Gene doping

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gene therapy

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, [1] [2] and for reasons other than the treatment of disease. As of April 2015, there is no evidence that gene doping has been used for athletic performance-enhancement in any sporting events. [1] 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. [1]

Contents

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. [3]

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. [4] 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. [4] 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. [5] 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. [5]

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. [4] [6] 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. [7]

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. [7] [8] 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". [7]

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. [4] The scientists from that company also received calls from athletes and coaches. [4] In that same year the World Anti-Doping Agency held its first meeting to discuss the risk of gene doping, [7] [9] and the US President's Council on Bioethics discussed gene doping in the context of human enhancement at several sessions. [10] [11] [12]

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, [13] but children in France who had seemingly been effective treated with gene therapy for severe combined immunodeficiency (non-human) began developing leukemia. [6] In 2003 the BALCO scandal became public, in which chemists, trainers and athletes conspired to evade doping controls with new and undetectable doping substances. [7] In 2003 the World Doping Agency proactively added gene doping to the list of banned doping practices. [4] Also in 2003, a symposium convened by the American Association for the Advancement of Science focused on the issue. [14]

Research published in 2004 showing 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. [4] 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. [4] [9]

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. [4] [5] This was the first public disclosure that athletes were interested in gene doping. [4]

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. [15] [16]

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. [17] [18]

As the field of gene therapy has developed, the risk of gene doping becoming a reality has increased with it. [6]

Agents used in gene doping

There are numerous genes of interest as agents for gene doping. [1] [19] [7] 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. [1] [19]

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. [6] [7]

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. [19] [20] 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. [19]

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. [6] This has been demonstrated in knockout mice lacking the gene that were dubbed "Schwarzenegger mice". [21] 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. [22] The advanced muscle growth continued after birth, and the boy could lift weights of 3 kg at the age of 4. [6] 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. [6]

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. [6] [23] Recent studies suggest it may be possible to introduce another EPO gene into an animal in order to increase EPO production endogenously. [22] 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. [22] However, the endogenous and transgene derived EPO elicited autoimmune responses in some animals in the form of severe anemia. [22]

Insulin-like growth factor 1

Insulin-like growth factor 1 is a protein involved in the mediation of the growth hormone. Administration of IGF-1 to mice has resulted in more muscle growth and quicker muscle and nerve regeneration. [19] [6] If athletes were to use this the sustained production of IGF-1 could cause heart disease and cancer. [19]

Others

Modulating the levels of proteins that affect psychology are also potential goals for gene doping; for example pain perception depends on endorphins and enkephalins, response to stress depends on BDNF, and an increase in synthesis of monamines could improve the mood of athletes. [19] Preproenkephalin has been administered via gene therapy using a replication-deficient herpes simplex virus, which targets nerves, to mice with results good enough to justify a Phase I clinical trial in people with terminal cancer with uncontrolled pain. [6] Adopting that approach for athletes would be problematic since the pain deadening would likely be permanent. [6]

VEGF has been tested in clinical trials to increase blood flow and has been considered as a potential gene doping agent; however long term follow up of the clinical trial subjects showed poor results. [6] The same is true of fibroblast growth factor. [6] Glucagon-like peptide-1 increases the amount of glucose in the liver and has been administered via gene therapy to the livers of mouse models of diabetes and was shown to increase gluconeogenesis' for athletes this would make more energy available and reduce the buildup of lactic acid. [6]

Detection

The World Anti-Doping Agency (WADA) is the main regulatory organization looking into the issue of the detection of gene doping. [9] Both direct and indirect testing methods are being researched by the organization. Directly detecting the use of gene therapy usually requires the discovery of recombinant proteins or gene insertion vectors, while most indirect methods involve examining the athlete in an attempt to detect bodily changes or structural differences between endogenous and recombinant proteins. [6] [24] [25]

Indirect methods are by nature more subjective, as it becomes very difficult to determine which anomalies are proof of gene doping, and which are simply natural, though unusual, biological properties. [6] For example, Eero Mäntyranta, an Olympic cross country skier, had a mutation which made his body produce abnormally high amounts of red blood cells. It would be very difficult to determine whether or not Mäntyranta's red blood cell levels were due to an innate genetic advantage, or an artificial one. [26]

First generation of gene doping detecting methods

Gene doping detection idea started in 2004 when WADA has put gene doping in the banned list and started investigating a new method that can detect the inserted transgenes.

The first generation of gene doping detection techniques used PCR tests that targets the transgenes’ sequences. It can be obtained from a blood sample which will contain endogenous and transgene DNA since a small amount of the transgene will leak into the bloodstream. It can be easily distinguished from endogenous DNA because it lacks introns since the transgene will most likely use cDNA that is obtained by reverse transcriptase from RNA, which has removed its intones though RNA splicing leaving only exon-exon junction that include only the coding sequences and some important sequences like promoters since the viral victors has a limited capacity. Therefore, PCR can target these exon-exon junctions as a unique sequence that is not present in gDNA [27]

Real time PCR

PCR has many applications in molecular biology field including DNA analysis. The main purpose of PCR is to amplify and double the DNA sequences exponentially.

