Please welcome Laurel Mylonas-Orwig, author of today’s post and a new contributor to the blog!
Every two years, the best athletes in the world gather to compete in the modern Olympic Games. Against a backdrop of sand or snow, these seemingly superhuman competitors push their bodies to perform feats that would be impossible for the average person. Yet in the past few decades, concerns have mounted over whether some participants have gone beyond what the human body is truly capable of, relying on performance enhancers to reach new heights. In the 2004 Summer Olympics, a record number of athletes tested positive for banned substances, leading to several disqualifications and stripped medals. But in the just-completed 2010 Winter Olympics in Vancouver, drug testing has only caught two athletes thus far.
Despite this low number, experts are skeptical that athletes have stopped looking for illegal ways to gain a competitive edge. Instead, officials suspect that those who want to cheat have found ways around the current doping tests. The biggest elephant currently in the drug-testing room is an enhancement that is not yet reliably detectable, or even proven to be scientifically possible: gene doping.
Gene doping is a new and dangerous frontier in performance enhancement. An offshoot of gene therapy, gene doping may someday allow athletes to produce extra copies of genes that provide a competitive advantage such as increased muscle mass or endurance. At present, however, both gene doping and gene therapy remain largely untested in humans. Although some animal studies have shown promising results, others have demonstrated deadly side effects, leaving the effects of such treatments questionable at best.
When research into gene therapy began, it was not intended to yield performance-enhancing technology. Gene therapy is designed to treat debilitating or deadly medical conditions via the insertion of corrective genes into the body’s cells. But the theory behind gene therapy indicates that if the right gene were to be spliced into a healthy person’s DNA, a competitive edge could be gained. One example is that of erythropoietin, more commonly known as “Epo.” First purified in the late 1960’s by University of Chicago researcher Eugene Goldwasser, Epo is a hormone that promotes the production of oxygen-carrying red blood cells.
In 1997, a group of University of Chicago scientists led by Dr. Jeffrey Leiden experimented with Epo gene therapy as a treatment for Epo-responsive anemia, a debilitating condition caused by chronic renal failure. The study focused on the safety and efficacy of injecting a virus carrying the gene into the muscles of mice and non-human primates. Overall, the experiments proved successful: researchers were able to establish a threshold dose required for long-term Epo expression, and the elevated hematocrit, or red blood cell volume, in the animals that underwent the treatment led to increased aerobic ability. More importantly, no adverse reactions to the treatment were observed.
In the wake of this and other Epo studies, the potential benefits for athletes became clear: inject Epo, improve athletic performance. The first major Epo-doping controversy hit in 1998, when the Festina-sponsored team in the Tour de France was disqualified after being caught with large quantities of Epo and other banned substances. Others followed in their footsteps, and throughout the late 1990’s and early 2000’s several athletes were caught exploiting Epo in an attempt to enhance endurance and aerobic performance.
Epo is not the only gene therapy turned gene doping target in the past decade. A study published in 1998 by researcher H. Lee Sweeney from the University of Pennsylvania grabbed headlines with reports of the “super mice” that resulted from injecting normal mice with a virus containing the gene for insulin growth factor 1 (IGF-1), a protein that interacts with cells on the outside of muscle fibers and makes them grow larger. Just as Epo is crucial to aerobic endurance, IGF-1 could give athletes an edge in sports that depend on large muscle mass and explosive anaerobic ability. Although Sweeney’s research goal was to develop a treatment for muscle-wasting diseases, it was not long before he was deluged with requests from healthy athletes longing for larger muscles. He quickly developed a “stock response,” telling anyone who asked that gene therapy is still experimental, and there is no proof that it would be safe for humans – a warning that has proven to be all too true.
The Dangers of Doping
In 1999, Jesse Gilsinger, a nineteen-year-old from Tucson, AZ, entered a clinical trial at the University of Pennsylvania. Jesse suffered from ornithine transcarbamylase deficiency, a rare X-linked genetic disease of the liver that prevents the body from metabolizing ammonia, a byproduct of protein breakdown. Although the disease is usually fatal at birth, Jesse had survived because his condition was the result of a genetic mutation instead of inheritance. This important difference allowed him to manage the disease with medication and a restrictive diet. Jesse entered the clinical trial in the hopes that a new type of gene therapy would help infants born with the disorder, and on September 13, 1999, he was injected with a virus vector carrying a corrected copy of the gene mediating ammonia breakdown. The theory was that the gene would incorporate itself into Jesse’s DNA, replacing his mutated copy and allowing his body to begin metabolizing ammonia. Instead, Jesse suffered a massive immune response, leading to multiple organ failure. He died four days later.
