Jump to content

Gene doping: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
Tag: Redirect target changed
Tag: Removed redirect
Line 1: Line 1:
{{Doping in sport sidebar|expanded=Substances and types}}
#REDIRECT [[Human_genetic_enhancement#To_improve_athlete_performance_in_sporting_events_(gene_doping)]]
'''Gene doping''' is the hypothetical non-therapeutic use of [[gene therapy]] by athletes in order to improve their performance in those [[Sports competition|sporting events]] which prohibit such applications of genetic modification technology,<ref name="PEDs in sports review" /><ref>World Anti-Doping Agency [https://web.archive.org/web/20071030051804/http://www.wada-ama.org/rtecontent/document/2008_List_En.pdf The World Anti-Doping Code: The 2008 Prohibited List of International Standards] pages 7-8</ref> 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.<ref name="PEDs in sports review" /> Gene doping would involve the use of [[Transfection#Methods|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.<ref name="PEDs in sports review">{{cite journal | vauthors = Momaya A, Fawal M, Estes R | title = Performance-enhancing substances in sports: a review of the literature | journal = Sports Med. | volume = 45 | issue = 4 | pages = 517–531 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 | quote = }}</ref>


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 [[Peroxisome proliferator-activated receptor gamma|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.
{{Redirect category shell|

{{R from move}}
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.<ref name=Wells>Wells DJ. 2008. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2439520&tool=pmcentrez&rendertype=abstract "Gene doping: the hype and the reality"]. Br. J. Pharmacol. [Internet] 154:623–31.</ref>

===History of gene doping===
The history of concern about the potential for gene doping follows the [[Gene therapy#History|history of gene therapy]], the medical use of genes to treat diseases, which was first clinically tested in the 1990s.<ref name=Barry2008/> 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.<ref name=Barry2008/> The lab had been seeking treatments for [[Muscle atrophy|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.<ref name =NYT>Gretchen Reynolds for The New York Times. June 3, 2007. [https://www.nytimes.com/2007/06/03/sports/playmagazine/0603play-hot.html?_r=0 Outlaw DNA]</ref> 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.<ref name =NYT/>

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.<ref name=Barry2008/><ref name=GouldRev2013/> 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]].<ref name=GeneDoping2013rev/>

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.<ref name=GeneDoping2013rev/><ref>{{Cite journal|pmid= 11407894 |url=http://www.nature.com/mt/journal/v3/n6/pdf/mt2001106a.pdf|year=2001|last1=Friedmann|first1=T|title=Gene transfer and athletics- an impending problem|journal=Molecular Therapy|volume=3|issue=6|pages=819–20|last2=Koss|first2=J. O.|doi=10.1006/mthe.2001.0347}}</ref> 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".<ref name=GeneDoping2013rev/>

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]].<ref name=Barry2008/> The scientists from that company also received calls from athletes and coaches.<ref name=Barry2008/> In that same year the [[World Anti-Doping Agency]] held its first meeting to discuss the risk of gene doping,<ref name=GeneDoping2013rev/><ref name ="WADA"/> and the US [[President's Council on Bioethics]] discussed gene doping in the context of [[human enhancement]] at several sessions.<ref>President's Council on Bioethics [https://bioethicsarchive.georgetown.edu/pcbe/transcripts/apr02/index.html April 25-26, 2002 Agenda, [https://bioethicsarchive.georgetown.edu/pcbe/background/workpaper7.html Working Paper 7]</ref><ref>President's Council on Bioethics [https://bioethicsarchive.georgetown.edu/pcbe/transcripts/jul02/index.html July 11-12, 2002 Meeting Agenda] [https://bioethicsarchive.georgetown.edu/pcbe/transcripts/jul02/session4.html Session 4]</ref><ref>President's Council on Bioethics [https://bioethicsarchive.georgetown.edu/pcbe/transcripts/sep02/index.html September 12-13, 2002 Meeting Agenda] [https://bioethicsarchive.georgetown.edu/pcbe/transcripts/sep02/session7.html Session 7: Enhancement 5: Genetic Enhancement of Muscle], H. Lee Sweeney, Ph.D., Professor and Chairman of Physiology, University of Pennsylvania</ref>

