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How close are we to gene doping?

We know from the third law of motion described in the midseventeenth century by Sir Isaac Newton in his Principia Mathematica that every action in the physical universe generates an equal and opposite reaction. That's what enables fish to swim, birds to fly, rockets to soar. It's what allows us to sit quietly in chairs without falling through the floor or floating off into space. It seems to me very likely that the Newtonian laws of motion also explain some aspects of the emergence and evolution of new concepts. A prime example might be a nettlesome new cottage industry that has arisen to evade the international effort to curb doping in sports.

This new movement is founded on the position that it is the very existence of antidoping regulation and oversight that produces a climate of cheating and distrust in sports, and that regulation and prohibition should be replaced by a more laissez-faire approach. (1) This argument would lead us to accept all methods for enhancing performance outside of those permitted by the rules of that sport--drugs, supplements, materials, surgery, and now gene-based enhancement--should be allowed, even encouraged and valued. Some have even suggested that our society has a moral duty to promote active and unregulated use of any and all methods to achieve athletic "excellence." Bizarrely, one prominent proponent of this approach labels such a process "natural." (2)

As troublesome as traditional, drug-based doping has long been, the emergence of gene doping is seen by some to represent an ominous new opportunity in cheating technology. (3) The concept of gene doping grew out of the important development in the early 1970s of a novel approach in medicine that promised to treat human disease by attacking underlying genetic defects. Thus was born the idea of gene therapy. (4) In early, phase I safety studies, gene therapy has produced effective treatments for a number of diseases, such as pediatric immune deficiency, a genetic form of blindness, and neurodegeneration, (5) with more sure to come in the very near future. While the efficacy of treatments has not yet been confirmed in more extensive phase III studies, the success so far teaches us is that it is clearly possible to introduce new genetic functions into human beings in forms efficient and stable enough to modify traits that produce serious disease and thus to ameliorate life-threatening illness and ease suffering.

The same methods can undoubtedly be used to enhance normal human traits, including traits that affect athletic ability. One might readily envision genetic modification of healthy young athletes to augment functions useful for athletic performance, such as muscle growth and contraction, endurance, blood production, pain perception, and oxygen delivery to exercising muscle. But how close we are to gene doping in sports is a matter of debate.

When the concept of gene doping first emerged a decade or so ago, some critics considered it improbable and far from imminent. One of my most respected colleagues, who had a prominent role in the gene therapy oversight process, called the potential for using genetic modification methods for gene doping "a lot of gale-force hand waving." In contrast, others saw it to be the obvious next and inevitable step in doping and cheating technology and believed it offered potential advantages over drug-based doping--that it might be more effective and more difficult to detect. Many feared that gene doping would enter the world of competitive sports very quickly; in fact, the sports media have predicted that every Olympic Games in the last decade would probably be the first genetically doped games.

Indeed, several instances have come to light that can only be interpreted as serious attempts at gene doping. An athletic coach in Germany was found to be making diligent efforts to obtain a gene vector called Repoxygen that contains and expresses the erythropoietin gene and was developed to increase blood production in patients with serious diseases such as cancer and chronic kidney disease. The product of the gene, erythropoietin, is in fact one of the most widely used drugs in the world for treatment of these disorders and, of course, is known to be heavily abused in some endurance sports, such as cycling. One imagines that the intended use of this material by the coach might have been other than for research on gene-based treatment of diseases. In addition, shortly before the Beijing Games in 2008, a German investigative television team broadcast a program identifying a Chinese scientist who was reported to be offering genetic manipulation for athletes.

Even though many suspect genetic doping among athletes who have performed feats that seem to lie outside of normal human physiological boundaries in Olympic and other elite sporting events, these suspicions have never been confirmed. There is no documented case of genetic techniques having been used to enhance athletic ability in people. We do know that genetic manipulations have produced mice and, in some cases, primates with enhanced traits crucial for athletic performance, including increased muscle function, prolonged endurance, and elevated blood production. If gene therapy is becoming increasingly feasible and available and if the pressure for gene doping is so great, why has it not yet been documented in athletes?

