Gene doping is doping based on gene therapy which is a medical treatment involving the use of gene modification in the patients. That is, gene therapy is to add or alter genes in cells within the body in order to treat a disease. Gene therapy is still at the experimental state, but the potential is very high. As with normal medical treatment some treatments may have a beneficial effect on the performance of athletes and can therefore be expected to be used as doping.
At present gene doping is most likely not in use, but the fear is that when gene therapy develops it will create a huge potential for doping that will have high impact on the performance and be virtually impossible to detect (McCrory 2003). Therefore, already back in 1998 some Danish scholars initiated the discussion on how to deal with this potential threat to the sports society (Hundevadt 1998). The concern has been taken up by the World Anti-Doping Agency (WADA) and since 2003 gene doping has been placed on the official doping list (www.wada-ama.org).
Until recently most artificial genes used for gene therapy tests simply had a permanently active promoter in front of the coding region for the protein of interest. By this approach the amount of protein produced is simply a function of the efficiency of insertion of the gene into the body. However, for most proteins, especially the hormones, too much production can be very problematic. Therefore, a better approach is to use a promoter for which the activity can be regulated. To construct a regulatory promoter for use in humans has proven difficult. But, in the recent years different regulatory systems have been described that can do the trick. These promoters respond to different kind of drugs, e.g. antibiotics and hormones that can be given to the patients to activate the artificial gene (Agha-Mohammadi et al 2000). These promoters are still in their infancy, but demonstrate that it can be done.
In the early phase gene doping cases will probably be the direct abuse of treatments already developed for gene therapy. Below is given some illustrative examples of gene therapy experiments which have a potential for gene doping.
Erythropoietin (EPO) is a potent hormone for regulating the amount of the oxygen-carrying red blood cells in the blood. The blood volume percent of red blood cells (hematocrit) is tightly regulated by EPO, which is produced in the kidneys. Since the hematocrit level is very important for the endurance performance EPO has received a great deal of focus in doping. The use of EPO requires injections several times a week to sustain an increased hematocrit level. Within few weeks after cessation the hematocrit level will return to normal.
In 1994, Tripathy et al. demonstrated in mice that one single injection with a virus delivering an activated EPO gene increased the hematocrit level from the normal 48% to 70% for at least 4 months (Tripathy et al 1994). Later similar experiments were performed in monkeys, where the hematocrit level was raised from the normal 40% to 60-70% for at least 6 months (Svensson et al 1997, Zhou et al 1998). These experiments demonstrated the potential in gene therapy in that this huge effect lasted for many months just by one single injection. Presumably they can last even longer but the experiments were terminated. However, they also illustrated the current weakness of gene therapy, namely that the level of production cannot easily be controlled. A hematocrit level of 60% will increase the viscosity of the blood to dangerous high levels and therefore, very likely, cause a heart failure.
The success with EPO production has led to many experiments with regulatory promoters to try to gain control over the EPO production (Bohl et al 1998, Ye et al 1999, Rizzuto et al 1999, Terada et al. 2002, Nordstrom 2003, Siprashvili et al 2004). These regulatory systems all used engineered promoters that are responsive to different kinds of drugs like the antibiotic tetracycline and the abortion drug mifeprestrone. To achieve this, another artificial gene is included that produce a protein responsive to the drug. In the presence of the drug this protein will then activate the promoter of the artificial EPO gene. Recent reports have shown in mice and rat models that such a regulated system can be used to treat anemia (Ataka et al 2003, Johnston et al 2003).
Whereas EPO gene therapy has a high potential to be abused in endurance type sports, there is not yet any obvious gene therapy targets that would be useful for strength-dependent sports. The normal use of anabolic steroids is not easily transferable to gene therapy since steroids are not proteins and therefore not directly produced from a gene. Instead they are produced by conversion of other substances with different enzymes (proteins). To produce anabolic steroids by gene therapy it would therefore be necessary to include several different genes in a coordinated fashion. At present this is still too complicated but might be possible in the future.
