Gene doping": will athletes go for the ultimate high?

In 1998, the press jumped on H. Lee Sweeney's first study showing that gene therapy could enhance mouse muscle. Soon, the calls and e-mails started flowing in, first as a trickle, then as if from a fire hose. They're still coming, Sweeney says. Some people beg him to reverse their muscle degeneration caused by disease or aging. However, about half of the calls and e-mails come from healthy individuals--professional power lifters, sprinters, and weekend wannabe athletes of all stripes. They want bigger, higher-performing muscles. One caller offered $100,000 for muscle enhancement, and a high school football coach asked Sweeney to treat his whole team.

The requests from healthy athletes "really caught me off guard" says Sweeney, a physiology professor at the University of Pennsylvania in Philadelphia. His goal had been to stave off the muscle wasting that comes with muscle dystrophy and just plain aging.

Now, Sweeney finds himself in the middle of what could become the sports world's next serious dilemma: Should gene enhancement, or doping, be permissible for athletes attempting to improve their performance? And if not, how can it be prevented?

Gene doping could someday provide extra copies of genes that offer a competitive advantage, such as those that increase muscle mass, blood production, or endurance. The products of gene doping would be proteins similar, if not identical, to the body's versions and would therefore be less detectable in an athlete than are performance-enhancing drugs such as steroids and insulin. Consequently, rules against gene doping might be difficult to enforce.

Heading off what they see as an inevitable problem for the future, the Montreal-based World Anti-Doping Agency (WADA), which works with Olympic officials to prevent athletes from using performance-boosting drugs, already has banned genetic enhancement.

Some researchers predict that gene doping might become a problem as early as the next summer Olympics, in 2008. "Gene doping is going to happen because technology is going to ripen in the gene therapy setting," says Ted Friedmann, director of the Human Gene Therapy Program at the University of California, San Diego and a consultant for WADA. "Of course, it's going to be too tempting for athletes to avoid."

NATURAL HEALING, BABY The roots of gene doping lie in gene therapy, the decades-old idea of inserting genes into the body's cells to correct genetic flaws that cause diseases such as juvenile diabetes, hemophilia, and cystic fibrosis. Although simple in concept, gene therapy has been tricky to carry out reliably in patients. Scientists can count only one success: a 2000 study that cured nine French infants of severe combined immune deficiency, also known as "bubble-boy syndrome" (SN: 4/29/00, p. 277). Even then, two of these patients developed leukemia 2 years later, a mystery that scientists have yet to fully explain.

Some biologists currently are developing new methods to introduce target genes into cells by using electricity, chemicals, or pressure. But for now, researchers typically infect cells with a virus, nature's mastermind at getting foreign genetic material past stringent cellular defenses.

The viruses that scientists have modified for use in gene therapy are vastly different from those that circulate in nature. Researchers pare down the viruses' genetic code, trimming away the genetic material that enables the agents to cause disease. They retain only the genes associated with the proteins making up a virus' outer coat.

Such stripped-down viruses can transform cells into factories that churn out empty shells, "like hollow M&Ms," said James Mason, director of the Gene Therapy Vector Laboratory at the Institute for Medical Research in Long Island, N.Y. Then, researchers paste a human gene--such as one for a blood-clotting protein that a patient lacks--within the virus' remaining genetic sequence to craft a vector that shuttles a therapeutic gene into the patient's cells.

The original idea behind gene therapy was to replace a missing or damaged gene, thereby providing an essential substance that the patient had been lacking. Many scientists have taken this initial concept one step further, says Sweeney. Instead of simply supplying a copy of a missing gene, he and others realized that gene therapy could also fortify muscle, bones, and other tissue at the first signs of disease or aging. This approach could slow the progress of muscle wasting from aging or diseases, such as muscular dystrophy and osteoporosis, he says.

It's not a big technical leap from gene therapy to gene doping. "The sorts of things you'd want to do to help make muscle stronger or repair itself better in a diseased or old person would also make a healthy young person's muscles stronger and repair faster," Sweeney says.

According to Thomas Murray, president of the Hastings Center in Garrison, N.Y., and chairman of WADA's ethics panel, gene doping crosses an ethical line. The traditional draw of athletics, he says, is the combination of an athlete's natural talents with complementary virtues such as determination and discipline.

"What's chilling about the prospect of gene doping is that it arguably changes a person's natural abilities," Murray says. "It violates our understanding of what should make for success in sports."

MIGHTY MICE When his work attracted athletes' attention, Sweeney had been focused on the problem of muscle-mass depletion that occurs with aging. He and his colleagues had noted that when a protein called insulin growth factor 1, or IGF-1, interacts with cells on the outside of muscle fibers, the muscles grow. The researchers reasoned that if they could insert the gene responsible for making IGF-1 inside muscle cells, those cells would then proliferate and increase the muscle's size.

To test this idea, Sweeney's group injected a virus carrying the gene for IGF-1 into the leg muscles of mice and then monitored the animals. The scientists found that when the mice became senior citizens, at about 20 months of age, the animals retained the muscle strength and speed of their early adult days.

