Gene Doping

 

 

What is Gene Doping?

 

Gene doping is the use of DNA to alter how a gene works. It involves injecting new DNA into the body directly for the sole purpose of enhancing performance of an athlete.  The world anti-doping agency (WADA) is the international organisation tasked with ensuring sport is free from doping. Its core vision is “A world where all athletes can compete in a doping-free sporting environment.”   

 

WADA has undergone its fair share of criticism of late. The uncovering of systemic doping by athletes of the Russian federation in collusion with the authorities and the unsubstantiated counter claims made by them against other nations has sown discord and doubt in the public mind’s eye about the effectiveness of the international governing body that is supposed to prevent these kinds of abuses. Is a higher game afoot? A kind of 3D chess among competing geopolitical interests, although using the syringe as a chess piece? This article aims to examine the new frontier in performance enhancement, its leaps, its bounds and how we all might have to face its consequences.  

 

A brief history of gene technology and how we got to gene doping 

 

The Human Genome project (HGP) was an international research project to map all of the genes in all Human beings. The HGP project completed the sequencing of all Human genes. The circa 25,500 genes that form the hereditary blueprint for all Humans is now used across the world in research laboratories to try and understand how the genes are expressed. The HGP has had direct and indirect influences in fields as diverse as forensics, agriculture, molecular medicine, microbial genomics, and archaeology and now it seems sport too.  

 

Key Dates in the development of gene therapy and editing. 

 

To understand the role of gene doping in sport and exercise it is necessary to have an overview of the current state of gene technology and from the starting point of the HGP. These are some of the key developments in this field.  

 

  • 2005 – Gene therapy approved and used for the first time by scientists in Japan. In this case, the P53 gene had been delivered to a patient with squamous cell head and neck cancer.  

 

 

  • 2006 – Development of genetically engineered lymphocytes shows promise as a cancer treatment.  

 

  • 2011 – Successful use of gene therapy to treat haemophilia in mice.  

 

  • 2013Studies into the efficacy of using transcription activator like effector nuclease (TALENS) to correct an inherited skin disorder Epidermolysis Bullosa 

 

  • 2015 – Results from a phase 2 trial using Zinc finger nuclease to modify CD4 and CD8 cells to treat HIV patients.  

 

 

 

 

How Gene Expression is Regulated

 

There are two main ways that genes are regulated; control of transcription (DNA converted into its complimentary RNA code – think of a coat zip being undone) and translation (messenger RNA (mRNA) is used to make amino acids that make up proteins in your body) and changes in the structure of DNA.  Your DNA is a blueprint for the production of proteins which make up you. The blueprint is made up of four different bases; Adenine (A), Cytosine (C), Thymine (T) and Guanine (G). In RNA, Thymine is replaced with Uracil (U). The bases link up with specific bases to form base pairs; A&T, C&G 

 

Mutations are ways that the DNA can be altered and in some cases the alteration of DNA has effects on the way a protein is made and the gene is expressed.  One example of this is a point mutation.  Mutations to individual bases can be introduced by either substituting a base with another base or when a base pair is either substituted or deleted. Furthermore, an example of a point mutation is Tay- Sachs disease, Cystic fibrosis and Sickle cell anaemia 

 

There are a number of ways in which gene doping can potentially enhance performance. The up-regulation of some cellular functions in certain organs and tissues that lead to enhancing the capacity of the tissue or organ to deliver increased performance.  There are a number of candidate genes that if tweaked, could lead to performance enhancements.  

 

Endurance – Red Blood Cell Production  

 

Red blood cells (erythrocytes) are cells responsible for the transport of oxygen from the lungs to the cell and carbon dioxide from the cell to the lungs. It is easy to see why this would be a target for genetic manipulation for the purposes of performance enhancement. Erythropoietin is a hormone responsible for the production and maturation of erythrocytes.

 

Gene doping - Altering EPO to increase erythrocyte production

Credit: Human Genome Research Institute

90% of EPO is produced in the kidneys whilst the remaining 10% produced in the Liver.  Furthermore, the production of erythrocytes is regulated by the concentration of oxygen circulating in the body. In normal oxygen concentration conditions (normoxia) of the body, the activation of hypoxia-inducible transcription factor 1 alpha (HIF1α) is curtailed. As a result, the production of red blood cells in the body ameliorated. However, in conditions where oxygen levels are low (hypoxia) HIF1α binds to the Erythropoietin (EPO) gene leading to the gene being up-regulated which leads to increased levels of EPO. Therefore, the production of erythrocytes will increase as will the haemoglobin and haematocrit levels.Furthermore, this leads to an increase oxygen and carbon dioxide carrying capacity of the body. Ergo… increased performance.  

 

Muscle Strength and Endurance – Insulin like Growth Factor type 1 (IGF1)

 

IGF1 is produced in the liver and is controlled by growth hormone. The release of IGF1 stimulated by sleep, low blood glucose levels, hypoglycemia, high intensity exercise and low levels of IGF1 itself. This in turn stimulates the pituitary gland to release growth hormone which then releases IGF1.  