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,<ref name="Gend">{{cite journal|title=China approves first gene therapy|journal=Nature Biotechnology|year=2004|volume=22|issue=1|pages=3–4|doi=10.1038/nbt0104-3|pmid=14704685|last1=Pearson|first1=Sue|last2=Jia|first2=Hepeng|last3=Kandachi|first3=Keiko|pmc=7097065}}</ref> but children in France who had seemingly been effective treated with gene therapy for [[severe combined immunodeficiency (non-human)]] began developing leukemia.<ref name=GouldRev2013/> In 2003 the [[BALCO scandal]] became public, in which chemists, trainers and athletes conspired to evade doping controls with new and undetectable doping substances.<ref name=GeneDoping2013rev/> In 2003 the World Doping Agency proactively added gene doping to the list of banned doping practices.<ref name=Barry2008/> Also in 2003, a symposium convened by the [[American Association for the Advancement of Science]] focused on the issue.<ref>UCSD Public Relations: February 18, 2003 [http://ucsdnews.ucsd.edu/archive/newsrel/health/friedmann0218.htm News Release: Bigger, Faster, Stronger: Genetic Enhancement and Athletics]</ref>

Research published in 2004 showing that mice given gene therapy coding for a protein called [[Peroxisome proliferator-activated receptor gamma|PPAR gamma]] had about double the endurance of untreated mice and were dubbed "marathon mice"; those scientists received calls from athletes and coaches.<ref name=Barry2008/> 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.<ref name=Barry2008/><ref name ="WADA"/>

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.<ref name=Barry2008/><ref name =NYT/> This was the first public disclosure that athletes were interested in gene doping.<ref name=Barry2008/>

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]].<ref>AdisInsight [http://adisinsight.springer.com/drugs/800041695 Vascular endothelial growth factor gene therapy - HSCI] Page accessed June 5, 2016</ref><ref name="Neuvasculgen">{{cite news|title=Gene Therapy for PAD Approved|url=http://www.dddmag.com/news/2011/12/gene-therapy-pad-approved|accessdate=5 August 2015|date=6 December 2011}}</ref>

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.<ref name=Richards2012>{{cite web|last=Richards|first=Sabrina|title=Gene Therapy Arrives in Europe|url=http://www.the-scientist.com/?articles.view/articleNo/33166/title/Gene-Therapy-Arrives-in-Europe/|work=The Scientist|date=6 November 2012}}</ref><ref name=Gallagher>Gallagher, James. (2 November 2012) [https://www.bbc.co.uk/news/health-20179561 BBC News – Gene therapy: Glybera approved by European Commission]. BBC. Retrieved 15 December 2012.</ref>

As the field of gene therapy has developed, the risk of gene doping becoming a reality has increased with it.<ref name=GouldRev2013/>

=== Agents used in gene doping===
There are numerous genes of interest as agents for gene doping.<ref name="PEDs in sports review" /><ref name=Birzniece2015>{{Cite journal|pmid=25369881|year=2015|last1=Birzniece|first1=V|s2cid=4983625|title=Doping in sport: Effects, harm and misconceptions|journal=Internal Medicine Journal|volume=45|issue=3|pages=239–48|doi=10.1111/imj.12629}}</ref><ref name=GeneDoping2013rev>{{Cite journal|pmid= 23322893|year= 2013|last1= Van Der Gronde|first1= T|title= Gene doping: An overview and current implications for athletes|journal= British Journal of Sports Medicine|volume= 47|issue= 11|pages= 670–8|last2= De Hon|first2= O|last3= Haisma|first3= H. J.|last4= Pieters|first4= T|doi= 10.1136/bjsports-2012-091288}}</ref> They include [[erythropoietin]], [[insulin-like growth factor 1]], [[human growth hormone]], [[myostatin]], [[vascular endothelial growth factor]], [[fibroblast growth factor]], [[endorphin]], [[enkephalin]] and [[ACTN3|alpha-actinin-3]].<ref name="PEDs in sports review" /><ref name=Birzniece2015/>

