The age of gene-doping is here!
Recent advances in human genome research will soon make it easy to go shopping for tailor-made cardiovascular systems and muscles to suite your sport. According to some, even as we speak, athletes may already be ‘doing it’ (in fact, since the Beijing Olympics in 2008!).
Mention of gene doping (as a prohibited method) appeared in WADA’s banned anti-doping list for the first time in 2003. (To download the 2012 list of banned substance, click here – please look under M3 (banned method 3) for gene doping).
The list mentions that gene doping – with the potential to enhance sport performance – remains banned. This includes the following methods:
1. Transfer of nucleic acids or nucleic acid sequences
2. Use of normal or genetically modified cells
This novel technique has the potential to drastically (and permanently) change performance enhancement for sports. In a world with rampant gene doping, tablets and capsules will be history. Furthermore, most doping tests (as we know them) will be rendered defunct. As the science behind gene doping gets more hi-tech, it will become increasing difficult to differentiate between the ‘gene-cheats’ and the ‘gene-freaks-of-nature’.
What Is Gene Doping?
So, what is gene doping and how does it enhance performance?
To know the answer, let’s have a closer look at the science behind it all:
A gene is a snippet of human DNA containing information (genotype) which is used to produce individual characteristics (phenotypes) like blue eyes, black hair and so on. In nature, these pieces of information are handed down by parents to their offsprings. However, advances in science has now made ‘gene tampering’ a reality.
Scientists working on the human genome have been able to separate specific genes coding for hormones and growth factors which can specifically enhance performance in elite athletes.
Some of these are:
a. Human growth hormone gene
Human growth hormone (hGH) produced by the anterior pituitary serves the following functions:
• anabolism (gain of lean muscle mass) by increased protein deposition and retention
• lipolysis (break down of fats)
Methods of hGH doping are administration of recombinant hGH, precursors or secretogogues.
In addition, gene manipulation for muscle growth by inducing hGH secretion is a rapidly emerging technique1. Administration of a recombinant adenovirus encoding for hGH has demonstrated anabolic actions2.
Up until recently, hGH doping was difficult to detect. Abnormal ratios between different isoforms of hGH was the basis of current methods to detect ‘wrong-doing’. Unless better analytical tests for detection are developed, growth hormone gene-doping promises to be a very realistic threat.
b. IGF-1 or MGF gene
Genes which target specific proteins like IGF-1 (insulin like growth factor – 1) and MGF (mechano-growth factor) possess the potential to enhance lean muscle mass and thus performance, especially in sports dependant on explosive muscle power and strength.
IGF-1, in combination with growth hormone and insulin, is responsible for most of the anabolic growth stimulus in the human body. Synthesised and secreted by the liver, it serves a plethora of functions3:
• hypertrophy of skeletal muscles by inducing increased protein synthesis and retention
• protection of cartilage and neurons
• maintenance of bone density by stimulating osteogenesis (constant deposition of new bone to counter the constant resorption (taking off) of bones that occurs normally)
• additionally, IGF-1 can stimulate insulin receptors (albeit, at higher doses) and thus mimic anabolic actions of insulin like protein retention and actions on carbohydrate and fat metabolism
As opposed to IGF-1 (growth regulation in adults), IGF-2 provides the major stimulating force during foetal (intra-uterine) development of an individual.
Since IGF-1 is localised to the muscles, chances of systemic side effects with spiked up levels are (currently thought to be) minimal.
c. Erythropoietin gene
Doping with Erythropoietin gene increases red blood cell counts. Improved delivery of oxygen to exercising muscles, as a consequence, helps in enhanced performance in endurance events.
Erythropoietin (EPO) is a hormone produced by the kidney; it serves the following actions:
1. maintenance of optimal red cell mass for oxygenation of tissues; production of EPO is regulated by the demand of oxygen by tissue4
2. absorption of iron to facilitate the production of haemoglobin (to be packed inside red cells)
3. improved cardiac function (including contractility) in low doses5
4. production of new blood vessels5 (angiogenesis) to complement increased red cell mass
These processes (together) ensure enhanced supply of oxygen to tissues especially to exercising muscles.
Method of Administration
A popular method, allegedly, used to deliver genes to their loci is by coupling these genes to a vector (carrier) like an adenovirus.
Animal studies have conclusive proved that such method of administration of EPO does succeed in increasing haematocrit by up to 81%; these effects last for almost a year6;7.
Is Gene Doping Detectable?
Present gene doping techniques cannot be detected by studying bodily fluids: urine or blood samples. Doping even with recombinant EPO has proved to be quite difficult.
Although recombinant EPO is detectable in serum and urine samples, it is difficult to prove ‘wrong-doing’ conclusively. Furthermore, a high haematocrit (a measure of high red cell count) does not necessarily suggest ‘doping’. This is so because it is quite difficult to differentiate between physiological rise in haematocrit (athletes from high altitude, pregnancy and genetic mutation) and that induced by ‘doping’.
Furthermore, close monitoring can ensure that even in athletes using recombinant EPO, serum and urine levels as well as haematocrit can be maintained within normal ranges.
Similarly, in athletes (who have been) administered genes (coding) for IGF-1, detection of any ‘wrongdoing’ is bound to prove difficult. A major practical difficulty is the need to take muscle biopsies for such detection. (Ouch! Don’t know about you, but I would definitely have concerns for such invasive procedures!).
Future of Gene Doping
Gene doping is still at a stage of infancy. As more and more genes enhancing health and fitness parameters are discovered, the list of genes with the potential to enhance sports performance will expand exponentially. Even as we speak, more than 100 intra-cellular and intra-nuclear sites for such genes have been discovered; more genes are being discovered every single year8.
As of now, gene doping seems to be near impossible to detect. Unless foolproof tests for genetic ‘wrong-doing’ can be designed and implemented, a scramble for ‘designer genes’ in the very near future seems to be very much on the cards.
(1) Segura J, Guti+®rrez-Gallego R, Ventura R, Pascual JA, Bosch J, Such-Sanmart+¡n G et al. Growth Hormone in Sport: Beyond Beijing 2008. Therapeutic Drug Monitoring 2009; 31(1).
(2) He X, Goldsmith CM, Marmary Y, Wellner RB, Parlow AF, Nieman LK et al. Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands. Gene Ther 1998; 5(4):537-541.
(3) FLORINI JR, EWTON DZ, COOLICAN SA. Growth Hormone and the Insulin-Like Growth Factor System in Myogenesis. Endocrine Reviews 1996; 17(5):481-517.
(4) Eckardt KU, Kurtz A. Regulation of erythropoietin production. European Journal of Clinical Investigation 2005; 35:13-19.
(5) Lip+íic E, Westenbrink BD, van der Meer P, van der Harst P, Voors AA, van Veldhuisen DJ et al. Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit. European Journal of Heart Failure 2008; 10(1):22-29.
(6) Svensson EC, Black HB, Dugger DL, Tripathy SK, Goldwasser E, Hao Z et al. Long-term erythropoietin expression in rodents and non-human primates following intramuscular injection of a replication-defective adenoviral vector. Hum Gene Ther 1997; 8(15):1797-1806.
(7) Zhou S, Murphy JE, Escobedo JA, Dwarki VJ. Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates. Gene Ther 1998; 5(5):665-670.
(8) Rankinen T, Perusse L, Rauramaa R, Rivera MA, Wolfarth B, Bouchard C. The human gene map for performance and health-related fitness phenotypes: the 2003 update. Med Sci Sports Exerc 2004; 36(9):1451-1469.