Genetic engineering in athletes

Abstract

Safeguards are needed before the hypothetical threat becomes a reality

Athletes who want to maximise their performance are continually tempted to use illegal drugs to gain competitive advantage and to aid recovery from training and injuries. Recent revelations of widespread doping arising from investigations of the distributionof the anabolic steroid tetrahydrogestrinone by the American company BALCO (Bay Area Laboratory Co-operative) demonstrate the extent of this problem in world class athletes.¹

Some commentators have raised concerns that genetic modification or “gene doping” will be the next step in the search for enhanced performance.^{2 3 4 5} These concerns are based on some impressive studies in genetically modified rodents where manipulation of individual genes has increased muscle mass, muscle strength, or running endurance, depending on the gene that was manipulated. Reviews of these animal studies conclude that such genetic manipulations could also improve human athletic performance.^{6 7}

How likely is it that athletes will use genetic modification? About 10% of athletes have used existing drugs,⁸ so it is likely that some will be tempted to experiment with genetic modification. However, translating studies performed in rodents into effective treatments in humans will not be easy. Some of the rodent studies were performed in transgenic mice in which the genetic modification was introduced into the germline and transmitted from one generation to the next. For practical and ethical reasons it is not possible to do this in humans.

Widespread genetic modification of somatic rather than germline tissues can be achieved in mice by using modified viruses to deliver the genetic modification, but only when used at very high doses. Scaling up such doses from a 25 g mouse to a 75 kg human will prove challenging, both in terms of the facilities needed to generate such viral vectors and the potential difference in immune responses to such viruses between mice and humans. It is also not known how well these vectors will work in humans.

Current clinical trials—for example, those targeted at muscular dystrophies—use only small amounts of these viral vectors, and they are early stage safety trials that will not tell us whether we can achieve the high efficiencies needed to improve muscle function.⁹ It will be many years before agents for gene therapy are available for general clinical use.

Could black market laboratories generate the necessary viral vectors? Many laboratories can make small amounts suitable for cell cultures and a few experiments in mice, but it would be a major logistical exercise to produce high quality preparations in bulk. If this were possible, athletes would be running considerable risks. Activation of the innate immune system by a relatively high dose of viral vector caused the death of a patient in a clinical trial in 1999. The man, who had ornithine transcarbamylase (OTC) deficiency, developed disseminated intravascular coagulation and organ failure after a delivery of a relatively high dose of recombinant adenovirus carrying the OTC gene into the hepatic artery.¹⁰

Interfering with genes that could increase athletic performance carries substantial health risks. For example, high levels of growth hormone and insulin-like growth factor-I have been associated with the development of cancers, and overexpression of erythropoietin can lead to stroke and heart failure. Other genes such as those regulating specific aspects of muscle physiology have not been studied for long enough to know what health risks might be associated with their long term use.

What needs to be put in place in anticipation of potential gene doping? Athletes will be less tempted to consider it if tests are in place that could potentially detect such genetic modification. Some aspects that are specific to gene doping make detection more likely, even without the use of complicated diagnostic tests. Firstly, proteins expressed in the athlete after gene transfer are sometimes different from the normal protein. For example, erythropoietin is normally produced in the kidney and stimulates red blood cell production, but after transfer of the erythropoietin gene into muscle changes in the post-translational modification of the protein would enable doping to be detected.¹¹

Secondly, athletes are aware of the time needed for current performance enhancing drugs to clear from the system, which is why testing outside of competitions is so important in the fight against doping. One of the disadvantages of gene doping is that it will be more difficult for athletes to tailor their treatments to avoid detection. Thirdly, although gene expression can be controlled after gene transfer, this requires the use of drugs that can readily be detected. Other approaches that are being investigated are the development of a sensitive test for transgenic DNA and protein or gene profiling of athletes over their competitive lifetime.¹²

Although at present gene doping is a threat rather than a reality, it is important to put safeguards in place that will prevent athletes from being tempted not only to cheat but to put their health at substantial risk.

Cite this as: BMJ 2008;337:a607