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.<ref name=GouldRev2013/><ref name=GeneDoping2013rev/>

====Alpha-actinin-3====
[[ACTN3|Alpha-actinin-3]] is found only in [[skeletal muscle]] in humans, and has been identified in several genetic studies as having a different [[Genetic polymorphism|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.<ref name=Birzniece2015/><ref name=2016revGenetics/> 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]].<ref name=Birzniece2015/>

==== Myostatin ====
{{see also|Myostatin-related muscle hypertrophy}}
[[Myostatin]] is a [[protein]] responsible for inhibiting [[muscle]] differentiation and growth. Removing the myostatin [[gene]] or otherwise limiting its [[gene expression|expression]] leads to an increase in muscle size and power.<ref name=GouldRev2013/> This has been demonstrated in [[knockout mouse|knockout mice]] lacking the gene that were dubbed "[[Schwarzenegger]] mice".<ref name="DopInSport">{{Cite journal|url=http://biologyofexercise.com/images/issues/51.pdf|doi=10.4127/jbe.2009.0021|title=Gene doping in modern sport|journal=Journal Biology of Exercise|volume=5|year=2009|last1=Cieszczyk|first1=Pawel|last2=MacIejewska|first2=Agnieszka|last3=Sawczuk|first3=Marek}}</ref> 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.<ref name="Haisma">{{Cite journal|pmid=6572366|pmc=393457|year=1983|last1=Gavish|first1=B|title=Adiabatic compressibility of globular proteins|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=80|issue=3|pages=750–4|last2=Gratton|first2=E|last3=Hardy|first3=C. J.|doi=10.1073/pnas.80.3.750|bibcode=1983PNAS...80..750G}}</ref> The advanced muscle growth continued after birth, and the boy could lift weights of 3&nbsp;kg at the age of 4.<ref name=GouldRev2013/> 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.<ref name=GouldRev2013/>

==== 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.<ref name=GouldRev2013>{{Cite journal|pmc=3731603|year=2012|last1=Gould|first1=D|title=Gene doping: Gene delivery for olympic victory|journal=British Journal of Clinical Pharmacology|volume=76|issue=2|pages=292–298|doi=10.1111/bcp.12010|pmid=23082866}}</ref><ref>{{Cite journal|pmid= 16180943|year= 2005|last1= Diamanti-Kandarakis|first1= E|title= Erythropoietin abuse and erythropoietin gene doping: Detection strategies in the genomic era|journal= Sports Medicine|volume= 35|issue= 10|pages= 831–40|last2= Konstantinopoulos|first2= P. A.|last3= Papailiou|first3= J|last4= Kandarakis|first4= S. A.|last5= Andreopoulos|first5= A|last6= Sykiotis|first6= G. P.|doi=10.2165/00007256-200535100-00001}}</ref> Recent studies suggest it may be possible to introduce another EPO gene into an animal in order to increase EPO production [[endogenous]]ly.<ref name="Haisma"/> EPO genes have been successfully inserted into mice and [[monkey]]s, and were found to increase [[hematocrit]]s by as much as 80 percent in those animals.<ref name="Haisma"/> However, the endogenous and [[transgene]] derived EPO elicited [[autoimmune]] responses in some animals in the form of severe [[anemia]].<ref name="Haisma"/>

==== 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.<ref name=Birzniece2015/><ref name=GouldRev2013/> If athletes were to use this the sustained production of IGF-1 could cause heart disease and cancer.<ref name=Birzniece2015/>

====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 [[Monoamine neurotransmitter|monamines]] could improve the mood of athletes.<ref name=Birzniece2015/> [[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.<ref name=GouldRev2013/> Adopting that approach for athletes would be problematic since the pain deadening would likely be permanent.<ref name=GouldRev2013/>

[[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.<ref name=GouldRev2013/> The same is true of [[fibroblast growth factor]].<ref name=GouldRev2013/> [[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]].<ref name=GouldRev2013/>