 

IGF1 has a role in muscle building (hypertrophy) this leads to increases in muscle power. Therefore, performance. It has been postulated that copies of the IGF1 gene could be inserted into muscle cells to cause hypertrophy. This could be valuable for strength and power events such as weightlifting and sprinting.  

 

Vascular Endothelial Growth Factor (VEGF) & Fibroblast Growth Factor (FGF) 

 

Oxygen, carbon dioxide, nutrients and metabolic waste are all delivered or extricated by the vascular system. The body has a series of vessels connected to all organs and tissues for this purpose. Also, VEGF promotes the growth of the existing vasculature in a process termed angiogenesis. Whereas, FGF has a role in angiogenesis and tissues repair. The idea is that when copies of the gene coding for VEGF or FGF are introduced into muscle, this then will have the effect of promoting angiogenesis and increase muscles blood supply as a result.  

 

The role in sports performance is that a greater vascular micro structure results in increased oxygen deliver to the muscles and greater energy production for exercise.  

 

Gene doping and VEGF expression

The Vascular System.

Alpha Actinin 3

 

Alpha Actinin 3 (ACTN3) is postulated to play a role in fast twitch muscle contractions. This type of muscle fiber (fast twitch) is different from other fibers primarily by the way in which energy is derived for muscles contractions and how efficient the fiber is at producing energy from that ‘energy system’. ACTN3 has been termed the ‘speed gene’. A recent study suggests that ACTN3 plays an important role in muscle metabolism and the fatigability of the muscle. However, the study does not suggest that it plays a role in muscle hypertrophy.   

 

ACTN3 would be an obvious candidate for genetic manipulation to enhance speed performance in athletes. However,  if ACTN3 were to be down regulated to cause a deficiency, there could be a performance benefit for more endurance trained athletes.  

 

 

Peroxisome Proliferator-Activated Receptor – α, β, δ, γ

 

PPAR’s play a role in cell differentiation and metabolism. There actions differ between to the four subsets but their use for the performance enhancement is interesting. They play a role in fat (lipid) metabolism, glucose homeostasis and insulin sensitivity. All three would be beneficial to an athlete interested in surreptitiously improving performance. Lipid metabolism in the liver and fat cells (adipocytes) is regulated by PPARα as is the breakdown (catabolism) and β oxidation of fatty acids (lipid metabolism). PPARβ, δ and γ on the other hand are responsible for the metabolism of glucose.  

 

The up-regulation of these genes would provide benefits in the increase in uptake of glucose by the cell. Therefore, increasing energy metabolism for exercise. Increased β oxidation would also provide benefits to energy production for exercise but it would also help athletes who need to ensure they are in the right weight category during competition such boxing, MMA and even bodybuilding.  

 

If the PPAR gene expression is exploited, it is also easy to see how this could easily cross into the main stream from elite sport. The proliferation and widespread abuse of anabolic steroids and growth hormone in gyms and health clubs today only reinforces the idea that societal pressure placed upon people to look good can lead people down all sorts of quick fix avenues.  

 

Gene Doping to Increase Psychological Performance.  

 

Several studies have assessed the possible candidates for altering the expression of certain genes that govern emotional control, stress and an athletes outlook during competitions. There are two main gene candidates in this regard; serotonin transporters (5HTT) and Brain-derived neurotrophic factor (BDNF). Altering the expression of these genes could produce improvements in all of the above psychological factors to accompany any physical changes the athlete experiences due to gene doping.  

  

Ethical and Philosophical Considerations

 

Altering the genes to enhance performance, is this cheating? Is this dangerous? Or is it inevitable? Gene doping raises some obvious ethical arguments.  Because the pace of change in the field of genetics means that we are fast approaching the point at which we will be in a world where athletes routinely alter their genes to gain the advantage. However. this has ramifications for us all. The use of anabolic steroids in the competitive bodybuilding in the 60’s and 70’s and the subsequent rise of the health and fitness industry in the intervening time has leached into the mainstream.  

 

Should we expect this to cross over too? Will society deal with it when gene doping does come along and what are the implications for society when we are in the era when gym members start to artificially alter the ways their genes are expressed just to look good? One could also argue that we all inherit  DNA, chromosomes and genes from successive generations with their own unique mutations. Some beneficial, some not so and some fatal.  

 

Why is Usain Bolt so fast? Is it to do with how ACTN3 is expressed and used in his muscles? What if another 100m runner didn’t have the same mutation as Usain Bolt or other runners. Therefore, giving a genetic disadvantage.  

 

By artificially altering our genes aren’t we just introducing mutations in a controlled way and leveling the playing field?  

 

In conclusion, It has only been since 2003 that we managed to map the Human genome. Although the pace of change in the field of gene editing, therapy, molecular medicine and others are increasing exponentially. However,  we are still in its infancy and there is a lot we have yet to learn and the dangers have not yet been fully realised.  

 

 Gene doping - Gene editing

Gene Doping: Editing the your way to performance?