The chime on H. Lee Sweeney’s laptop dings again: another e-mail. He doesn’t rush to open it. He knows what it’s about. He knows what they are all about. The molecular geneticist gets a handful every week—often many more, depending on what is in the news—all begging for the same thing, a miracle. Ding. A woman with carpal tunnel syndrome wants a cure. Ding. A man offers $100,000, his house, and all his possessions to save his wife from dying of a degenerative muscle disease. Ding, ding, ding. Jocks, lots of jocks, plead for quick cures for strained muscles or torn tendons. Weight lifters press for larger deltoids. Sprinters seek a split second against the clock. People volunteer to be guinea pigs.
Sweeney has the same reply for each ding. “I tell them it’s illegal and maybe not safe, but they write back and say they don’t care. A high school coach contacted me and wanted to know if we could make enough serum to inject his whole football team. He wanted them to be bigger and stronger and come back from injuries faster, and he thought those were good things.”
The coach was wrong. Gene therapy is risky. In one experiment a patient died. In another the therapy worked, but 4 of the 10 human subjects—young children—got leukemia. To some, such setbacks are minor hiccups, nothing to worry about if you want to cure the incurable or win big. In the last several years, Sweeney, a professor of physiology and medicine at the University of Pennsylvania, and a small cadre of other researchers have learned how to manipulate genes that repair weak, deteriorating, or damaged muscles, bones, tendons, and cartilage in a relatively short time. They can also significantly increase the strength and size of undamaged muscles with little more than an injection. At first the researchers worked with only small laboratory rodents, mice and rats. More recently their efforts have shown promise with dogs. Human testing is years away, but gene therapy has already become a controversy in professional and amateur sports, where steroids, human growth hormone, and other performance-enhancing drugs have been a problem for years. With the Olympics opening in Beijing on August 8, the subject is only going to get hotter. “It’s the natural evolution of medicine, and it’s inevitable that people will use it for athletics,” Sweeney says. “It’s not clear that we will be able to stop it.”
Sweeney became interested in gene therapy in 1988, shortly after scientists pinpointed the gene responsible for Duchenne muscular dystrophy. He wanted to find out if there was a way to counteract the disease genetically. Children with muscular dystrophy lack the gene required to regulate dystrophin, a protein for muscle growth and stability. Without enough dystrophin, muscle cells atrophy, wither, and die. Sweeney’s plan was to introduce the dystrophin gene by hitching it to the DNA of a virus that can transport genes into cells. As it turned out, viruses were too small to carry that gene, so Sweeney began searching for a smaller gene that would at least mimic dystrophin. He settled on a gene that produces insulin-like growth factor 1 (IGF-1), a powerful hormone that drives muscle growth and repair. The IGF-1 gene fit nicely inside a virus and was more appealing because it could potentially treat several kinds of dystrophy. In a series of experiments beginning in 1998, Sweeney and his team at the University of Pennsylvania injected IGF-1 genes into the muscles of mice and rats and watched in wonder as damaged tissue repaired itself.
It’s inevitable that people will use gene therapy for athletics. It’s not clear that we will be able to stop it.
For years afterward, Sweeney spent much of his time scrutinizing the rats and mice he had injected with IGF-1 genes. He put them through a rigorous exercise program, strapping weights to their hind legs and repeatedly prodding them up a three-foot-high ladder. After two months, the rodents could lift 30 percent more weight, and their muscle mass had swollen by a third—double what his control group of mice (those without IGF-1) achieved with weight training alone. In another experiment Sweeney gave IGF-1 to mice but curbed their exercise. They too bulked up, jumping 15 percent in muscle volume and strength.
Next up for testing were dogs, which come closer than rodents to approximating human biology. The results were similarly striking. Sweeney has now begun developing and testing another type of gene therapy in dogs and comparing its effects to those of IGF-1. The new therapy is based on a protein called myostatin, which normally regulates muscle growth. By dosing dogs with the gene for a myostatin precursor, Sweeney has found he can throw a wrench into the molecular machinery of myostatin signaling, removing a critical check on muscle growth and allowing deteriorating muscles to regain their strength.
