The Specific Genes By Danny Mackey

October 23, 2008

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).

Post a Comment

#9	Danny Mackey October 23, 2008 at 10:42pm Good comment Harry. So there is a physiological (from what I know so far) difference from "buying" the genes verses thanking Mom and Dad. The next article will get into more depth but one problem is turning "off" the gene expression. Imagine pushing blood with a hematocrit of 58 through your arteries? Also the metanomics and proteomics are different because the genes in the virus are synthetic. Can this cause a problem? Not sure. Just my own personal opinion is the human body is so complex beyond our understanding, once you start changing things in the system I think a negative consequence is inevitable. It may not happen now but when these people are in there 40-50s. (think of some suspect athletes back before we had tests and there health condition no, or some that have passed). Mark's point is good in that durability and ability to handle the hormonal stresses of 160 miles a week is a talent. I think it's vary rare that we are capable of totally maximizing our ability, so if someone like Sell can get 97% of his ability and someone like Ritz is 91% for injuries etc..(I'm just throwing numbers out there) then you could have a race on your hands. Last comment. Nathan you brought up a topic I talk about quite a bit. My opinion; yes, training enhancement is cheating. So that includes exogenous hormones to get your levels to "normal" and thus train harder. But then where does the line get drawn, anti-inflammatory pills, inhalers, you can see where this might go.... Interesting to see what other people say on that? reply
#8	Nathan H October 23, 2008 at 6:39pm Great article. This is so interesting. I was wondering about the line between using accepted drugs (like ibuprophen) to help heal from and injury faster verses using gene therapy (like the gene to speed bone recovery). How are these fundamenally different other than that the gene therapy is a newer technology? When gene therapy eventally becomes a standard treatment for medical problems, should athletes still not be allowed to benefit from it? I know I'm kinda playing the devils advocate. Maybe I'm just enticed by the possibility of being able to use technology to train harder. Is it cheating to use 'training enhancement' drugs as opposed to 'performance enhancing' drugs? reply
#7	Harry X October 23, 2008 at 6:29pm I don't know, i admit that Mark makes a good point with both Brian Sell and Deena Kastor, but I have trouble buying that theres a difference between being born with a high EPO production factor or buying the gene that encodes for it. Granted, we are all born genetically unique and have each our own strenghts and weaknesses, perhaps its our duty to maximize our strengths and weaknesses using intuition, hard work, and a little bit of biochemical, physiological understanding of our bodies. reply
#6	Mark From Flotrack October 23, 2008 at 6:00pm Yes German is more talented then Harry but a lot of people were more talented then Brian Sell and he makes an olympic team. I think the same can be said for Deena Kastor. She won Bronze and major marathons and she does it bc she runs 140 miles a week and has an amazing work ethic. Hard work can overcome talent. The great Arthur Lydiard said, The are champions everywhere. ARthur believed anyone could become a champion if he or she worked hard enough. Visit Flotrack For More Videos reply
#5	John Petricevic October 23, 2008 at 5:01pm Harry, Who cares?! Some people are more gifted than others. Its life if you haven't figured that out by now! reply
#4	Harry X October 23, 2008 at 2:49pm To play the devil's advocate for a moment... Is it fair that some people are born with talent such as a tendency for the body to produce more than average EPO or have a higher distribution of slow twitch muscle fibers than avearage? Is it fair that an average person with a strong work ethic could never make it to the big leagues because they weren't born with the right stuff? I've only run 26 minutes for an 8k, but when I see German Fernandez running low 23:00s, I have to wonder is he suffering/ working just as hard as I am? or does his body have a genetically predisposed condition to recover better/ utilize more oxygen/ tolerate the pain better? reply
#3	ReRob October 23, 2008 at 10:20am Have you seen the movie Gattaca? Its about a future in which gene alteration is normal. People who have not been genetically engineered are suppressed minority. It is great movie that raises some interesting points. reply
#2	Rob October 23, 2008 at 9:05am Thanks for the insights. I saw a special on the National Geographic channel, I beieve, on gene therapy in general, and immediately thought of its implications in sports. There were examples of kids who were undersized at their given stage of development, and parents who sought medical/gene therapies to enhance growth. The first thing that came to mind was, well that is a gray area, isn't it? At what point on the continuum is it appropriate to give a kid a chance to be "normal" and play with the other kids, and when does it become a means of enhancing performance for competitive reasons? Whether a kid, or in latter stages, competitive athlete, is genetically challenged in some way, is it appropriate to resolve this issue via the lab? How far back do you track and/or test? If parents are utilizing science to resolve inadequacies if their offspring just so they can be "normal" and play youth sports, we can only imagine what long-term plans underhanded athletic programs are attempting and implementing. How would you test for this years after-the-fact in a so-called genetically engineered athlete, if that is yet possible? reply
#1	Patrick Chessar October 23, 2008 at 4:26am I am surprise that no one has really responded to this article yet. I am enjoying how deep this is getting into the subject. As many do not want to believe that doping of any kind is prevalent in our sport the truth remains that it is going on in every sport at various degrees. The extent we will never know. Cheaters, hey they can do what they want. Everybody gets there’s at some point. I mean look at everyone from the Balco scandal. That is why when it comes to our sport you just focus on yourself and what you have to do (or your team has to do) to achieve your goals. All this other stuff with cheating is just something that will continue to cloud sports for all time. Always a game of catch up for those attempting to get the ones who do cheat. However, I do want to see more on the breakdown of the drugs and ways these amazing feats can be established. It still is quite astonishing to see what can be achieved. I guess I am a exercise science nerd at heart. Ha! Ha!... ~Patrick reply