Katrin Gerlinger, Thomas Petermann, Arnold Sauter
In all likelihood a new form of doping will emerge in the coming years, posing new challenges in the fight against doping, namely the widespread use of a number of cutting-edge substances and procedures aimed specifically at modulating gene activity. These may be methods derived from gene and cell therapy or methods for manipulating gene expression based on the use of highly specific agents (collectively termed gene doping in the broad sense). By contrast, strategies aimed at inducing permanent changes in the genetic makeup of athletes (so far only theoretical in nature) are unlikely in the foreseeable future.
The following key questions form the keystones of the TAB report. What scientific findings might potential gene doping utilize? Where are the future points of entry in top-level and recreational sport? And how can bans and monitoring be applied in response these developments? To complement these thematic perspectives, gene doping will also be viewed in the context of social trends and structures. We will ask what behavioral patterns and attitudes play a role at the level of the individual athlete and how gene doping as a form of deviant behavior is influenced by various social contexts and actors.
This final report concludes the TAB Gene Doping Project. It was commissioned by the Select Committee for Education, Research, and Technology Assessment on the recommendation of the Sports Committee of the German Bundestag.
The Term Gene Doping – in the Narrow and Broad Senses
The term gene doping is often construed very narrowly, namely as the misuse of gene and cell therapy methods, by means of which genetic material in the form of DNA or RNA is inserted into a cell, an organ, or an organism. The TAB analysis is based on the broader perspective adopted by the World Anti-Doping Agency (WADA), which –in line with its Prohibited List – explicitly understands gene doping to also include the use of other methods aimed at modulating gene activity: »the nontherapeutic use of cells, genes, genetic elements, or the modulation of gene expression having the capacity to improve athletic performance«.
Only by adopting this broader interpretation is it possible to include as many relevant methods, procedures, and agents as possible in the impact assessment. The scientific basis for new methods of (gene) doping is formed by the everadvancing techniques of molecular biology and growing knowledge of the molecular mechanisms of cell function. The social and political explosiveness of the topic arises from the fact that these advances will increase the possibilities for manipulating gene activity in specific and subtle ways that are likely to be increasingly difficult to detect. Whether this process of manipulation occurs by transmission of actual genetic material, i.e. DNA or RNA, or by some other pharmacologic mechanism is not a reasonable exclusion criterion for the purposes of an impact analysis, especially in respect of future antidoping measures.
No »Genetically Optimized« Athletes in the foreseeable Future
According to a widely held notion, gene doping is aimed at »improving« the genetic makeup of athletes based on knowledge of which gene variants can bring about a particularly high level of performance, either by specifically manipulating the whole organism or by prenatal selection. However, a detailed analysis of genome research findings shows that molecular genetic knowledge of »highperformance gene variants« is still extremely limited, imprecise, and contradictory, with the result that »promising« techniques for inducing specific alterations in an individual’s genetic constitution are h unlikely to be developed in the foreseeable future. Accordingly, the TAB project has uncovered no evidence that any strategies based on human selection or breeding for enhanced athletic ability are likely to become technically feasible within the foreseeable future. At present, therefore, notions about the possibility of gene doping in this narrow sense have no scientific basis.
The Aim of Gene Doping: Gene Regulation
The objective of gene doping is therefore to specifically influence (modify) the activities of the body’s genes by activating them or by strengthening, weakening, or blocking their expression. The underlying biochemical and physiological processes are highly complex, both at the cellular level and at the level of overall regulation in the body (and therefore will only be outlined in this report). The network of regulatory mechanisms controlling attributes relevant to physiological performance presents a broad array of targets for pharmacological and molecular biological modulation – for new therapeutic treatment strategies as well as for doping purposes. The potential consequences of such interventions are extremely hard to predict. This continues to be seen in medical trials of treatments for patients (in the form of side effects or lack of drug efficacy). Where such methods and procedures are misused in healthy or highly trained individuals – who are also highly susceptible to interference despite their high level of physiological performance – the consequences are again likely to be highly unpredictable.
Gene Therapy and other Methods of modifying Gene Activity
Gene doping in the narrow sense misuses the techniques of gene and cell therapy for the purpose of enhancing physical performance. The term »gene therapy« is used to denote strategies in which genes or genetic elements are introduced into cells from outside to remedy inherited or acquired genetic disorders. Genes are introduced into the cells (a process known as gene transfer) by means of vectors (or gene carriers, usually specially modified viruses). Gene therapies already tested on humans have been directed mainly at cancers, monogenic inherited diseases, infectious diseases (especially HIV), and cardiovascular disorders. In contrast to what is commonly reported, the objective here is often not to effect a permanent change. Instead, the procedures are transient measures that may have to be repeated.