On a visit to the University of Pennsylvania, I ask Sweeney to show me his IGF-1 mice. He leads me to a cramped lab where a bubbling tank of liquid nitrogen spews a cold fog across the floor. Rows of transparent plastic containers, each about the size of a shoe box, are stacked on a chrome pushcart, a pungent, musky odor emanating from them. Inside each box are several chocolate-colored mice. Sweeney points out two groups in neighboring containers and asks, “Which set do you think we’ve given IGF-1?” I lean in for a closer look. The mice in the left box look as if they have been watching Buns of Steel videos. Each mouse boasts a rock-hard rump and shockingly large, perfectly chiseled gastrocnemius and soleus muscles (which, in humans, make up the calf). In the adjacent cage, two control mice appear scrawny by comparison. The results are impressive, and I wonder out loud just how easy it would be for someone to reproduce Sweeney’s results in a human. “I wouldn’t be surprised if someone was actively setting up to do it right now,” he says. “It’s not that expensive, especially if you are just going to do it to a small population of athletes.”
That is exactly what worries officials at the World Anti-Doping Agency and the U.S. Anti-Doping Agency. In anticipation of the 2004 summer Olympics, in Athens, the world agency put gene doping on the International Olympic Committee’s prohibited list, which includes everything from cough syrup to cocaine. The prohibition defines gene doping as “the nontherapeutic use of genes, genetic elements, and/or cells that have the capacity to enhance athletic performance.” But no one thinks for a minute that gene doping isn’t already starting to happen. “Sport is supposed to be fun,” says former Olympic swimmer Richard Pound, ex-president of the world agency and a vocal champion of the antidoping cause. “But it is surrounded by people who are conspiring to destroy the athlete and the game.”
Gene doping is different from chemical performance-enhancing techniques. Human growth hormone, for example, occurs naturally in the body and will accelerate cell division in many types of tissue. Taken in high doses, it can provide a head-to-toe muscle boost and can even add a few extra inches of height. Anabolic steroids are chemical relatives of testosterone. They are believed to be in wide use in professional sports—although most athletes deny it—and their illegal use recently ignited explosive, high-profile controversy in Major League Baseball and Olympic track-and-field events. Last year track star Marion Jones admitted that she had used steroids while training for the 2000 Olympics and was stripped of all five of her medals. Steroids are also popular with weight lifters because they foster new muscle growth in the upper body. Synthetic erythropoietin, or EPO, a chemical naturally produced by the kidneys, is a favorite of triathletes, marathon runners, Tour de France cyclists, and others who engage in long periods of aerobic activity. EPO flushes fatigued muscles with oxygen to stave off exhaustion.
These and other substances can be detected in blood and urine tests because they drift through the circulatory system for hours, days, or months. Gene doping is not so easy to spot. Genetic modifications become an indistinguishable element of the DNA in targeted muscles. The only way to prove that someone has used gene doping is to biopsy a suspicious muscle and look for signs of DNA tampering. It is not hard to imagine that most athletes will object to having bits of flesh sliced from the very muscles they’ve spent years honing. “Athletes aren’t going to say, ‘Hey, take a muscle biopsy before my 100-meter run,’” comments Johnny Huard, who developed his own set of muscle-building genes as professor of molecular genetics, biochemistry, and bioengineering at the University of Pittsburgh School of Medicine.
Lack of easy detection makes gene doping extremely attractive to athletes. But the incredible muscle-building power of doping is the big draw. Sweeney believes gene-doped athletes would readily surpass their personal bests and could even smash world records. Sprinters and weight lifters would see the most benefit, their peak speeds and maximum strength amplified. “Athletes would be able to push their muscles harder than ever before because their muscles would repair themselves so much faster,” he says. “And they wouldn’t have to retire when they were 32.”
Antidoping agency officials are convinced that athletes will try gene doping, despite its dangers. “In the current climate there is even more pressure than when I was competing,” says Norway’s 1994 Olympic speed skating gold medalist, Johann Koss, a physician and former member of the World Anti-Doping Agency’s executive board. “People will take shortcuts. Being the best in the world offers huge financial gains.”
In a poll, American athletes said they would take any drug that would help them win, even if they knew the drug would eventually kill them.
Pound cites a poll of American athletes who said they would take any drug that would help them win, even if they knew the drug would eventually kill them. “Nobody ever said athletes are ?the smartest people in the world,” he comments. “This is why there has to be paternalism. This is why I don’t let my kids drive the car at age 13, even though they tell me they can do it safely.”