Nevertheless, some interesting genes can be found that might be useful in strength-dependent sports, but since they currently do not receive much interest as potential drugs in normal gene therapy the development of functional constructs is limited. Insulin-like growth factor 1 (IGF-1) and myostatin are such potential candidates. IGF-1 is a growth factor for many organs in the body and localized production of IGF-1 in an organ can induce growth of the specific organ. So, by taking the IGF-1 coding region, fuse it with an active promoter and inject the gene into a muscle Barton-Davis et al. demonstrated in mice that the muscle then grows and increases in strength (Barton-Davis et al 1998). Myostatin on the other hand is a negative regulator of muscle growth. By inactivating the gene entirely in mice (knock-out mice) a super mouse was generated with enormous muscles (McPherron et al 1997). These mice have acquired the nickname Schwarzenegger mice. Inactivation of the myostatin production requires that the gene is inactivated in most cells, which is not currently possible in the adult human body. Instead factors interfering with myostatin function could be used. Inhibition of the normal myostatin function has been accomplished by expression of different versions of modified myostatin in mice resulting in increased muscle mass (Zhu et al 2000, Lee et al 2001, Yang et al 2001). Also expression of other factors interfering with myostatin has been shown to increase muscle size, e.g. follistatin (Lee et al 2001).
While none of the above mentioned genes have been tested in humans similar effects as in mice and monkeys would be expected. One candidate for gene doping that has been tested in humans is the vascular endothelial growth factor (VEGF). VEGF is a growth factor for blood vessels and is among the front runners in gene therapy trials. Many elderly people have problems with the blood supply to the limbs due to a reduction in the number of blood vessels. In the worst cases causing ischemia in the extremities leading to amputations of the limbs. Since the patients simply need new blood vessels to replace the dead ones VEGF gene therapy is considered a promising solution. By using a virus carrying an activated VEGF gene and injecting this virus into the limbs of such patients it has been demonstrated that new blood vessels are formed and the blood flow within the limbs improved (Baumgartner et al 1998).
Increasing the blood flow in muscles of endurance athletes might have a beneficial effect on the performance. Since the construct already exists for human use, although only in the laboratories, in principle this offers an opportunity for misuse already today.
When gene therapy becomes an established technique then most likely artificial genes developed specifically for gene doping will emerge. Here the possibilities would be numerous for improving the human body.
The examples given above for the possibilities today all concerns the use of genes for hormones. The reason for this is that hormones function between cells and therefore, modification in one cell can have effect on many more cells. So even if the efficiency of introducing the artificial gene is low, a substantial effect can be achieved. However, the use of hormones also limits the possibilities of specific changes that can be achieved. A much broader span of possibilities opens up if genes for transcription factors are used. Transcription factors are the proteins within the cell that govern the activity of genes. So by expressing the correct transcription factor within a cell many different genes can be activated or down regulated. For instance, muscle fibers contains transcription factors which controls the genes for oxidative enzymes, so by expressing these transcription factors in the muscle fibers the oxidative profile can be improved (Ekmark et al 2003, Lin et al 2002). The current problem when using transcription factors is the efficiency of transferring the artificial gene into cells. Whereas a very small fraction of cells need to be genetically modified with hormone genes to accomplish a large effect, with transcription factors a substantial fraction of the cells need to be modified to achieve a significant effect since only the modified cells will change phenotype. However, the efficiencies of delivering the artificial genes are continuously improving, so the use of transcription factors most likely will become feasible.
Further out in the future it might even be possible not only to optimize on the existing phenotype, but to actually construct new phenotypes. In other tissues or other animals better protein versions may exist which could then be expressed in the relevant tissue. For instance, the human genome contains the gene for a contractile protein that is even faster than the ones expressed in normal muscles, and one could imagine that this “silent” gene could be forced to be expressed in the normal muscles, giving rise to a super fast sprinter (Andersen et al. 2000).
Today it is only possible to add new genes but not to change the existing ones in the human body cells. However, in the future it might be possible to change the existing genes (Kmiec 2003). Together with the increasing knowledge about the small differences within genes that give rise to the genetic differences between the athletes, one can image that in the future it might be possible to fine-tune the genetic makeup of an athlete to have the best versions of the relevant genes.
Gene therapy is a new medical treatment with vast perspectives. However, the experiments has been hit by a couple of very unfortunate accidents were patients has died from the treatment. The first major setback for gene therapy was in 1999 when the 18 year old Jesse Gelsinger died from a gene therapy treatment (Hollon 2000). He had a defect gene for an enzyme in the nitrogen metabolism, ornithine transcarboxylase, and was injected with a virus carrying a healthy copy of the gene. Apparently, his body responded so vigorously to the infection by the virus itself that he died from multiple organ failure. Recently, a gene therapy trial to cure severe immunodeficiency in children caused cancer in two of the children (Hacein-Bey-Abina et al 2003). Although these accidents seem problematic, they appear to be special cases that can be avoided in other trials. However, the progress in gene therapy trials has been slowed down due to the very high security measures that have been imposed on such trials in order to prevent new unexpected deaths.