=== Detection ===
The [[World Anti-Doping Agency]] (WADA) is the main [[regulation|regulatory]] organization looking into the issue of the detection of gene doping.<ref name ="WADA">World Anti Doping Agency. [https://web.archive.org/web/20160107013459/https://www.wada-ama.org/en/gene-doping Gene Doping] Page archived January 7, 2016</ref> 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 DNA|recombinant proteins]] or gene insertion [[Vector (molecular biology)|vectors]], while most indirect methods involve examining the athlete in an attempt to detect bodily changes or structural differences between [[endogenous]] and recombinant proteins.<ref name=GouldRev2013/><ref name = "Brazil">{{Cite journal|pmid=22030863 |url=http://www.scielo.br/pdf/bjmbr/v44n12/1177.pdf|year=2011|last1=Oliveira|first1=R. S.|title=The use of genes for performance enhancement: Doping or therapy?|journal=Brazilian Journal of Medical and Biological Research|volume=44|issue=12|pages=1194–201|last2=Collares|first2=T. F.|last3=Smith|first3=K. R.|last4=Collares|first4=T. V.|last5=Seixas|first5=F. K.|doi=10.1590/s0100-879x2011007500145}}</ref><ref name=PerezRev2013>{{Cite journal|pmid= 23912835|year= 2013|last1= Perez|first1= I. C.|title= PCR-based detection of gene transfer vectors: Application to gene doping surveillance|journal= Analytical and Bioanalytical Chemistry|volume= 405|issue= 30|pages= 9641–53|last2= Le Guiner|first2= C|last3= Ni|first3= W|last4= Lyles|first4= J|last5= Moullier|first5= P|last6= Snyder|first6= R. O.|doi= 10.1007/s00216-013-7264-8}}</ref>

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.<ref name=GouldRev2013/> For example, [[Eero Mäntyranta]], an [[Olympic Games|Olympic]] [[Cross-country skiing|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.<ref name = "SciAm">{{cite journal | last1 = Sweeney | first1 = H.L. | year = 2004 | title = Gene Doping | url =https://www.scientificamerican.com/article/gene-doping/ | journal = Scientific American | volume = 291| issue = 1| pages = 63–69| doi = 10.1038/scientificamerican0704-62 | pmid = 15255589 |archiveurl=https://web.archive.org/web/20051113090004/http://www.sciam.com/print_version.cfm?articleID=000E7ACE-5686-10CF-94EB83414B7F0000|archivedate=13 November 2005 }}</ref>

===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.<ref name=2016revGenetics>{{Cite book|pmid= 26231489|id=review|year=2015|last1=Ahmetov|first1=I. I.|title=Current Progress in Sports Genomics|volume=70|pages=247–314|last2=Fedotovskaya|first2=O. N.|doi=10.1016/bs.acc.2015.03.003|series=Advances in Clinical Chemistry|isbn=9780128033166}}</ref>

The 11 replicated markers were:<ref name=2016revGenetics/>
;Endurance:
* [[Angiotensin-converting enzyme|ACE]] Alu I/D (rs4646994) (Called ACE I)
* [[ACTN3]] 577X
* [[PPARA]] rs4253778 G,
* [[PPARGC1A]] Gly482;
; power/strength markers:
* [[Angiotensin-converting enzyme|ACE]] Alu I/D (rs4646994) (called ACE D)
* [[ACTN3]] Arg577
* [[AMPD1]] Gln12
* [[HIF1A]] 582Ser
* [[MTHFR]] rs1801131 C
* [[NOS3]] rs2070744 T
* [[PPARG]] 12Ala

The six GWAS markers were:<ref name=2016revGenetics/>
* [[CAMP responsive element modulator|CREM]] rs1531550 A,
* [[Dystrophin|DMD]] rs939787 T
* [[GALNT13]] rs10196189 G
* [[NFIA]]-AS1 rs1572312 C,
* [[RBFOX1]] rs7191721 G
* [[TSHR]] rs7144481 C

