Specific Genes Altered

(Continued from Gene Doping series part 2)

by Danny Mackey M.S.

We are still looking the topic of Gene Doping.  As I’m writing this (and listening to The Carps featuring The Cool Kids and the new Saul Williams album) I think it might be a 4 part series.  But, we will see what happens. 

      I always end up in a bad mood talking about cheating, so before we go on… how about Pre Nats!?  I was lucky enough to watch it live from LA (I went down there to race myself but got sick, let me tell you how much fun that trip was).  The men’s individual race is shaping up tough and the women’s PAC-10 conference meet will be a mini NCAA meet.  Then, the IAAF half marathon champs the week before were interesting; I always find it amazing that athletes like Zersenay Tadese can win year after year with such consistency.  He’ll be someone to watch in the marathon, his running economy was tested last year, and it was off the charts.

      Now to the gene doping, this article will focus on specific genes that can be altered and what performance benefits an athlete can see.  I tried to give the science “stuff” and then say what it means to athletics…..that being said….I hope I make sense, if not, post the question as I’m sure other people can have a similar question, or they might be able to answer better than me.

      Over the years several studies have been carried out on associations between genes and elite athlete status.   From the studies, a small number of these genes are used today by athletes for gene doping.  The altered genes may improve athletes in a range of areas from improved muscular strength, overall recovery and aerobic endurance.  The athlete and his or her scientist will simply choose which specialty areas the performance gains are needed.

      The angiotensin-converting enzyme (ACE) gene in human skeletal muscle may be a popular gene in the future.  ACE can be encoded by one of the two variants.  The two variants of the ACE I gene are, ACE Insertion (I), or presence of the ACE I gene or, ACE (D) which is the absence/deletion (D).  The ACE I variant of the ACE gene is associated with both lower tissue ACE activity and elite performance in endurance activities .  The ACE gene is important in the endocrine rennin-angiotensin system or circulating system which has a homeostatic role in human circulation (8).  ACE I breaks down vasodilator kinins while promoting formation of the vasoconstrictor angiostensin II.  Angiostensin II also causes the adrenal aldosterone release (9).  The release causes humans to retain salt and water which influences are blood volume and pressure, both important variables in endurance activities.  The take home point, after all this jabbering is; that the ACE I allele frequency, or lower tissue ACE activity, is greater among elite endurance athletes because it lowers enzyme activity and is associated with enhanced endurance performance.  Delivering the ACE I gene locally via a virus into the athletes’ skeletal muscle may have profound benefits on their performance.

      The ability of the athlete to train injury free for long periods of time can improve his or her performance.  Stress fractures are common injuries in competitive athletes.  Stress fractures make up 10% of the total injuries in competitive athletes (10).  Acute fractures occur more often in sports that involve collision such as football, basketball and soccer.  Doctors and trainers have standardized treatments for fractures but the recovery times may differ greatly.  Prolonged time of recovery for more than 4 months after the injury is frequently described as a cause of insufficient training that will decrease an athlete’s performance.  There is evidence that the bone will heal more quickly and stronger if the healing process uses appropriate growth factors.  Studies have shown bone morphogenetic proteins, insulin-like growth factors and transforming growth factor-Bs to increase bone formation and to promote the process of fracture healing (11).  These factors are delivered locally to the injury via adeno viruses.  The gene expression persists in the injured bone for up to 6 weeks, which is the standard healing time recommended by doctors.  This means that a single shot may be sufficient enough for the athlete to heal the bone appropriately and get back into full training verses coming back slowly from the injury and losing precious training time.

      This third gene is very familiar to all of us, as we hear about it the most in the news.  Athletes can take exogenous erythropoietin or Epoietin (EPO) to boost his or her performance. Endurance is affected by the amount of oxygen reaching the muscles.    Erythropoietin is a naturally occurring protein that produces oxygen carrying red blood cells.  EPO was first created to treat people with anemia but now athletes abuse EPO to receive gains in their performance.  Gene transfer to raise erythropoietin production has already been tried in animal studies.  In 1997, Leiden et al. used an adeno virus to deliver the EPO gene in mice and monkeys.  The EPO gene increased the mice and monkey’s haemotocrit from their red blood cell counts by nearly double and the effects lasted from anywhere to 12 weeks to one year (12).

      The discovery of a family of proteins called hypoxia inducible factors (HIFs) has helped with understanding human’s response to hypoxia.   Hypoxia occurs in hard working muscles with a high oxygen demand.  HIF’s are transcription factors, which modulate the activity of different genes in low oxygen conditions.  In low oxygen conditions activity of the enzymes that breakdown HIF-1alpha are slowed.  When this happens HIF-1alpha binds to HIF-1beta and crosses the nuclear membrane to bind with intranuclear proteins which promote gene transcription.  The genes that are controlled by the HIFs also code for proteins that promote red blood cell production and glycolytic enzymes that create addition energy (13).   Researcher can target HIFs and create drugs that modulate HIF expression and metabolism.  The benefits to endurance athletes will be great because of the knowledge that oxygen deficiency stimulates EPO production through the HIF pathway. 

      There are clinical treatments for muscle wasting disorders that help regenerate muscle and increase its strength in the clinical setting.  There are synthetic genes that can last for years to produce high amounts of naturally occurring muscle building chemicals which will be beneficial to athletes concerned with muscle strength.  The protein insulin-like growth factor 1 (IGF-1) and the isoform, mechano-growth factor (MGF) are genes that may be altered (14).  When skeletal muscle is used in exercise, microscopic tears in the fibers causes the tissue to regenerate and repair itself.  The muscle fiber is repaired on the outer membrane of existing fibers and new myofibrils interior.  To make these new proteins in the skeletal muscle, certain genes need to be activated by way of local satellite cells.  Satellite cells respond to IGF-1.  Researchers injected a synthetic gene that would produce IGF-1 only in skeletal muscle in mice and witnessed a 20-50 percent increase in size (14).  The increase in size was only one benefit. IGF-1 overproduction helped to shorten the time for muscle repair, which would allow athletes to train harder day to day.

      Scared that we might see Lebron James running a 3:50 mile?  Pissed off at what cheaters have access to?  You probably should be, BUT, we have not yet looked at the “good guys” that try and find the cheaters OR worse yet the risks.  Messing with this amazing human body has consequences, and the next section will look at those and draw a grim light on what these people give up (other than their cheating soul).