Currently, gene therapy is still a very dangerous technique and the treatments are only available in a few experimental laboratories. However, as gene therapy becomes a more established technique and approved for normal treatments, the treatments will be much more easily available and safer to use. Even then, due to the huge power of gene therapy, the potential risks are still very high when used in uncontrolled environments. So if the athletes start using it on their own, we will see some bad cases. On the other hand due to the current high focus on safety, in controlled environment it may be relatively safe in the future. Perhaps the danger would be relatively small if used in organized sports teams where physicians are involved as well. However, the physicians may also be pressed to allow the use to go too far to achieve the maximal effect.
Present genetic technology poses a challenge to sport so deep that is hard to over-estimate. What is at stake is the very ethos of sport, nothing less than an epochal confrontation between a model of human identity as spelled out in Genesis, and a science-based libertarian model. According to the former model sports is a means by which we explore the human nature, admire it at its peek, and gain self-understanding. It is not up to us to “play Good” or to “meddle” with our human nature as it has been handed over to us by evolution. On the latter model, moulding of our biological nature is exactly what we should do. On this view, we have at last reached a point where this so hotly desired goal is becoming a possibility. Hence, we better see to it that our human nature will turn out to be of a kind that is worthy of admiration. Moreover, when moulding our biological nature, the sport arena is a perfect place to test the results of new biological inventions. Which of these views is the more appropriate one? This is the overarching question to be investigated in the project.
Two more specific moral problems in relation to genetic enhancement in sport will be addressed. One has to do with elitism and the notion of justice or fairness in sport. The other has to do with gender equality.
The general idea when we contemplate sport seems to be that, when all “irrelevant” factors have been eliminated those worthy of our admiration should be those who are most “fit”. One might suspect that this notion of justice direct us to praise people at least partly for achievements based on factors for which they are not themselves responsible, such as their genetic makeup. It is of interest to confront this notion of justice with what we think about justice in other areas. On a more traditional understanding of the notion of justice, people only deserve praise for such achievements for which they are responsible. This kind of philosophical discussions about justice in sport are well-known. (Tansjö & Tamburrini, 2000) However, this discussion has yet not been put into the context of genetic enhancement. What would the impact be were genetic enhancement accepted and generally practiced within sport? How would this influence the idea of justice in sport? What impact would it have on the ethos of sport itself? These are the kinds of problems that will be addressed in the project.
The second more specific theme has to do with gender equality and genetic enhancement. Roughly speaking, feminist thinking comes in two radically different varieties. On the one hand there is a gender blind egalitarian version of feminist thought, dating back to Plato, Wollstonecraft, and J.S. Mill, stressing that men and women are fundamentally not different in any morally relevant aspect. On the other hand, there is also a gender essentialist feminist tradition which stress that men and women are different in morally relevant ways. According to this tradition, a just treatment of men and women means that these differences are taken properly into account. (Bock & James 1992; Littleton 1987; Minnow 1990; Scott 1988) Within the sport context, the differences between these two traditions become conspicuously clear. We shall examine what kind of stance is appropriate within the context of elite sport.
One possible position would be the gender blind one, that men and women should be allowed to compete on equal terms against each other in sport. If women in some sports have difficulties to compete on equal terms, statistically speaking, then genetic enhancement could be a tool for catching up with men. Would this be a desirable development? This question will be addressed in the project where the gender blind view will be contrasted with the gender essentialist position with respect to sport. The latter view could be roughly described in the following way: In order for women to be treated equally in sport all they have to do is to become men. However, women presumably want to be treated equally in sport as women. One could argue that requiring oppressed groups to be the same as dominant groups in order to be given equal respect creates a double-bind because the group is usually oppressed on the very basis of some difference, e.g., gender, skin colour, sexual orientation, and (dis)ability. On this notion of gender equality, genetic enhancement becomes, rather than a means to equality, a further threat to it. Which notion of gender equality, the gender blind one, or the gender essentialist one, makes most sense? This question will be addressed by the research team.
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