=== 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").<ref name=Miah>{{cite journal|last1=Miah|first1=A|s2cid=840205|title=Rethinking enhancement in sport.|journal=Annals of the New York Academy of Sciences|date=December 2006|volume=1093|issue=1|pages=301–20|doi=10.1196/annals.1382.020|pmid=17312265|bibcode=2006NYASA1093..301M}}</ref>

Kayser et al. argue that gene doping could [[Level playing field|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.<ref>{{cite journal | vauthors = Kayser B, Mauron A, Miah A | title = Current anti-doping policy: a critical appraisal | journal = BMC Medical Ethics | volume = 8 | pages = 2 | date = March 2007 | pmid = 17394662 | pmc = 1851967 | doi = 10.1186/1472-6939-8-2 }}</ref>

The high risks associated with gene therapy can be outweighed by the potential save 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."<ref name=Filipp2007>{{cite journal|last1=Filipp|first1=F|title=Is science killing sport? Gene therapy and its possible abuse in doping.|journal=EMBO Reports|date=May 2007|volume=8|issue=5|pages=433–5|pmid=17471256|pmc=1866212|doi=10.1038/sj.embor.7400968}}</ref> As seen with past cases, including the steroid tetrahydrogestrinone ([[Tetrahydrogestrinone|THG]]), athletes may choose to incorporate risky genetic technologies into their training regimes.<ref name=Wells/>

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.<ref name=Barry2008>{{cite journal|last1=Barry|first1=Patrick|title=Finding the Golden Genes|journal=Science News|date=2008|volume=174|issue=3|pages=16–21|jstor=20494726|doi=10.1002/scin.2008.5591740321}}</ref><ref>{{Cite journal | last1 = Kayser | first1 = B. | last2 = Mauron | first2 = A. | last3 = Miah | first3 = A. | title = Current anti-doping policy: A critical appraisal | doi = 10.1186/1472-6939-8-2 | journal = BMC Medical Ethics | volume = 8 | pages = 2 | year = 2007 | pmid = 17394662| pmc =1851967 }}</ref><ref name=FriedmannSci2010>{{Cite journal|url= http://www.aaas.org/sites/default/files/migrate/uploads/Science-2010-Friedmann-647-8.pdf|pmid= 20133558|year= 2010|last1= Friedmann|first1= T|title= Ethics. Gene doping and sport|journal= Science|volume= 327|issue= 5966|pages= 647–8|last2= Rabin|first2= O|last3= Frankel|first3= M. S.|doi= 10.1126/science.1177801|access-date= 2016-06-06|archive-url= https://web.archive.org/web/20160806141354/http://www.aaas.org/sites/default/files/migrate/uploads/Science-2010-Friedmann-647-8.pdf|archive-date= 2016-08-06|url-status= dead}}</ref><ref name=GeneDoping2013rev/><ref>{{Cite journal|pmid= 20391845|year= 2010|last1= Friedmann|first1= T|title= How close are we to gene doping?|journal= The Hastings Center Report|volume= 40|issue= 2|pages= 20–2|doi=10.1353/hcr.0.0246}}</ref> Others, who support [[human enhancement]] on broader grounds,<ref name="Miah 2004">{{cite book| author = Miah, Andy| title = Genetically Modified Athletes: Biomedical Ethics, Gene Doping and Sport| publisher = Routledge| year = 2004| isbn = 978-0-415-29880-3| author-link = Andy Miah}}</ref> 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.<ref>{{cite journal|last1=van Hilvoorde|first1=Ivo|last2=Vos|first2=Rein|last3=de Wert|first3=Guido|title=Flopping, Klapping and Gene Doping: Dichotomies Between 'Natural' and 'Artificial' in Elite Sport|journal=Social Studies of Science|date=1 April 2007|volume=37|issue=2|pages=173–200|doi=10.1177/0306312706063784|language=en|issn=0306-3127|url=https://research.vu.nl/ws/files/3047279/280266.pdf}}</ref>