The Gilsinger case represents the danger inherent to gene therapy, and underscores the perils of gene doping. The fact is, scientists simply do not know enough about how the body will react to these substances to safely inject them into humans. While IGF-1 might give one person stronger muscles, it could easily kill another. Moreover, Jesse Gilsinger is not the only fatality linked to gene therapy. In 2000, a study of nine French infants with severe combined immune deficiency-“bubble-boy syndrome”-who had undergone gene therapy showed that all nine were cured by the treatment. However, this initial success was overshadowed when two of the patients developed leukemia only two years later – a side effect that researchers are still unable to explain.
It is ambiguities like this that lead Eugene Goldwasser, now Professor Emeritus of Biochemistry and Molecular Biology and a co-author on Leiden’s 1997 Epo gene therapy paper, to question why anyone would engage in gene doping. Though Goldwasser has some doubts about the viability of gene doping, he finds the idea of it deplorable. “If [gene doping] is happening, it’s happening under the worst possible circumstances, because we don’t know enough about gene transfer,” he says. “If I were an athlete, I wouldn’t let them fiddle around, putting in genes, no matter what the stakes were.”
Goldwasser’s point is underscored by the ill effects of Epo revealed in a study done at the University of Pennsylvania shortly after the University of Chicago study was published. Several macaque monkeys were injected with virus vectors carrying the gene for Epo. Initially, the therapy proceeded as expected, increasing oxygen transport. However, the high concentrations of Epo soon produced so many red blood cells that the monkeys’ blood became sludge-like, and the researchers were forced to thin it at regular intervals. What came next was entirely unexpected: the monkeys’ Epo concentrations plummeted, leading to severe anemia. After the animals were euthanized and autopsied, researchers discovered that the immune response to the high Epo concentrations cleared out not only the inserted gene, but the macaques’ natural Epo.
It is this kind of unpredictable outcome, Goldwasser says, that makes gene doping foolhardy. “It would be the height of stupidity. If you want to get your hematocrit up, you go to Mexico City, go the Andes, and train at high altitudes. Then you’re not getting some [gene] you didn’t make.”
Risk Versus Reward
After watching the 2010 Winter Olympics in Vancouver, one begins to understand the lure of gene doping. Even with the questions surrounding safety and efficacy, the possibility of gaining an edge that translates into a gold medal will certainly tempt some. But the risks related to gene doping are undeniable in the face of the gene therapy-related deaths reported in both animals and humans.
Nevertheless, sports officials are not counting on common sense to keep athletes from attempting to gene dope. In 2003, the World Anti-Doping Agency (the body that does the drug testing for the Olympics) formally banned gene doping, despite the fact that there was little evidence that it was occurring. Since then, the medicine has advanced, and with it the likelihood that some athletes are gaining an illegal advantage. However, because detection techniques are still unreliable, it is difficult to conclusively prove that an athlete is gene doping. But the International Olympic Committee isn’t taking any chances. Officials have collected samples from athletes at the 2010 Winter Olympics, and will store them until detection tests are refined enough to be trustworthy. Until then, there is little to do other than warn of the dangers and appeal to the athletes’ integrity.
Even with full knowledge of the risks, Goldwasser admits that he is not surprised that athletes are trying to capitalize on experimental gene therapies to gain a competitive edge. “People do all sorts of dopey things. The problem is, the reward isn’t worth the danger of what could happen.”
Svensson, E., Black, H., Dugger, D., Tripathy, S., Goldwasser, E., Hao, Z., Chu, L., & Leiden, J. (1997). Long-Term Erythropoietin Expression in Rodents and Non-Human Primates Following Intramuscular Injection of a Replication-Defective Adenoviral Vector Human Gene Therapy, 8 (15), 1797-1806 DOI: 10.1089/hum.1997.8.15-1797