An assessment of the current results of gene therapy is important for evaluating its potential relevance to doping. Overall, gene therapy is not yet an established medical practice. It is essentially still at the experimental stage, and the evaluation of current therapeutic results is a matter of considerable controversy. Treatments are still frequently associated with serious side effects, including death. The vectors used are believed to be responsible for some of the side effects observed. The proportion of clinical experiments that forgo the use viral vectors, which are more efficient but also particularly risky, in favor of the use of socalled »naked« DNA has increased steadily in recent years. This is significant for potential gene doping, since nonviral DNA is probably much simpler and also less risky to use.
In addition to the methods that are unambiguously described as constituting gene therapy, there exist many other modern pharmacologic strategies that are intended to induce a specific modification of the body’s gene activity in order to achieve a desired therapeutic outcome. The pharmacologic agents concerned include a broad range of, in some cases very complex, biomolecules such as proteins and RNA, but also some easily synthesized simple compounds.
Physiological Approaches and molecular Targets – Research Strategies and Development Projects
The most likely methods by which gene doping might be attempted relate to three areas of physiology and their molecular regulation, namely formation of skeletal muscle, oxygen supply, and energy supply.
Among the research strategies and development projects identified in the TAB project and described in detail in the report which have already reached the stage of clinical testing, there is only one that pursues an explicit gene therapy approach. The other techniques at an advanced stage of development are all pharmacological strategies for modifying gene activity. Success in the preclinical phase, i.e. in animal experiments, has been achieved with a large number of techniques that constitute gene doping both in the narrow sense (e.g. the wellknown case of Repoxygen) and in the broad sense.
Specific Health Risks: An effective Obstacle?
Common to all doping practice is the fact that the relevant techniques and agents were developed for the treatment of diseases and accordingly have not been studied in relation to their use for performance enhancement in healthy persons. Hence, the health risks associated with their misuse for doping purposes cannot be assessed. This is evidenced by the severe to catastrophic dopinginduced ill effects on health, in some cases leading to death, that some athletes have suffered in the past.
From this point of view gene doping techniques could scarcely be riskier. At the same time, the principles that underlie the techniques used to bring about specific modifications of gene activity entail specific risks which, in the absence of empirical evidence, must be regarded merely as scientifically plausible assumptions. In this respect a distinction can be made between risks that arise as a result of insertion of genetic material into the organism (lack of tissue specificity of vectors leading to uncontrolled spread of the foreign gene in the organism; mutations and immune reactions) and risks that result from overexpression (i.e. excessive production in the body) of performance-relevant biomolecules (e.g. promotion of uncontrolled cell growth). Given the complexity of the mechanisms that regulate gene activity, it is highly likely that manipulation of these mechanisms can result in a broad variety of side effects and potentially in severe damage to health.
Nevertheless, experience gained with conventional doping practices casts considerable doubt on the notion that these imponderable health risks constitute an effective disincentive to the use of these methods, even if those that are scientifically unproven. Besides their availability, of course, the crucial factors governing the use and spread of gene doping techniques will probably be their presumed achievable effect – i.e. a potential improvement in performance – and their detectability or lack thereof (see below).
Routes of Access
Therapeutic techniques and drugs that are either already licensed or at least at the clinical trial stage would appear to be the most likely initial candidates for misuse for doping purposes. In order to predict which gene doping strategies could become relevant within what period of time, it is essential to monitor progress in research and development, especially in pharmaceutical companies, on a continuous basis. Nevertheless, it must be assumed that by no means all projects that could be relevant in terms of gene doping become known to the public (at least in their early stages).
Along with misuse of licensed therapeutic agents or those in the process of being licensed, another, and potentially even more worrying, possibility is emerging – namely a form of »individual« gene doping in which all the testing procedures that form part of the drug regulatory process are circumvented. As in the case of the designer steroids that were explicitly manufactured by the Balco company for doping purposes, genetic-pharmaceutical gene doping agents could also be produced that are specifically tailored to individuals or a small group of athletes. In some cases, the time and expenditure involved would probably be no greater than for non-designer agents. Relatively simple methods include construction of virus-based gene vectors, production and administration of naked DNA, and the construction of gene vaccines to induce the production of antibodies. These are all routine tasks for molecular biologists, and many of the individual steps can be performed using standard procedures and apparatus and commercially available kits.
