbor on Long Island to discuss gene doping. “People intent on subverting the gene therapy will do so,” says Friedmann. “The technology is too easy. It’s just graduate student science.”
That bothers Arne Ljungqvist, the world agency’s health, medical, and research committee chairman, who doles out several million dollars in grant money every year to research groups looking at gene doping and its detection. Additionally, Friedmann, who serves on the agency’s anti-doping commission, is working to establish testing protocols. “So far the results are sitting in the form of research advances,” he says, “but not in the form of real detection methods.” One concept is to hunt for what Friedmann calls physiological fingerprints. Introducing foreign genes into muscles, he says, “is going to produce changes in the way muscles secrete things into the blood and, therefore, into the urine.” In the same way breast and colon cancer alter the pattern of proteins in the bloodstream, genes linked to IGF-I or EPO will, in theory, leave traces. Surveillance organizations like the U.S. and world agencies “will look for those signatures and patterns that can be tied, with confidence, to the existence of a foreign gene,” Friedmann says. Although it may be years yet in development, Friedmann envisions a noninvasive imaging device akin to an X-ray that detects bits and pieces of leftover viruses used to introduce performance-enhancing genes.
Ironically, the misuse of gene doping in sports is more clearly defined than its proper use. When physicians begin curing athletic injuries with gene therapy, the boundaries of healing and enhancement will blur. “There will be a fuzzy line between what is a medically justifiable treatment of injuries and what is performance enhancement,” says Friedmann. “There is nothing terribly noble about an athlete destroying a career with an injury if one can medically prevent or correct it. I would be hard-pressed to say that athletes are not eligible for this or that manipulation. It has always been obvious that there are therapeutic-use exceptions. There is no reason to think that therapeutic-use exceptions would be disallowed for genetic tools.”
That, of course, opens the door for abuse. In some instances, athletes would require only minuscule improvements to nudge them into the winner’s circle. “For Olympic athletes, they don’t need to see a drastic change,” says Johnny Huard. “Sometimes the gold medalist is only a fraction of a second over the silver.” It would be very easy for a team physician to let therapeutic genes continue working for a few hours, days, or weeks after an officially sanctioned treatment ends.
With no viable testing mechanism on the horizon, the possibility remains that at least one of the 10,000-plus Olympic competitors in Athens this summer will have experimented with gene doping. By the 2006 Winter Games in Turin, Italy, it’s even more likely. And by the time Beijing 2008 rolls around, it could easily be a sure thing.
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