Gene doping is the hypothetical non-therapeutic use of gene therapy by athletes in order to improve their performance in those sporting events which prohibit such applications of genetic modification technology,World Anti-Doping Agency The World Anti-Doping Code: The 2008 Prohibited List of International Standards pages 7-8 and for reasons other than the treatment of disease. , there is no evidence that gene doping has been used for athletic performance-enhancement in any sporting events. Gene doping would involve the use of gene transfer to increase or decrease gene expression and protein biosynthesis of a specific human protein; this could be done by directly injecting the gene carrier into the person, or by taking cells from the person, transfecting the cells, and administering the cells back to the person.
The historical development of interest in gene doping by athletes and concern about the risks of gene doping and how to detect it moved in parallel with the development of the field of gene therapy, especially with the publication in 1998 of work on a transgenic mouse overexpressing insulin-like growth factor 1 that was much stronger than normal mice, even in old age, preclinical studies published in 2002 of a way to deliver erythropoietin (EPO) via gene therapy, and publication in 2004 of the creation of a "marathon mouse" with much greater endurance than normal mice, created by delivering the gene expressing PPAR gamma to the mice. The scientists generating these publications were all contacted directly by athletes and coaches seeking access to the technology. The public became aware of that activity in 2006 when such efforts were part of the evidence presented in the trial of a German coach.
Scientists themselves, as well as bodies including the World Anti-Doping Agency (WADA), the International Olympic Committee, and the American Association for the Advancement of Science, started discussing the risk of gene doping in 2001, and by 2003 WADA had added gene doping to the list of banned doping practices, and shortly thereafter began funding research on methods to detect gene doping.
Genetic enhancement includes manipulation of genes or gene transfer by healthy athletes for the purpose of physically improving their performance. Genetic enhancement includes gene doping and has potential for abuse among athletes, all while opening the door to political and ethical controversy.Wells DJ. 2008. "Gene doping: the hype and the reality". Br. J. Pharmacol. [Internet] 154:623–31.
There are many negative effects of gene doping. The main technique used in gene doping is delivering genes via a vector. One vector is a virus which inserts the gene into the body and directs it toward the desired area(s). There are many risks using a virus as the carriers. The body may see the virus as an intrusion and attack it, which can cause harm to the individual. Additionally, there is always a risk of infection from inserting foreign elements into the body. Another risk is that of the virus causing errors in the genes which could lead to cancer, diseases, or possibly death, a process called insertional mutagenesis. The viruses may also attack healthy cells. Another vector is one's own stem cells, but this also poses a risk of infection.
History of gene doping The history of concern about the potential for gene doping follows the history of gene therapy, the medical use of genes to treat diseases, which was first clinically tested in the 1990s. Interest by the athletic community was especially spurred by the creation in a university lab of a "mighty mouse", created by administering a virus carrying the gene expressing insulin-like growth factor 1 to mice; the mice were stronger and remained strong even as they aged, without exercise. The lab had been seeking treatments for muscle wasting diseases, but when their work was made public, the lab was inundated with calls from athletes seeking the treatment, with one coach offering his whole team.Gretchen Reynolds for The New York Times. June 3, 2007. Outlaw DNA The scientist told The New York Times in 2007: "I was quite surprised, I must admit. People would try to entice me, saying things like, 'It'll help advance your research.' Some offered to pay me." He also told the Times that every time similar research is published he gets calls and that he explains that, even should the treatment became ready for use in people, which would take years, there would be serious risks, including death; he also said that even after he explains this, the athletes still want it.
In 1999, the field of gene therapy was set back when Jesse Gelsinger died in a gene therapy clinical trial, suffering a massive inflammatory reaction to the drug. This led regulatory authorities in the US and Europe to increase safety requirements in clinical trials even beyond the initial restrictions that had been put in place at the beginning of the biotechnology era to deal with the risks of recombinant DNA.
In June 2001, Theodore Friedmann, one of the pioneers of gene therapy, and Johann Olav Koss, an Olympic gold medallist in speed skating, published a paper that was the first public warning about gene doping. Also in June 2001, a Gene Therapy Working Group, convened by the Medical Commission of the International Olympic Committee noted that "we are aware that there is the potential for abuse of gene therapy medicines and we shall begin to establish procedures and state-of-the-art testing methods for identifying athletes who might misuse such technology".