A common objection to gene doping is that the relevant methods are not validated and in particular that enhanced performance has not been demonstrated either in normal subjects or in highly trained athletes. Nevertheless, results obtained in preventive research oriented towards doping practice show that even when the effectiveness of a particular doping strategy has been repeatedly denied (as in the case of growth hormone), athletes will nevertheless continue to use it.
Points of Entry: Elite Sport, Bodybuilding, and anti-aging Applications?
Overall we can assume that gene therapy-based methods (i.e. gene doping in the narrow sense) probably pose far greater obstacles to misuse than the many different techniques and pharmaceutical developments used for the specific manipulation of gene activity. Given the present state of advancement of a number of projects being pursued by the biotechnology and pharmaceutical industries, it must be assumed that such methods can already be misused for doping purposes, since – as is apparent from experience gained with peptide hormones (EPO, growth hormone) – abusers can gain access to them in clinical studies.
In this respect it should be noted that misuse of myostatin inhibitors, for example, is far less likely to occur in competitive sport than in recreational sport, most notably in the world of bodybuilding, and these new drugs have long been discussed and sought after in internet forums that cater to bodybuilders.
In the longer term, a potentially far more significant route of access than illegal appropriation of gene-modulating substances and techniques from clinical trials (or the sort of »designer« gene doping referred to above) could arise at the fringes of the treatment of age-related disabilities, e.g. the treatment of excessive muscle loss with (by then) licensed drugs. This area of medicine borders on and blends imperceptibly into what has become known as »enhancement«, i.e. the nontherapeutic use of lifestyle drugs to improve everyday performance, an increasingly discussed topic that is of considerable social and political relevance.
Detectability and Test Development
When strategies for preventing and combating doping are being devised, a key question is whether, and if so how, gene doping can be detected. Past experience suggests that reactive development of detection methods is quite inadequate as a means of combating doping effectively. The WADA responded to this problem some years ago by establishing an international program to promote research into methods of detecting gene doping.
Techniques of gene therapy or gene modulation are aimed either at inserting a gene or genetic element into specific somatic (body) cells and activating it, or else at activating or inhibiting an existing gene or genetic element. Where the inserted genetic or gene-regulating element is chemically different from the body’s natural substances, direct detection should be both possible and qualitatively sufficient. However, due to the rapid pace of development in this field and the variety and complexity of gene modulation, most experts believe that techniques for direct detection are likely to become less important, since it would be far too expensive to test for all possible forms of genetic manipulation.
Though theoretically plausible, approaches based on vector detection (in gene therapy procedures) pose a number of problems, e.g. the difficulty of distinguishing them from naturally occurring viruses. Detection of nonviral vectors (naked DNA, siRNA) is likely to be far more difficult because of the short biological half-life of nucleic acids. At present it is entirely unclear whether and how detection might be possible in the case of gene doping techniques where cells are removed from the body, genetically altered outside of the body, and then returned to the body (ex vivo techniques).
The vast majority of the 20 research projects currently being supported by the WADA are therefore aimed at identifying deviations from normal physiological conditions as indirect evidence of gene doping. This involves the determination of highly differentiated profiles of all sorts of molecules (DNA, RNA, proteins)in blood and tissue samples, so-called biomarkers or »molecular fingerprints«. The aim or strategy here is to develop an intelligent form of biomonitoring which provides unambiguous evidence of manipulated gene activity. This in itself might suffice as proof of tampering. This method might, however, also only allow an initial suspicion to be substantiated, requiring additional specific evidence in order to prove with reasonable analytic certainty that anti-doping regulations have been violated. The question as to whether the biomonitoring strategy will be successful in the long run cannot be answered at this time, since the relevant projects are in an early stage of development (for instance, the development of a specific practical test to determine overall myostatin activity is mentioned as an aim in just one project). There is, however, currently no alternative in sight.