One reason may be that the procedures for safe, successful, and legitimate genetic manipulation for medical purposes are extremely complicated, lying outside the capability of most rogue operations. Even though the production of gene doping materials is achievable using standard graduate school or even undergraduate molecular biology technology, the truly difficult aspect of gene therapy is its execution: bringing about the safe and effective performance of complicated human clinical manipulations by methods consistent with international ethical standards of human clinical work. Even for legitimate gene therapy, it has taken several decades of experimental refinement and testing to learn how to express added genetic information safely in human patients. For those with medically urgent conditions--such as severe combined immunodeficiency or adrenoleukodystrophy, a rare fatal brain disease--the risks of using still imperfect and even dangerous tools to ameliorate disease and ease suffering are ethically justified. Gene therapy remains a highly experimental and potentially risky technique, and even some of the successful therapies have caused serious side effects, including leukemia and even death.

Another possible reason for the absence of documented human gene doping lies in the flawed logic of some of the justifications for its development. Genetic and other pharmacological manipulations are often rationalized as attempts to bring all athletes to the same base level of capability, evening out all innate gene-based traits and ignoring that glaring fact that we do not understand the multiple genetic, environmental, and acquired traits that shape athletic "talent"--ambition, educational and economic opportunities, and the "fire in the belly" component, for instance--well enough to even begin to "level" them. On its face, such an extreme leveling seems an impossible task. And yet, even if all athletes could be brought to a "level playing field" genetically, physically, environmentally, and socially, wouldn't all be expected to perform identically? Where then is the sport? Where is the competition? Who gets the gold medal and the lucrative endorsements--the "athlete" or the molecular biologist sitting on the sidelines?

We know from vast experience that, like all technology, the use of apparently sophisticated genetic doping methods will not await demonstration of safety, much less efficacy, before being applied in sports. For that reason, the World Anti-Doping Agency has included genetic doping in its list of banned methods since 2004 and has instituted major research projects to identify potential methods for gene doping and for detection. And yet, those intent on using illicit methods are likely to pay little attention to WADA lists or to comply with the multiple layers of local and national oversight and regulation required for gene therapy--review and approval of local institutional review boards, human subjects committees, and federal oversight and regulatory bodies like the National Institutes of Health's Recombinant DNA Advisory Committee and the Food and Drug Administration. The financial and other rewards are too great and the sources of funding too deep in sports for those intent on gene doping to be concerned about such troublesome niceties.

It seems inevitable that genetic tools for doping will eventually be developed and applied. There is little question that attempts at gene doping will be made at an increasing pace in the near future. But the perpetrators will almost certainly fail, probably technically and certainly ethically, and they will do medical mischief in the process. In the course of their premature misadventures, they are far more likely to do harm than to provide athletic advantage.

Sport is a deeply human activity dependent on an honest and transparent rule-based "contract" between participants. Those who love it deserve protection from those who would weaken or destroy its rules and introduce unethical, ineffective, and probably harmful materials and tools. Those who practice genetic manipulation, evading requirements for ethical and scientific review and applying genetic tools without full disclosure and informed consent, should certainly be considered guilty of scientific or medical malpractice and professional misconduct.

(1.) J. Tierney, "Let the Games be Doped," New York Times, August 14, 2008; N. Fost, "Let the Doping Begin," New York Times, August 12, 2008; "A Level Playing Field?" Nature 454 (2008): 667.

(2.) A. Miah, "Enhanced Athletes: It's Only Natural," Washington Post, August 1, 2008.

(3.) T. Friedmann et al., Gene Doping and Sport," Science 327 (2010): 647-48.

(4.) T. Friedmann and R. Roblin, "Gene Therapy for Human Genetic Disease?" Science 175 (1972): 949-55.

(5.) S. Hacein-Bey-Abina et al., "Sustained Correction of X-Linked Severe Combined Immunodeficiency by Ex Vivo Gene Therapy," New England Journal of Medicine 346 (2002): 1185-93; A. Aiuti et al., "Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency," New England Journal of Medicine 360 (2009): 447-58; A.M. Maguire et al., "Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis," New England Journal of Medicine 358 (2008): 2240-48; N. Cartier, et al., "Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy," Science 326 (2009): 818-23.

Theodore Friedmann, "How Close Are We to Gene Doping?" Hastings Center Report 40, no. 2 (2010): 20-22.
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Author:Friedmann, Theodore
Publication:The Hastings Center Report
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2010
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