In gene doping detection, If the sequence started to amplify producing an exponential graph, then the test is positive and indicates the presence of the gene in the sample obtained from that person. But if the sequence didn't amplify and a linear graph was produced, then the test is said to be negative and the targeted DNA sequence was not present in that person's sample. [28]

Next generation sequencing

With the limitation of the first-generation detection methods, it was important to develop a new method that overcomes the previous failures with a high accuracy and can detect the manipulation in DNA sequences that could evade to be detected by PCR methods.

The solution was using Next Generation Sequencing (NGS) method that can determine the nucleotide orders of the whole genome or targets the exon-exon junctions in transgene and compare it with reference gene sequence. This method is fast accurate and is getting cheaper by the time and has opened a new field in science that wasn't possible before like sequencing the whole genome sequencing. [29]

DNA sequencing was established in the 1970s with the two-dimensional chromatography and kept improving until 2001 with the completion of human genome project which costed about three billion dollars and required 15 years to finish sequencing the whole genome. However, with nowadays sequencing technology, whole genome sequencing (WGS) takes only a single day and costs around a thousand dollars. Moreover, a new sequencing technology is under development that will cost only 100 dollars for WGS. [30]

There are many NGS techniques that are used in DNA sequencing but the most used method is the one done by illumina [31]

Research

A 2016 review found that about 120 DNA polymorphisms had been identified in the literature related to some aspect of athletic performance, 77 related to endurance and 43 related to power. 11 had been replicated in three or more studies and six were identified in genome-wide association studies, but 29 had not been replicated in at least one study. [20]

The 11 replicated markers were: [20]

Endurance
power/strength markers

The six GWAS markers were: [20]

Ethics of gene doping

The World Anti-Doping Agency (WADA) determined that any non-therapeutic form of genetic manipulation for enhancement of athletic performance is banned under its code. There are guidelines to determine if said technology should be prohibited in sport: if two of the three conditions are met, then the technology is prohibited in sport (harmful to one's health, performance enhancing, and/or against the "spirit of sport"). [32]

Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports. [33]

The high risks associated with gene therapy can be outweighed by the potential of saving the lives of individuals with diseases: according to Alain Fischer, who was involved in clinical trials of gene therapy in children with severe combined immunodeficiency, "Only people who are dying would have reasonable grounds for using it. Using gene therapy for doping is ethically unacceptable and scientifically stupid." [34] As seen with past cases, including the steroid tetrahydrogestrinone (THG), athletes may choose to incorporate risky genetic technologies into their training regimes. [3]

The mainstream perspective is that gene doping is dangerous and unethical, as is any application of a therapeutic intervention for non-therapeutic or enhancing purposes, and that it compromises the ethical foundation of medicine and the spirit of sport. [4] [35] [36] [7] [37] Others, who support human enhancement on broader grounds, [38] or who see a false dichotomy between "natural" and "artificial" or a denial of the role of technology in improving athletic performance, do not oppose or support gene doping. [39]

See also

Related Research Articles

Molecular biology is a branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions.

<span class="mw-page-title-main">Polymerase chain reaction</span> Laboratory technique to multiply a DNA sample for study

The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA sufficiently to enable detailed study. PCR was invented in 1983 by American biochemist Kary Mullis at Cetus Corporation. Mullis and biochemist Michael Smith, who had developed other essential ways of manipulating DNA, were jointly awarded the Nobel Prize in Chemistry in 1993.

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.

<span class="mw-page-title-main">Molecular genetics</span> Scientific study of genes at the molecular level

Molecular genetics is a branch of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the structure and/or function of genes in an organism's genome using genetic screens. 

<span class="mw-page-title-main">Myostatin</span> Mammalian and avian protein

Myostatin is a protein that in humans is encoded by the MSTN gene. Myostatin is a myokine that is produced and released by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

<span class="mw-page-title-main">Human genetic enhancement</span> Technologies to genetically improve human bodies

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases, prevent the possibility of getting a particular disease, to improve athlete performance in sporting events, or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable.

Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.

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Repoxygen was the tradename for a type of gene therapy to produce erythropoietin (EPO). It was under preclinical development by Oxford Biomedica as a possible treatment for anaemia but was abandoned in 2003.

A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the phenotype of an organism. Transgene describes a segment of DNA containing a gene sequence that has been isolated from one organism and is introduced into a different organism. This non-native segment of DNA may either retain the ability to produce RNA or protein in the transgenic organism or alter the normal function of the transgenic organism's genetic code. In general, the DNA is incorporated into the organism's germ line. For example, in higher vertebrates this can be accomplished by injecting the foreign DNA into the nucleus of a fertilized ovum. This technique is routinely used to introduce human disease genes or other genes of interest into strains of laboratory mice to study the function or pathology involved with that particular gene.

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<span class="mw-page-title-main">Genetic engineering techniques</span> Methods used to change the DNA of organisms

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<span class="mw-page-title-main">Molecular diagnostics</span> Collection of techniques used to analyze biological markers in the genome and proteome

Molecular diagnostics is a collection of techniques used to analyze biological markers in the genome and proteome, and how their cells express their genes as proteins, applying molecular biology to medical testing. In medicine the technique is used to diagnose and monitor disease, detect risk, and decide which therapies will work best for individual patients, and in agricultural biosecurity similarly to monitor crop- and livestock disease, estimate risk, and decide what quarantine measures must be taken.

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