Testing and Sanctions
Five years ago, as a precautionary measure, the WADA placed gene doping on the list of banned substances and methods (Prohibited List), which together with the World Anti-Doping Code (WADC) forms an important basis for measures employed by sports associations and national governments in their common fight against doping. All the defined violations of the WADC anti-doping regulations are applicable to gene doping. Self-administration, refusal to undergo testing, possession, trafficking, administration to others, and participation in various other activities are prohibited. Sports associations that have incorporated the WADC or NADA code for Germany into their statutes have thereby formally prohibited their members from engaging in gene doping. This is true of large sections of competitive sport, but not of individual sports activities such as those practiced at fitness clubs and the like.
The Prohibited List has also been incorporated into German law. The German Drug Law (Arzneimittelgesetz, AMG) forbids trafficking in substances on the Prohibited List, prescribing them, or administering them to others for doping purposes in sport (including any attempt at such actions). The same applies to substances required for use in the methods listed [including gene doping; § 6, no. 2, AMG]. However, there is no reference to § 4, no. 9, AMG which, defines gene transfer agents as medicinal products.
In the particular case of gene doping, the principal problem will lie not so much in prohibiting actions as in monitoring compliance with the prohibition and obtaining proof of violations that will stand up in a court of law (problem of enforcement). The main tool available to sports associations for monitoring compliance with these prohibitions is that of doping tests. The most reliable evidence that can be obtained by sports organizations is to be found in samples of body tissues and fluids on the basis of which a prohibited act can be demonstrated using detection methods that provide a sufficient degree of certainty. The state enjoys broader investigative authority. Since doping tests violate the individual rights of the athlete, the nature of the prohibited act must be formulated in a sufficiently precise manner (principle of clarity and definiteness). From the legal perspective it is doubtful whether the present definition of gene doping satisfies this requirement.
Detection of gene doping is likely to prove far more demanding than in the case of current doping practices. If gene doping is to be detected, the present system of in-competition and out-of-competition testing will need to be expanded. If it is necessary to take more blood samples or indeed tissue samples, the sampling requirements increase considerably. Since this bears on the personal rights of the athlete, the legality of the procedure must be well-founded as a matter of principle. This is probably possible only if a violation can be detected with sufficient certainty – i.e. if there is a test able to stand up in a court of law. All in all, as a result of gene doping the entire process of detecting gene doping will place even greater demands on sport jurisdiction than is the case with current doping practices.
The state has the capacity to assist organized sport in the pursuit of cases of gene doping. The setting up and training of special police units and specialized public prosecutor’s offices for effective criminal prosecution of offenders, clearly defined contact routes and contact persons, and closer cooperation between prosecuting authorities and other relevant entities and individuals (science, sport, pharmaceutical manufacturers) are already important means for combating conventional doping and will be indispensable in the fight against gene doping.
Since these repressive measures in the fight against gene doping will be very expensive and are still beset by a number of unresolved legal issues, they are by themselves unlikely to act as an effective deterrent against gene doping and will need to be supplemented by strategies to prevent gene doping from occurring in the first place.
Table 1: Doping Violations and the Regimen of Sanctions in Germany
Social Aspects of Doping
Doping is an act of an individual in a social context. Like other rule-breaking behavior, it is the outcome of individual developmental processes and conscious decisions. In view of the magnitude that doping has assumed in sport, however, it is not sufficient to point the finger at the deviant behavior of individual athletes. Rather, to gain a comprehensive understanding of doping activity it is important to consider its social contexts. These include, for instance, the global commercialization of competitive and top-level sport. Sport itself has become a business and for many athletes a professional career. This has been promoted by the media and the expectations of a global audience, which also intensify the process of commodization of athletic performance. This makes winning »at any price« all the more important. The dominance of the performance imperative, together with the prospect of profits, gives rise to structures that are receptive to any means of improving performance.
In the system of sport, sports associations are the entities that seek to mediate between the demands for performance and success surrounding the athlete – politics, the media, sponsors, the public – on the one hand and the athlete him/herself on the other. They promote their athletes’ willingness and capacity to perform, and they organize competitions to test performance. Their position and their influence on the overall course of events depend on the success of their athletes. Hence, like the athletes, they too are caught in a kind of »doping trap«. They must satisfy demands for clean, rule-abiding competitive sport by taking an active role in the fight against doping. But by testing and sanctioning, they tend to jeopardize their athletes’ success. Much of what the sports associations do or fail to do with regard to doping can be better understood by considering their involvement in the »system logic« of competitive sport.
