Gene Doping and its Dangerous Edge

Gene Doping

Gene Doping

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 instead on performance enhancers to reach new heights. In the 2004 Summer Olympics, 24 athletes—a record number—tested positive for banned substances, leading to several disqualifications and stripped medals [1]. But in the 2010 Winter Olympics in Vancouver, only two athletes, to date, have tested positive for performance-enhancing drugs [2].

Despite this low number, experts are skeptical that athletes have stopped looking for illegal ways to gain a competitive edge. Instead, many suspect that would-be cheaters have found ways around the current doping tests. At present, the biggest suspect is an enhancement that is not yet reliably detectable, or even proven to be scientifically possible: gene doping, a new and dangerous frontier in performance enhancement. An offshoot of gene therapy, gene doping may allow athletes to produce extra copies of genes that provide a competitive advantage such as increased muscle mass or endurance [3]. Currently, 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 [4,5].

When research into gene therapy began, it was intended to treat debilitating or deadly medical conditions—a far cry from performance-enhancing technology. But the theory behind gene therapy—that the insertion of a corrective gene can treat genetic defects—also indicates that if the right gene were to be spliced into a healthy person’s DNA, a competitive edge could be gained, as the gene would cause or increase production of, for example, a hormone that produces a beneficial byproduct.  The hormone initially targeted for this purpose was erythropoietin, more commonly known as “Epo.” First purified in the late 1960’s by University of Chicago researcher Eugene Goldwasser, Epo promotes the production of oxygen-carrying red blood cells [6, 5].

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 [5]. The study focused on the safety and efficacy of injecting a virus carrying the gene into the muscles of mice and non-human primates. The experiments proved successful, as researchers were able to establish a threshold dose required for long-term Epo expression. The elevated hematocrit, or red blood cell volume, in the animals that underwent the treatment also led to increased aerobic ability. More importantly, no adverse reactions to the treatment were observed [5].

In the wake of this and other Epo studies, the potential benefit for athletes became clear: inject Epo, improve athletic performance. The first major Epo-doping scandal 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 [7]. Other athletes followed in their footsteps, and throughout the late 1990’s and early 2000’s several were caught exploiting Epo in an attempt to enhance endurance and aerobic performance, despite the fact that Epo’s benefits remain unproven in humans.

Epo is not the only therapy-turned-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 [4, 8]. 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.

In 1999, Jesse Gelsinger, 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. The disease is usually fatal at birth, but 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. Although there was no hope of a cure for him, Jesse entered the clinical trial in the hopes that a new type of gene therapy would help infants born with the disorder. On September 13, 1999, Jesse 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 [4].

Jesse’s 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. And Jesse Gelsinger is not the only fatality linked to gene therapy. In 2000, a study about nine French infants with severe combined immune deficiency—or “bubble-boy syndrome”—who had undergone gene therapy reported 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 [9, 10].

When studies on the efficacy of Epo injections originally appeared, the positive results intrigued many. But these studies were eclipsed by the publication of a University of Pennsylvania study performed in 2004 testing the efficacy of Epo therapy in macaque monkeys [11]. After researchers injected several monkeys with virus vectors carrying the gene for Epo, the therapy initially 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 as well [11].

It is this kind of unpredictable outcome, says Eugene Goldwasser, now Professor Emeritus of Biochemistry and Molecular Biology, that make any sort of 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” [12].

 After watching athletes compete in the Olympics, though, one begins to understand the lure of gene doping. Even though scientists have yet to prove that is even possible for humans to benefit from injecting a substance like the gene for Epo, 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.

Sports officials are not counting on common sense to keep athletes from attempting to gene dope, however. In 2003, the World Anti-Doping Agency, which oversees Olympic drug testing, formally banned gene doping, despite the fact that there was little evidence that it was occurring [5, 13]. Since then, gene therapy research has continued, making it ever more likely that some athletes are exploiting it in an attempt to gain a competitive advantage. Because detection techniques remain unreliable, however, it is difficult to conclusively prove that an athlete is gene doping [14]. 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.”

References

  1. Weir, Tom. “Doping Cases Hit Record.” USATODAY.com. USA Today, 29 Aug. 2004.
  2. Canadian Press, The. “Anti-doping Lab Still Processing Samples.” CBCSports.ca. 1 Mar. 2010.
  3. Friedmann, Theodore, Oliver Rabin, Mark S. Frankel. “Gene Doping and Sport.” Science 327 (2010): 647-48.
  4. Brownlee, Christen. “Gene Doping.” Science News 166.18 (2004): 280-81. JSTOR. 02 Nov. 2010.
  5. Svensson, Eric C., Hugh B. Black, Debra L. Duggar, Sandeep K. Tripathy, Eugene Goldwasser, Zengping Hao, Lien Chu, and Jeffrey M. Leiden. “Long-Term Erythropoietin Expression in Rodents and Non-Human Primates Following Intramuscular Injection of a Replication-Defective Adenoviral Vector.” Human Gene Therapy 8 (1997): 1797-806.
  6. Easton, John. “Eugene Goldwasser to Receive the 2005 Prince Mahidol Award.” 2005 Press Releases. University of Chicago Medical Center, 1 Dec. 2005.
  7. “Drugs in Sport-Who Will Win the Drug Race?” Home – Australian Academy of Science. Web. 02 Feb. 2010. <http://www.science.org.au/nova/055/055key.htm>.
  8. Barton-Davis, Elisabeth R., Daria I. Shoturma, Antonia Musaro, Nadia Rosenthal, and H. Lee Sweeney. “Viral Mediated Expression of Insulin-like Growth Factor I Blocks the Aging-related Loss of Skeletal Muscle Function.” Proceedings of the National Academy of Sciences of the United States of America 95 (1998): 15603-5607.
  9. Juengst, Eric T. “What Next For Human Gene Therapy? Gene Transfer Often Has Multiple and Unpredictable Effects on Cells.” British Medical Journal 326.7404 (2003): 1410-411. JSTOR. Web. 02 Nov. 2010.
  10. Lyford, Jo. “Gene Therapy ’caused T-cell Leukemia'” The Scientist. 20 Oct. 2003. Web.
  11. Gao, Guangping, Corinna Lebherz, Daniel J. Weiner, Rebecca Grant, Roberto Calcedo, Beth McCullough, Adam Bagg, Yi Zhang, and James M. Wilson. “Erythropoietin Gene Therapy Leads to Autoimmune Anemia in Macaques.” Blood 103.9 (2004): 3300-302. Print.
  12. Goldwasser, Eugene. Personal interview. 18 Feb. 2010.
  13. Keim, Brandom. “Athletes Beware, Scientists Hot on Gene Doping Trail.” Wired.com. 4 Feb. 2010.
  14. Saey, Tina Hesman. “Foul Play.” Science News 173 (2008): 195. JSTOR.

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