After that promising start, the researchers made an even more startling observation. Young mice injected with the gene grew stronger and more muscular, even without exercise. In a later study, Sweeney noticed that rats' strength could be boosted further by a training regimen in which the animals climbed ladders after weights had been tied to their tails.

The genetic and physiological modifications that led to these "Schwarzenegger mice" as they became known in news reports, could prove intriguing to weight lifters, wrestlers, and other athletes whose sports hinge primarily on strength.

Another set of experiments, by scientists at the Salk Institute in San Diego, produced mouse muscles that just keep going without fatiguing. This result has obvious implications for long-distance swimmers, runners, and others for whom endurance is pivotal. Ronald Evans and his colleagues had started out with the intention of engineering mice that stay trim. To do this, the researchers inserted genes that code for a fat-burning protein called PPAR-delta.

The mice that resulted stayed slender, even when fed a high-fat diet, but also developed an unusually large number of slow-twitch muscle fibers, the type the body relies on during extended exertion. "This change produced the 'marathon mouse,' able to run twice the distance of its normal littermate" Evans says.

Genetic engineering differs from gene therapy in many ways, including that the genetic modifications are passed on to offspring. However, Evans predicts that eventually gene therapy could similarly enhance endurance.

LETHAL LEGACY Sweeney has developed a stock response to athletes who contact him. "I basically say this is experimental. It's in animals, and even if I had it available to give to humans, it has to go through clinical trials to make sure it's safe," he says.

Ascertaining the safety of gene therapy--and its gene-doping offshoot--couldn't be more important to Jim Wilson, a professor of medicine at the University of Pennsylvania in Philadelphia. He presided over the clinical trial in which 18-year-old Jesse Gelsinger died in 1999 after suffering a massive immune reaction to the virus used to deliver a target gene.

In a recent study designed to test the effectiveness of several viral vectors, Wilson discovered another deadly result. He and his colleagues injected macaque monkeys with different strains of the same virus that carried a gene for making erythropoietin (EPO), a protein that signals bone marrow to produce red blood cells. EPO is manufactured for patients with anemia resulting from kidney failure. It is also used as a doping agent among athletes because with bonus red blood cells, the body can absorb extra power-generating oxygen. Wilson chose EPO because it's easy to detect.

In his experiment, as expected, the high concentrations of EPO produced so many red blood cells that the macaques' blood thickened into sludge. As they had done in previous experiments, the researchers remedied this by drawing blood from the primates at regular intervals to thin the remaining blood enough to circulate properly. But as the experiment wore on, Wilson's team noticed an unusual response in some of the macaques. Rather than remaining at high concentrations, EPO concentrations in these animals' blood plummeted, leading to severe anemia.

After autopsying these monkeys, Wilson and his colleagues came to a troubling conclusion: The animals' immune systems had cleared out not only EPO produced by the inserted gene but also the macaques' natural EPO.

Wilson notes that unpredictable results such as these are common in the field of gene therapy, which is why the strategy is still experimental.

"[Gene therapy's] potential to treat disease is substantial, but we're now in a phase where we're still working on the technology," Wilson says. "We ought to pay attention to these kinds of immune responses not only for EPO but for other kinds of gene therapy." In other words, athletes who try gene doping could find themselves dead rather in the winners circle.

UNETHICAL ADVANTAGES Despite the dangers now inherent in gene therapy, some researchers worry that unprincipled scientists will inevitably gene dope unscrupulous athletes. "You have to remember that most of these athletes are very young, in their twenties, and so they have feelings of invincibility," says Olivier Rabin, scientific director of WADA.

The financial reward that accompanies athletic success adds to the incentive to try an untested procedure. "There's so much money in sports today, and when you see what a national title or gold medal around your neck will bring in your life, some are mentally ready to bear the risks," Rabin says.

He reports that, besides working with legislators and athletes, WADA is encouraging scientists to develop tests that could catch gene-doped competitors. Some researchers have feared that because an inserted gene's products can be extremely similar to the body's natural chemicals, routinely snagging rogue athletes could prove impossible. The only way to test for gene doping, some surmised, would be to biopsy muscles or other tissues into which gene vectors had been injected. The biopsy would require a surgical procedure right before competition.

However, a new study published in the September Molecular Therapy raises the likelihood that a test might be possible. A team led by Francoise Lasne and Philippe Moullier at the National Anti-Doping Laboratory in Chatenay-Malabry, France, found that monkeys doped with the gene for EPO by muscle injections produced a protein slightly different from their native EPO. These small differences could, in part, underlie the disastrous immune response that Wilson's team observed in some of the macaques in their study.

Although the scientists aren't sure why the doped EPO is different, they suspect that cells in various tissues might not make the same modifications to the protein after it is produced. Kidney cells normally produce EPO, but in response to the gene doping, muscle manufactured it too. Distinctive modifications by these organs eventually might provide a basis for detecting EPO from gene doping.

Someday, says ethicist Murray, gene doping might become widespread and even acceptable in all sports, Making such tests unnecessary. But he and other experts don't expect that to happen anytime soon.

"When we think about the meaning of sports, these days, it's about natural talents and virtues," he says. "I can't tell you what your grandchildren and great grandchildren will believe, but I hope that there will still be meaning in perfecting natural abilities."