Gene Doping

An Overview and Update

Gene therapy represents an exciting and promising step forward in medical research, but its misuse to enhance athletic ability poses a serious threat to the integrity of sport and the health of athletes. WADA has been tracking the threat of gene doping since it first became a notion and has devoted significant resources to enable its detection. As early as 2002, WADA hosted a conference on gene doping at the Banbury Center on Long Island (U.S.), the first time experts from both the scientific and athletic worlds came together to tackle this issue. Then, in December 2005, WADA, in collaboration with the Karolinska Institute and the Swedish Sports Confederation, held a second workshop meeting in Stockholm (Sweden) on gene doping in sport to take stock of the situation and develop worldwide consensus on the way forward.

Instrumental in leading the debate has been world-renowned expert Prof. Theodore Friedmann, professor of pediatrics and director of the gene therapy program at the University of California, San Diego (U.S.). Prof. Friedmann is head of WADA's panel on gene doping and shares his thoughts on the current state of gene therapy and its implications for doping and sport.

Play True: How have recent advances in genetics impacted the world of sport?

Prof. Theodore Friedmann: Sport is being affected seriously by genetics in two important ways. The first positive effect is the development of new kinds of tests for any and all kinds of doping. WADA has developed an important set of research studies and results that indicate that the tools of the modern genetic revolution—the same kinds of tools that produced the deciphering of the human genome several years ago— will be applied to finding evidence of exposure to performance-enhancing materials and procedures. On the negative side, the huge advances in gene therapy and the methods of introducing genes into humans to treat life-threatening disease are being seen by some to allow new ways to dope by introducing genes—not to cure disease but rather to enhance athletic performance. Genes control the function of muscle cells, blood-producing tissues and the ways in which our bodies utilize energy, and we know that many of those genes can be manipulated. The advances in methods to introduce new genes to cure are more or less identical to the methods that might be imagined for sport enhancement. That fact makes the likelihood of attempts at gene doping pretty high.

Do you believe that gene doping is happening right now?

My only honest answer to that question is, "I don't know." What we do know is that there is a growing level of interest in the sports world in the potential for gene doping, and that some scientists working on potential genetic cures for muscle diseases like muscular dystrophy or blood disorders are being approached by sports figures to inquire about the use of genes in sport. We also know that at least one prominent sport trainer in Germany has been accused of making attempts to obtain an experimental material designed to increase blood production in patients with cancer and kidney disease. His case is currently being investigated and I expect that more of this situation will come to light soon.

At the same time, I am very familiar with the problems that the field of gene therapy continues to have delivering foreign genes to humans in ways that are effective and safe. Although a number of remarkable new therapies have been developed, a number of gene therapy studies have also led to very serious and entirely unpredicted and unexpected harm to the patients, even death. This technology is highly experimental and completely inappropriate where the goal might be something other than the cure of life-threatening disease like cancer, neurological degenerations and so on. To apply this very immature technology to athletes or to any young, healthy people for the purpose of increasing some already-normal function, in my mind, is unethical and constitutes deliberate professional malpractice.

In terms of developing a detection method for gene doping, how high of a priority is this for the anti-doping community?

During the past four to five years, WADA has developed a vigorous research program designed to learn how foreign genes might be used in attempts to improve athletic performance. Many laboratories around the world are taking part in the program and the general genetics community is submitting high quality proposals to WADA. I would estimate that close to eight million dollars (U.S.) have been committed and spent in the WADA research program for gene doping, representing a significant portion of the entire WADA budget. I think that the size of the effort is appropriate for the size of the threat to sport. I am convinced that WADA will be able to develop and eventually implement effective new ways to detect doping in sport by these new methods.

What kind of outcomes has the research provided so far?

The scientists working under the WADA banner have learned a great deal about the function of some genes that are likely to be used illicitly in gene doping attempts, such as genes that produce growth factors (e.g. hGH, insulin-like growth factor and related muscle factors) and erythropoietin. This kind of science is complex and longterm, but the results of these studies are beginning to be published in the scientific journals and shared with the general scientific community. WADA-supported studies have shown that when these genes are introduced into test animals, some of the expected effects, such as muscle growth and increased blood production, do in fact occur but also that many other unwanted and potentially disruptive effects occur to many other normally functioning genes and to the normal metabolic processes that they regulate. In some studies, a number of these "side effects" changes to genes and to metabolism are being put together to try to develop a "signature" for exposure to potentially doping agents.

At the December 2005 Gene Doping Workshop, experts stated, in the Stockholm Declaration.* that "gene transfer for the purpose of therapy remains a very immature and experimental field of human medicine." Have there been any significant developments in gene therapy since then that would change the outlook for gene doping?

The technology of gene therapy is still very immature and while there continue to be advances in serious diseases, we have all been sobered by the magnitude of the problem of delivering genes safely into human beings and to the ways in which foreign genes can produce unwanted effects, some of which are lethal. Since the Stockholm workshop, there have been many improvements in these technologies, increasing evidence for success in some lethal diseases.
There have also been additional occurrences of setbacks and adverse events, including an additional death among the group of children who have been so successfully treated for immune deficiency by gene therapy. As we continue to improve the technology, we will sadly see more ways in which the methods can surprise us with unexpected effects and with serious harm to patients. In medicine, we recognize that treatment can be a two-edged sword: harm and benefit. To cure disease, we all accept both sides of the sword. For healthy young people, we should demand that we do no harm. Clearly, that is not the case for gene transfer technology.

You also stated that scientific progress "suggests that new detection methods are likely to emerge, which will help to keep sport untainted by gene doping methods." Is this true?

Yes. It is true. I have no doubt that new detection methods will be developed. Early methods are already being designed at this very moment. In exactly the same way that DNA technology has added so much in forensic science and crime detection, DNA technology will add very powerful new tools to detect doping.

Let me close by highlighting that WADA is not a basic research funding agency but WADA is certainly the lead agency-in fact the only one that I know of in the application of modern molecular genetics and DNA technology to the development of improved methods for detection in doping and in averting the use of gene therapy approaches to doping. WADA has also sponsored the most important and influential public forums for a discussion of this societal problem and discussions are underway for another conference in 2008.

WADA has done the world of sport a great service in undertaking this work.

Brief Bio

Prof. Theodore Friedmann received his undergraduate and M.D. degrees from the University of Pennsylvania and his clinical training in pediatrics at Boston Children's Hospital of Harvard University from 1960- 1962 and 1964-- 1965. He served as a medical officer with the U.S. Air Force and carried out post-doctoral research at the University of Cambridge (U.K.), the U.S. National Institutes of Health (NIH) and the Salk Institute in California. He has been on the faculty of the University of California San Diego (UCSD) since 1971 where he is now professor of pediatrics, Muriel Whitehill Professor of Biomedical Ethics and director of the UCSD program in gene therapy. He is currently president of the American Society of Gene Therapy, and in addition to his work with WADA's Health, Medical and Research Committee (gene doping panel chair), he has served on many national and international genetics panels and committees, including chairmanship of the U.S. NIH Recombinant DNA Advisory Committee.

*The complete text of the December 2005 Stockholm Declaration on Gene Doping is available online at www.wada-ama.org

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