Pound has good reason to worry. The newest gene therapies work on mice, rats, and dogs with no apparent adverse effects. Until clinical trials are completed, however, it is impossible to know exactly what the effects will be on humans. Sweeney acknowledges, for instance, that IGF-1 could make precancerous cells grow faster and stronger.
“We have absolutely no clue” about side effects, Huard says, but he and other researchers are worried about immunologic reactions to the virus that serves as the gene carrier. That reaction is apparently what killed 18-year-old Jesse Gelsinger, according to researchers at the University of Pennsylvania. Gelsinger had a rare liver disease and was participating in gene therapy research at the university when he died. The Food and Drug Administration immediately terminated all gene therapy trials there, and the incident prompted federal regulators to establish new rules for human gene therapy research.
More and more, Sweeney says, the immune system is proving to be the most difficult hurdle in developing gene therapy for humans. Treatments that appear perfectly safe in rodents and dogs can provoke a devastating immune response when adapted for humans and other primates. The problem, Sweeney says, is that the viruses researchers use for delivering therapeutic genes infect primates but not other mammals. So while a dog’s immune system will simply overlook the intruder, a human’s will recognize it and launch a massive attack. Researchers are now working to develop ways to suppress the immune system long enough for the virus to safely deliver its genetic cargo.
Another concern is that the vector virus might run amok. Scientists believe that is what happened during a 1999 French gene therapy trial on a group of 10 young children 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 them, and scientists initially deemed the trial an overwhelming success. Nearly three years later, however, doctors diagnosed two boys in the study with T-cell leukemia. Two more leukemia cases have since come to light; one patient has died. Somehow the virus carrier—not the replacement gene—had managed to touch off the blood disease, an international medical team reported in 2003. A parallel study in England initially looked more promising, but recently leukemia struck one of its participants as well.
Those incidents sparked widespread condemnation that stifled nascent research initiatives. The climate for gene therapy research has since begun a slow rebound. A variety of human trials are now under way with tighter safeguards, but most experiments are confined to animals.
Beyond the medical and regulatory setbacks, the largest roadblock to commercializing the technology is money. For years Sweeney’s efforts to launch dog studies were thwarted by a lack of funding. Human trials are even costlier, so for now, Sweeney says, IGF-1 and myostatin gene therapies remain on the distant horizon. He nonetheless keeps a list of telephone numbers from desperate parents who have contacted him.
Meanwhile, amateur athletics is trying to come to grips with gene doping. Every few years the World Anti-Doping Agency hosts a symposium where scientists, regulatory officials, and athletes gather to discuss gene doping. Theodore Friedmann, who directs the program in human gene therapy at the University of California at San Diego, spearheaded the first of these workshops six years ago. “People intent on subverting gene therapy will do so,” says Friedmann, who has advised the National Institutes of Health and congressional leaders on gene-related issues. “The technology is too easy. It’s just graduate student science.”
That bothers Arne Ljungqvist, the World Anti-Doping 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 chairs the agency’s antidoping panel, 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-1 or EPO will, in theory, leave traces. Surveillance organizations like the U.S. and world antidoping 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 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,” Friedmann says. “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. “Olympic athletes don’t need to see a drastic change,” Huard says. “Sometimes the gold medalist is only a fraction of a second over the silver.” It would be very easy for a team physician to surreptitiously 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, it is possible that at least one of the 10,000-plus Olympic competitors in Beijing this summer will have experimented with gene doping. “Nothing would surprise me,” Friedmann says. For the time being, though, gene doping is not only illegal but also unsafe and probably ineffective. “If it’s done now,” he says, “it will certainly be done badly.”Additional reporting by
The Muscle Maker
Gene therapy offers a shortcut to bulking up: At the University of Pennsylvania, H. Lee Sweeney is developing a way to turn the liver into a factory that churns out a muscle growth promoter called myostatin propeptide. He injects a virus carrying the growth promoter gene into an animal’s veins, where it courses through the bloodstream and into the liver. There, it infects liver cells and delivers its genetic package. A signal from the virus tells the liver cells to manufacture the growth promoter, which is then secreted back into the bloodstream and ferried off to muscles throughout the body. Normally, myostatin puts the brakes on excessive muscle growth. But when there is too much myostatin propeptide around—delivered by the virus and pumped out by the liver—myostatin cannot do its job and muscles keep growing.