Research was published in 2002 about a preclinical gene therapy called Repoxygen, which delivered the gene encoding erythropoietin (EPO) as a potential treatment for anemia. The scientists from that company also received calls from athletes and coaches. In that same year the World Anti-Doping Agency held its first meeting to discuss the risk of gene doping, and the US President's Council on Bioethics discussed gene doping in the context of human enhancement at several sessions.President's Council on Bioethics April 25-26, 2002 Agenda, Working Paper 7President's Council on Bioethics July 11-12, 2002 Meeting Agenda Session 4President's Council on Bioethics September 12-13, 2002 Meeting Agenda Session 7: Enhancement 5: Genetic Enhancement of Muscle, H. Lee Sweeney, Ph.D., Professor and Chairman of Physiology, University of Pennsylvania
In 2003, the field of gene therapy took a step forward and a step back; first gene therapy drug was approved, Gendicine, which was approved in China for the treatment of certain cancers, but children in France who had seemingly been effectively treated with gene therapy for severe combined immunodeficiency (non-human) began developing leukemia. In 2003 the BALCO scandal became public, in which chemists, trainers and athletes conspired to evade doping controls with new and undetectable doping substances. In 2003 the World Doping Agency proactively added gene doping to the list of banned doping practices. Also in 2003, a symposium convened by the American Association for the Advancement of Science focused on the issue.UCSD Public Relations: February 18, 2003 News Release: Bigger, Faster, Stronger: Genetic Enhancement and Athletics
Research published in 2004 showed that mice given gene therapy coding for a protein called PPAR gamma had about double the endurance of untreated mice and were dubbed "marathon mice"; those scientists received calls from athletes and coaches. Also in 2004 the World Anti-Doping Agency began to fund research to detect gene doping, and formed a permanent expert panel to advise it on risks and to guide the funding.
In 2006 interest from athletes in gene doping received widespread media coverage due its mention during the trial of a German coach who was accused and found guilty of giving his athletes performance enhancing drugs without their knowledge; an email in which the coach attempted to obtain Repoxygen was read in open court by a prosecutor. This was the first public disclosure that athletes were interested in gene doping.
In 2011 the second gene therapy drug was approved; Neovasculgen, which delivers the gene encoding VEGF, was approved in Russia to treat peripheral artery disease.AdisInsight Vascular endothelial growth factor gene therapy - HSCI Page accessed June 5, 2016
In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States.Gallagher, James. (2 November 2012) BBC News – Gene therapy: Glybera approved by European Commission. BBC. Retrieved 15 December 2012.
As the field of gene therapy has developed, the risk of gene doping becoming a reality has increased with it.
Agents used in gene doping There are numerous genes of interest as agents for gene doping. They include erythropoietin, insulin-like growth factor 1, human growth hormone, myostatin, vascular endothelial growth factor, fibroblast growth factor, endorphin, enkephalin and alpha-actinin-3.
The risks of gene doping would be similar to those of gene therapy: immune reaction to the native protein leading to the equivalent of a genetic disease, massive inflammatory response, cancer, and death, and in all cases, these risks would be undertaken for short-term gain as opposed to treating a serious disease.
Alpha-actinin-3 Alpha-actinin-3 is found only in skeletal muscle in humans, and has been identified in several genetic studies as having a different polymorphism in world-class athletes compared with normal people. One form that causes the gene to make more protein is found in sprinters and is related to increased power; another form that causes the gene to make less protein is found in endurance athletes. Gene doping agents could be designed with either polymorphism, or for endurance athletes, some DNA construct that interfered with expression like a small interfering RNA.
Myostatin
Myostatin is a protein responsible for inhibiting muscle differentiation and growth. Removing the myostatin gene or otherwise limiting its expression leads to an increase in muscle size and power. This has been demonstrated in knockout mice lacking the gene that were dubbed "Schwarzenegger mice". Humans born with defective genes can also serve as "knockout models"; a German boy with a mutation in both copies of the myostatin gene was born with well-developed muscles. The advanced muscle growth continued after birth, and the boy could lift weights of 3 kg at the age of 4. In work published in 2009, scientists administered follistatin via gene therapy to the quadriceps of non-human primates, resulting in local muscle growth similar to the mice.
Erythropoietin (EPO) Erythropoietin is a glycoprotein that acts as a hormone, controlling red blood cell production. Athletes have injected the EPO protein as a performance-enhancing substance for many years (blood doping). When the additional EPO increases the production of red blood cells in circulation, this increases the amount of oxygen available to muscle, enhancing an athlete's endurance. Recent studies suggest it may be possible to introduce another EPO gene into an animal in order to increase EPO production endogenously. EPO genes have been successfully inserted into mice and monkeys, and were found to increase hematocrits by as much as 80 percent in those animals. However, the endogenous and transgene derived EPO elicited autoimmune responses in some animals in the form of severe anemia.
Insulin-like growth factor 1