Revision as of 11:37, 27 October 2020

Part of a series on
Doping in sport
White pillsA Hypodermic needle
Substances and types
Terminology
History
Doping-related lists
Anti-doping bodies

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]

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

See also: Myostatin-related muscle hypertrophy

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]

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").[27]

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.[28]

The high risks associated with gene therapy can be outweighed by the potential save 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."[29] 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][30][31][7][32] Others, who support human enhancement on broader grounds,[33] 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.[34]

  1. ^ a b c d e Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250.
  2. ^ World Anti-Doping Agency The World Anti-Doping Code: The 2008 Prohibited List of International Standards pages 7-8
  3. ^ a b Wells DJ. 2008. "Gene doping: the hype and the reality". Br. J. Pharmacol. [Internet] 154:623–31.
  4. ^ a b c d e f g h i j k Barry, Patrick (2008). "Finding the Golden Genes". Science News. 174 (3): 16–21. doi:10.1002/scin.2008.5591740321. JSTOR 20494726.
  5. ^ a b c Gretchen Reynolds for The New York Times. June 3, 2007. Outlaw DNA
  6. ^ a b c d e f g h i j k l m n o p Gould, D (2012). "Gene doping: Gene delivery for olympic victory". British Journal of Clinical Pharmacology. 76 (2): 292–298. doi:10.1111/bcp.12010. PMC 3731603. PMID 23082866.
  7. ^ a b c d e f g h Van Der Gronde, T; De Hon, O; Haisma, H. J.; Pieters, T (2013). "Gene doping: An overview and current implications for athletes". British Journal of Sports Medicine. 47 (11): 670–8. doi:10.1136/bjsports-2012-091288. PMID 23322893.
  8. ^ Friedmann, T; Koss, J. O. (2001). "Gene transfer and athletics- an impending problem" (PDF). Molecular Therapy. 3 (6): 819–20. doi:10.1006/mthe.2001.0347. PMID 11407894.
  9. ^ a b c World Anti Doping Agency. Gene Doping Page archived January 7, 2016
  10. ^ President's Council on Bioethics April 25-26, 2002 Agenda, [https://bioethicsarchive.georgetown.edu/pcbe/background/workpaper7.html Working Paper 7
  11. ^ President's Council on Bioethics July 11-12, 2002 Meeting Agenda Session 4
  12. ^ President's Council on Bioethics September 12-13, 2002 Meeting Agenda Session 7: Enhancement 5: Genetic Enhancement of Muscle, H. Lee Sweeney, Ph.D., Professor and Chairman of Physiology, University of Pennsylvania
  13. ^ Pearson, Sue; Jia, Hepeng; Kandachi, Keiko (2004). "China approves first gene therapy". Nature Biotechnology. 22 (1): 3–4. doi:10.1038/nbt0104-3. PMC 7097065. PMID 14704685.
  14. ^ UCSD Public Relations: February 18, 2003 News Release: Bigger, Faster, Stronger: Genetic Enhancement and Athletics
  15. ^ AdisInsight Vascular endothelial growth factor gene therapy - HSCI Page accessed June 5, 2016
  16. ^ "Gene Therapy for PAD Approved". 6 December 2011. Retrieved 5 August 2015.
  17. ^ Richards, Sabrina (6 November 2012). "Gene Therapy Arrives in Europe". The Scientist.
  18. ^ Gallagher, James. (2 November 2012) BBC News – Gene therapy: Glybera approved by European Commission. BBC. Retrieved 15 December 2012.
  19. ^ a b c d e f g Birzniece, V (2015). "Doping in sport: Effects, harm and misconceptions". Internal Medicine Journal. 45 (3): 239–48. doi:10.1111/imj.12629. PMID 25369881. S2CID 4983625.
