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How to Be Popular during the Olympics: Be H. Lee Sweeney, Gene Doping Expert

Physiologist Lee Sweeney has been asked to dope an entire junior college football team, but his day job is studying age-related muscle decline
Gene therapy and gene doping



Lee Sweeney

It's an Olympics year, which means that Lee Sweeney's phone is ringing off the hook. Athletes call him three or four times a day asking for help, offering him money. They're persistent, practically begging, but he always says no.

After all, Sweeney is not an athletic coach; he is a soft-spoken physiologist at the University of Pennsylvania School of Medicine, and he is developing treatments that could stop age-related muscle decline. But "things that make the muscles healthy when you're older are going to make them healthier when they're young," Sweeney concedes, and athletes know it—which is why they want to be his guinea pigs.

Sweeney's work attracts athletes not just because he helps muscles function better—it's also because he focuses on gene therapy, a medical approach that inserts new or modified genes into patients' cells. It has not quite proved itself clinically yet, but gene therapy directly modifies DNA—so theoretically, treatments can persist for months, years or even for life. Its effects are more subtle and consistent than traditional pill-popping or daily injections. And because doctors can insert the genes directly into the tissues that need them, gene therapy should have fewer side effects than other treatments and is not detectable in the bloodstream.

What athlete wouldn't want a performance booster that is hard to detect, lasts a long time, and has few side effects? That is precisely why "gene doping," the use of gene therapy for enhancement purposes, is becoming such a headache for the World Anti-Doping Agency (WADA), the independent international agency that monitors sports doping. The Montreal-based watchdog organization has held three international meetings on the topic since 2002, focusing on how to both prevent and detect the practice. (So far, they have not gotten far with either.) According to WADA chairman Gary Wadler, gene doping is simply a matter of time: Athletes "read the scientific literature and they know what's cutting-edge—there's no question about it," he says.

 

Sweeney's work has been popular with athletes for a decade. In 1998 he and his colleagues published a study in the Proceedings of the National Academy of Sciences USA in which they used a common virus to insert the gene for insulinlike growth factor 1, or IGF1, into the DNA of muscle cells of young and old mice. Doing so increased muscle mass and strength by approximately 15 percent in young mice and reversed age-related muscle changes in old mice, making them 27 percent stronger than they were before.

These "Schwarzenegger mice," as the press referred to them, instantly propelled Sweeney to science stardom. Soon after, his phone started ringing. One of his first requests was from a football coach at a Pennsylvania junior college who wanted Sweeney to dope his entire team. Of course, he said no.

Sweeney is also developing gene therapies that inhibit the function of myostatin, a growth-regulating protein that counteracts the effects of IGF1. The absence of myostatin not only increases musculature but also sheds fat, because myostatin plays a role in fat deposition. Sweeney is using viruses to insert inhibitors of myostatin into healthy dogs as well as those that suffer from a form of muscular dystrophy. Because muscle tissue turnover in muscular dystrophy is so high, he inserts the gene into the liver, where it is made into a protein and excreted into the blood, which then travels to and modifies the muscles.

Sweeney focuses on muscle growth, but other scientists have recently developed drugs that boost endurance. Last month, scientists at the Salk Institute for Biological Studies in La Jolla, Calif., identified two new endurance-building compounds. One, which increases the activity of a muscle lipoprotein called PPARdelta, allowed mice to run 68 percent longer and 70 percent farther after a four-week training stint. The other activates a muscle enzyme called AMPK, which is typically produced after exercise. Mice given that drug did not even have to train to increase their endurance. Compared with sedentary mice that were not given the drug, AMPK-doped mice ran 23 percent longer and 44 percent farther.

Erythropoietin (EPO), a hormone that boosts red blood cell counts and therefore increases blood oxygen levels, also boosts endurance. It is currently available as an injectable hormone, and although WADA has a test that detects EPO administered in this form, EPO delivered via gene therapy could go unnoticed. England-based pharmaceutical company Oxford BioMedica is currently developing such a therapy: Called Repoxygen, it delivers the EPO gene into DNA, where it becomes activated whenever the body detects low blood oxygen levels. In 2006 German track coach Thomas Springstein, on trial for trying to supply underage female athletes steroids, was also found to have attempted to buy Repoxygen for his athletes even though it was still in development.

 

The U.S. Food and Drug Administration has yet to approve any gene therapies, but athletes do not seem to care. "No matter what I say to them about [gene therapy] being dangerous and experimental," Sweeney explains, "it doesn't slow them down—they just keep pushing, saying, 'I want to be the guinea pig, I want to the first person you try this on.' I kindly just say, 'look, it's not possible, I can't do it.'"

The question remains as to how, exactly, WADA will be able to detect gene doping in athletes who get their hands on such therapies. The agency is funding a project to develop ways of detecting molecules that interact with myostatin, based on the fear that myostatin inhibitors could soon become a popular doping choice. In addition, the agency is looking into developing a kit that could detect traces of gene transfer vehicles called plasmids in blood, which would help them catch gene dopers who use plasmid-based approaches.

But because some therapies would not make it into the bloodstream at all—they could be injected directly into the muscles, for example—these tests would, in some cases, be fruitless. "I personally think I can prove to [WADA], if they really want the challenge, that I can dope dogs and they will never figure out which dogs were doped unless they take tissue biopsies," Sweeney says.

It may, however, be possible to detect gene doping in other ways. Theodore Friedmann, a gene therapy specialist at the University of California, San Diego, and chairman of WADA's gene-doping panel, believes it will one day be possible to detect gene doping by looking for its more overarching impacts on the body and particular tissues. WADA is currently developing what it calls a "passport" program to build long-term blood and urine profiles of elite athletes based on the idea that if athletes are totally clean, their blood will look pretty much the same over time. If they are not, various parameters in their blood will be affected by the doping, thereby fluctuating—and thus be detectable—over time.

"The hope is that one will be able to identify signatures of changes, much like signs of cancer," Friedmann notes. The U.S. Anti-Doping Agency is developing a similar pilot program called Project Believe that will administer rigorous blood and urine tests to a dozen volunteer athletes to build a set of baseline profiles.

The fact is that if athletes are abusing gene therapy now and getting away with it, they're probably not getting much out of it. Gene therapies, Sweeney says, are not particularly effective yet because no one has found a way to get the foreign genes safely past the body's discerning immune system. In other words, it destroys the genes before they can do their job; in some cases, the body's reaction to them goes haywire and sickens, or even kills, patients.

But if Sweeney has anything to say about it, scientists will soon overcome these hurdles, so to speak. "And the minute that somebody actually can provide gene therapy with a half a chance of working, there'll be a line at the door," he says.

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