However, the diagnosis of structural involvement in doping activity is true not only of athletes, sports physicians, and organizations, but also of governmental entities. They promote sport because they are interested in success, but they also support structures for detecting and punishing doping and establish prohibitions and statutory offences in legal codes. Yet the success of anti-doping activities could mean a lack of success on the part of national athletes – possibly also because doping practices of foreign competitors are not countered with equal vigor.
Overall, doping must be understood as a product of specific social structures. By acting or failing to act, many actors have contributed to a system of organized irresponsibility. As a collectively engendered problem, the widespread practice of doping can only be solved through common action at multiple levels. Given the structures that have evolved over many years, optimism is out of place here. However, the considerable problems of credibility in competitive sport could certainly usher in effective curbing of doping practices. Gene doping could thus act as a warning sign, promote insights into the potential danger of doping for sport, and aid in the process of reorientation.
Need for Information and Action
Gene doping means entering a political sphere characterized by incomplete and uncertain knowledge coupled with an urgent need for action. The following actions could form the elements of a specific anti-gene-doping strategy.
Screening of biomedical and pharmaceutical Development Projects focusing on their rRlevance to Gene Doping
Gene doping misuses knowledge from basic and/or applied research in the life sciences that was intended to lead to new therapeutic strategies. Continuous predictive monitoring of biomedical and pharmaceutical development projects and of the potential demand side could provide strategically important information. This could become a kind of early warning system, providing guidance for those involved in the fight against doping and preventive doping research. A willingness on the part of the industry to cooperate in this area would be helpful.
Investigating Detectability, developing Tests, designing intelligent Monitoring Systems
There is a great need for research and development work in the detection of gene doping as a key element in the monitoring and sanctions system. A two-step approach currently appears to be the most promising. It covers intelligent monitoring and, where there are grounds for suspicion, specific tests for verification. This kind of monitoring requires both specialized (what parameters measured at what intervals provide evidence of doping-induced physiologic abnormalities?) and legal clarification with regard not only to sanctioning but also data protection and personal protection.
Concepts and Activities for public Information Campaigns specific to Gene Doping
In parallel with the further development of testing and sanctioning structures, independent public information campaigns focusing on gene doping must be devised. For these to have a preventive effect, a broad concept is needed which covers the whole process of individual sports development during which mentalities and attitudes favorable to doping can gradually arise. Such an approach should take into consideration both the athlete’s immediate milieu (trainers, managers, physicians) and the role of sponsors and the media.
Adapting funding Policies
In the context of the public funding of sport, those receiving financial support are now required to adhere to the rules set down by the WADA and NADA. To this extent, gene doping is covered. Repayment of financial support in the event of violations, however, requires proof that will stand up in court. Here again detection proves to be the Achilles heel. Nevertheless, the demand for compliance with anti-doping rules should be upheld in any case and, indeed, applied even more stringently to gene doping. To this extent, the state could serve as a role model for private-sector sponsorship in its funding activities.
German Drug Law: Checking its Applicability and further statutory Offences
The German Gesetz zur Verbesserung der Bekämpfung des Dopings im Sport (Law to Improve the Fight against Doping in Sport) has created better conditions for the prosecution of doping, particularly in the athlete’s own milieu. However, the legislature must investigate whether and, if so, how these and other legal norms will be adapted to the dynamics of scientific and technical progress and doping practice. For example, gene doping could be more clearly defined as a prohibited act in order to satisfy the principle of clarity and definiteness. Given the recent extension of the definition of doping to include any substance intended for use in conjunction with prohibited methods, it should be possible to include substances relevant to gene doping. To satisfy the principle of clarity and definiteness, for instance, reference could be made in § 6a, nos. 2 and 2a AMG to § 4, no. 9a, AMG. In this way, the use of gene transfer agents for the purpose of gene doping could be prohibited. Furthermore, it should be considered whether the constituent element »nicht geringe Menge« (= more than a small amount) is even valid for gene doping or whether instead any medically unindicated use of gene transfer agents in humans should be made a punishable offence.
Parliamentary Technology Impact Assessment
The relevance of gene doping stems not only from its significance as a factor that will probably intensify the problem of doping in sport. Rather, it reflects a general social trend towards the use of pharmaceutical agents to manipulate physical and psychological performance. »Routine doping« or »enhancement« is a topical subject that will continue to be relevant to technology impact evaluation and the select committees of the German Bundestag in the future.