  20. ^ a b c d Ahmetov, I. I.; Fedotovskaya, O. N. (2015). Current Progress in Sports Genomics. Advances in Clinical Chemistry. Vol. 70. pp. 247–314. doi:10.1016/bs.acc.2015.03.003. ISBN 9780128033166. PMID 26231489. review.
  21. ^ Cieszczyk, Pawel; MacIejewska, Agnieszka; Sawczuk, Marek (2009). "Gene doping in modern sport" (PDF). Journal Biology of Exercise. 5. doi:10.4127/jbe.2009.0021.
  22. ^ a b c d Gavish, B; Gratton, E; Hardy, C. J. (1983). "Adiabatic compressibility of globular proteins". Proceedings of the National Academy of Sciences of the United States of America. 80 (3): 750–4. Bibcode:1983PNAS...80..750G. doi:10.1073/pnas.80.3.750. PMC 393457. PMID 6572366.
  23. ^ Diamanti-Kandarakis, E; Konstantinopoulos, P. A.; Papailiou, J; Kandarakis, S. A.; Andreopoulos, A; Sykiotis, G. P. (2005). "Erythropoietin abuse and erythropoietin gene doping: Detection strategies in the genomic era". Sports Medicine. 35 (10): 831–40. doi:10.2165/00007256-200535100-00001. PMID 16180943.
  24. ^ Oliveira, R. S.; Collares, T. F.; Smith, K. R.; Collares, T. V.; Seixas, F. K. (2011). "The use of genes for performance enhancement: Doping or therapy?" (PDF). Brazilian Journal of Medical and Biological Research. 44 (12): 1194–201. doi:10.1590/s0100-879x2011007500145. PMID 22030863.
  25. ^ Perez, I. C.; Le Guiner, C; Ni, W; Lyles, J; Moullier, P; Snyder, R. O. (2013). "PCR-based detection of gene transfer vectors: Application to gene doping surveillance". Analytical and Bioanalytical Chemistry. 405 (30): 9641–53. doi:10.1007/s00216-013-7264-8. PMID 23912835.
  26. ^ Sweeney, H.L. (2004). "Gene Doping". Scientific American. 291 (1): 63–69. doi:10.1038/scientificamerican0704-62. PMID 15255589. Archived from the original on 13 November 2005.
  27. ^ Miah, A (December 2006). "Rethinking enhancement in sport". Annals of the New York Academy of Sciences. 1093 (1): 301–20. Bibcode:2006NYASA1093..301M. doi:10.1196/annals.1382.020. PMID 17312265. S2CID 840205.
  28. ^ Kayser B, Mauron A, Miah A (March 2007). "Current anti-doping policy: a critical appraisal". BMC Medical Ethics. 8: 2. doi:10.1186/1472-6939-8-2. PMC 1851967. PMID 17394662.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  29. ^ Filipp, F (May 2007). "Is science killing sport? Gene therapy and its possible abuse in doping". EMBO Reports. 8 (5): 433–5. doi:10.1038/sj.embor.7400968. PMC 1866212. PMID 17471256.
  30. ^ Kayser, B.; Mauron, A.; Miah, A. (2007). "Current anti-doping policy: A critical appraisal". BMC Medical Ethics. 8: 2. doi:10.1186/1472-6939-8-2. PMC 1851967. PMID 17394662.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  31. ^ Friedmann, T; Rabin, O; Frankel, M. S. (2010). "Ethics. Gene doping and sport" (PDF). Science. 327 (5966): 647–8. doi:10.1126/science.1177801. PMID 20133558. Archived from the original (PDF) on 2016-08-06. Retrieved 2016-06-06.
  32. ^ Friedmann, T (2010). "How close are we to gene doping?". The Hastings Center Report. 40 (2): 20–2. doi:10.1353/hcr.0.0246. PMID 20391845.
  33. ^ Miah, Andy (2004). Genetically Modified Athletes: Biomedical Ethics, Gene Doping and Sport. Routledge. ISBN 978-0-415-29880-3.
  34. ^ van Hilvoorde, Ivo; Vos, Rein; de Wert, Guido (1 April 2007). "Flopping, Klapping and Gene Doping: Dichotomies Between 'Natural' and 'Artificial' in Elite Sport" (PDF). Social Studies of Science. 37 (2): 173–200. doi:10.1177/0306312706063784. ISSN 0306-3127.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Gene_doping&oldid=985692494"