Is gene doping the future of cheating?

Thursday, June 15, 2017. Author Pleuni Hooijman Ph.D

Using DNA for an unfair advantage?

Elite athletes are lucky enough to have inherited the genetic variations enabling them to perform at the top level of their sport. Although environmental and motivational factors are as important for an athlete’s success, without the right set of genetic variants it makes it much tougher to reach the top. The use of gene doping can potentially increase someone’s physical capabilities in terms of strength and endurance, so it may emerge as the new frontier of cheating.

With hundreds of genetic variations linked to human fitness and performance, coupled with rapid developments in gene therapy, it is not surprising that the World Anti-Doping Association (WADA) included gene doping on their list of prohibited strategies long before it was ever found to occur in athletes.

So what exactly is gene doping, what are its consequences and dangers, and should you suspect your fellow competitors or admired elite athletes of being genetically enhanced anytime soon?

 

What is gene doping?

According to WADA, gene doping is the “transfer of polymers of nucleic acids or nucleic acid analogues, or the use of normal or genetically modified cells”.

Gene doping closely relates to gene therapy. In the past few decades, gene therapy has been developing as a strategy for preventing or treating diseases. Gene doping is a variant of gene therapy, where the goal is not to treat or prevent diseases but to enhance a healthy person’s performance.

Gene doping may look attractive for athletes who are prepared to cheat because most doping tests distinguish between endogenous (produced by the body) and exogenous (produced outside the body) biological compounds (e.g. banned substances are detected in urine or blood tests). With gene doping, the compounds of interest that have a positive effect on performance are produced by the body and are hence ‘endogenic’ and less easily detectable.

Also, if you gene dope, you may get a steady state dynamic which avoids peaks like those arising performance enhancing drugs, making detection more difficult. So what might be the genes of interest for potential gene dopers?

 

Which genes may be targeted?

Potential candidate genes are those that have a well-understood effect on performance. Some examples are those that affect muscle mass (such as growth hormone (GH), insulin-like growth factor (IGF-1) or myostatin), cardiovascular systems (Erythropoietin (EPO), vascular endothelial growth factor (VEGF), modifiers of muscle phenotype (PPARD, PGC1A) and those that raise pain threshold (endorphins).

Let’s take a closer look at an example of a gene affecting muscle mass: myostatin (MSTN). Myostatin is a negative regulator of muscle growth. There are natural and induced mutants in animals and humans where the myostatin gene is inactive. In humans for example, the rare AA genetic variation of c3735GA MSTN gene has so far been found only once, in a German boy. It results in a complete loss of function of the MSTN gene, and thus the total absence of the myostatin protein. The German boy who had this mutation was extraordinarily muscular, with protruding muscles in his arms and thighs. At the age of 4, he could hold two 3 kg dumbbells with his arms straight out to the side.

In order to tweak someone’s genes, for example by inserting the rare AA genetic variation of the c3735GA MSTN gene, a replacement or additional gene must be inserted into their DNA. This is done with a gene carrier, also called a vector.

 

How does gene delivery for gene doping work?

By having a close look at nature, particularly at viruses, scientists have found ways to insert DNA into the nuclei of cells in a very efficient manner. Viruses work like syringes injecting their genetic material into human cells. Viral vectors that are well tested in muscles are the herpesvirus, retrovirus, lentivirus, adenovirus, adeno-associated virus. The viruses are re-engineered so that the virus contains the gene of interest and the packaging signals to get it built in into the target DNA, but without being harmful. These systems have been optimized in the last few decades, reducing the chance of getting an endogenous virus infection, making it a relatively safe system.

Another way of delivering the gene is on a non-viral vector by way of plasmids, which are circular loops of DNA usually found in bacteria. Plasmids are very easy to engineer to get the genetic adaptation you need. Although producing and storing large quantities of plasmids is relatively straight forward, it is a much less efficient gene delivery system compared to viral vectors. Delivering plasmids into a cell can be difficult and requires either a chemical or physical delivery system. This brings us to the challenges of tissue engineering.

 

What are the technical and safety issues?

There are many difficulties and risks with gene therapy and gene doping. Although it may be relatively easy to deliver genes into certain cell types in a lab setting, if you want to use gene therapy to give an athlete stronger muscles, you need to target the right cells in the correct tissues and this is an extremely difficult process. Even in a highly controlled lab setting, only some cells will efficiently take up the gene delivery vector and incorporate the new doped gene into their genome. In a whole organism, this efficiency decreases even further. The vast majority of genetically modified animals used in scientific/medical research are born with genetic modifications or have been modified while they were still an embryo and are composed of a single or only a few cells. Modifying a fully grown, adolescent, or even infant organism which is made up of billions/trillions of cells is a far greater challenge.

Difficulties also arise with the size of the animal species to be modified. Whereas it might be quite easy to use viral vectors to genetically modify a mouse, doing so in larger animals, like humans, raises the issue of producing sufficient amounts of the viral vector. The efficiency of generating a viral vector containing the recombined genetic material can be remarkably poor and the majority of vectors delivered could potentially be non-functional. You may need to give a very large dose of the viral vector to get efficient incorporation of the modified gene. Also, it is not guaranteed that your genetic modification will be incorporated in a suitable place within the genome and the efficacy of the entire process might be extremely low.

Apart from the uncertainty of the effects of genetic modification, gene doping also comes with serious health risks like cancer and potential immune responses. If a genetic modification accidentally switches on a cancer gene or knocks out a cancer suppressing gene, cancer may develop. There are several examples of this from early gene therapy attempts on single cells and animals. Even more likely to occur, are severe immune reactions in response to the viral or plasmid vectors, in which the receiver’s own immune system tries to attack the foreign “invaders”. Usually, such immune reactions are mild and only lead to fevers, but they could be potentially lethal, so the risks are very high.

 

So are my competitors gene doping?

The chances are very low that gene doping is already being used and having a significant impact in sporting results. While our understanding of genetics and cell biology is extensive we are still not quite there in being able to apply our knowledge to effectively and efficaciously alter the genome of an athlete.

The technology is advancing quickly but until you start seeing reports of positive clinical trials treating human diseases using gene therapy it is highly unlikely that gene doping is being successfully carried out in illegal back alley laboratories or unregulated medical centers.

It has been shown in the past that athletes who cheat are prepared to take huge risks with their own health for potential performance improvements. While it is highly unlikely that an efficacious form of gene doping exists, it is possible that some athletes are looking and even trying unproven gene doping procedures in the off-chance that they can gain even a small boost to their performance.

 

I hope you enjoyed my blog. I invite you to read my other articles:

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References

The Physiological Society, The Biomedical Basis of Elite Performance, East Midlands Conference Centre, Nottingham, UK 6-8 March 2016, Professor Dominic Wells

Schuelke, M., Wagner, K.R., Stolz, L.E., Hübner, C., Riebel, T., Kömen, W., Braun, T., Tobin, J.F. and Lee, S.J., 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. New England Journal of Medicine,350(26), p2682­2688.

Friendmann, T., Rabin, O., Frankel, M.S., 2010 Gene Doping and Sport Science 327 (5966) p. 647-648

Wells, D.J., Gene doping: the hype and the reality. Br J Pharmacol. 2008 Jun; 154(3): p623–631.

World Anti-Doping Agency (WADA) http://www.wada-ama.org/en

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