Gene therapy to restore hearing!

@newscientist: ICYMI RT @newscientist: Deaf people to get gene therapy to restore natural hearing


Finding the mutants among us!


No, not those, those are the cool mutants!


NO, these are even cooler. We alllll like them, we do. 

We want to find the genetically “altered”, the genetically doped, the CHEATERS! 

In 2001, the medical commission of the International Olympic Committee met to discuss the implications of possible gene therapies in sports. Shortly after, the World Anti-doping Agency met to discuss gene doping further because a laboratory in New York started developing gene enhancements. In 2002, the agency banned the use of gene doping because of the same ethical implications that drug doping brings, and they started funding a research to find possible gene doping methods. 

“Good” scientists developed technologies to detect gene doping, but there are still many limitation. 

Generally, the tests are divided to direct and indirect testing.

Direct testing involves detecting recombinant proteins or gene insertion vectors, where they could, for example, use molecular testing to differentiate between genomic DNA and cDNA that doesn’t have introns. On the hand, in indirect testing they look for differences in cells, tissues, and changes in the immune system (1), by using transcriptome analysis. Transcriptome analysis characterizes the RNA extracted from a tissue, where the composition and the quantity of the transcriptome is highly reflective of the metabolic activity (2). 

But, if we think for a moment about the indirect test, which is the easiest to conduct, it is highly bias! Many people carrying natural PEPs that make them genetically athletic, will be easily mistaken for cheaters that used gene doping.

And in fact, it happened!

The Finnish cross country skier, Eero Antero Mäntyranta, tested positive for EPO gene doping. A research done on the athlete and 200 members of his family determined that they have a genetic mutation in the erythropoietin receptor (EPOR) gene, causing them to have increased red blood cell production. 

By the way, THANK YOU the Mäntyranta family for your great service for science!

On the other hand, the professional cyclist Lance Armstrong produced lactic acid over 50% less than what a normal person would, and he claimed it was caused by a PEP. LIE, later on it was proved that he was drug doping!


It is great that we are able to detect some of the gene doping possibilities, and that we are constantly developing technologies for doping detection and for a fairer competition. 

Athletes should appreciate their natural abilities that makes them exceed limitation,

and should be dope and not dope!

Gene doping: The creation of gene freaks

In the recent years genetics has become the next big thing in almost everything, and as we know now, sport was not an exception.

But is that it? Are we just interested in identifying the genetic makeup of elite athletes for the sake of science, and for the sake of predicting future Olympians? Knowing the greedy human nature, one must say no!

Figure   1.    A   breakdown   of	   golden	   medalist	   after	   failing	   an	   EPO	   gene	   doping	   test.

Figure 1. A breakdown of golden medalist after failing an EPO gene doping test.

Started from bottom, now we’re here!!

In 1972 geneticists were able to use their simple knowledge of the human genome and the availability of genomic tools to propose a futuristic type of treatments for genetic disorders, that for the most part were impossible to cure, but little was known about the human genome to make any progress. However, by the 1990s everyone was interested in contributing to the human genome project, where scientist began identifying more genes, and started developing evolutionary technologies to make the process faster and more accurate. The project was completed and published in 2004 with 99.9% “accuracy” (2). WOW!!

Scientist returned to the futuristic idea of gene therapy in the 1990s, and they were able to conduct the first gene therapy on a four-year girl with a severe immune system deficiency. The therapy was temporary but successful, which gave scientist the green light to proceed and develop more and better gene therapy treatments for variety of genetic disorders, such as Thalassemia that have been success as well (1).

BUT, for every great idea, there are risks; and the risk here is the use of gene therapy technologies for selfish human deeds, such as artificial athletic performance enhancements.

If we can fix a gene, we can make it better!

Gene doping

Is that even a thing? Apparently, it might very much be a thing by the next Olympic games in Brazil! The doping concept in sports, or the use of performance enhancing drugs is as ancient as the Olympics games. For example, historian have reported the use of poisonous mushroom to gain great amount of energy by the Berserkers who battled uncontrollably (3), and the use of laudanum for endurance sports by British athletes in the 1800s (4). Doping on synthetic drugs developed from the innocent use of anabolic steroids and other treatments that aimed in inducing bone growth, appetite, and treating chronic wasting conditions caused by cancers. The misuse however, started in the 1950s when a Russian physician told Dr. John Ziegler, who treated many American athletes, that he uses testosterone to enhance the athletic performance of Russian athletes, where Ziegler immediately tested the method on himself to show positive results (5).

And the madness began!

Gene doping development is taking the same path drug doping took, where scientist are using gene therapy technologies not to fix a gene, but to make it “better”!

The mechanism

Gene doping is simply altering or controlling different sites of a gene to make it athletically more efficient.

A gene could be altered by extracting the gene from a human cell, such as a muscle cell, and replacing the coding region that is responsible for the amount and type of protein by an artificial, more efficient coding region. The gene is then transferred back to the muscle tissues by direct injection, by injecting extracted muscle cells and reintroducing the cells to the body, or by replacing a virus genome with a modified gene and introducing the virus to the body (Figure2).

Figure 2. Genes are altered by extracting the original genes from the human body, cutting the original coding regions, and replacing them with artificial “enhanced” coding regions. Afterward, the new gene is inserted in a virus where it replaces the virus coding genome. The virus is then injected in the human body with the modified gene, where it affects multiple cells and could integrate in the human genome.

Figure 2. Genes are altered by extracting the original genes from the human body, cutting the original coding regions, and replacing them with artificial “enhanced” coding regions. Afterward, the new gene is inserted in a virus where it replaces the virus coding genome. The virus is then injected in the human body with the modified gene, where it affects multiple cells and could integrate in the human genome.

The most efficient and long lasting gene doping reintroduction mechanism is the use of viruses, because they are able to integrate in the genome. However, the mechanism will cause multiple unwanted side effects because the virus is able to bind to all types of cells. On the other hand, direct injection is safer but almost inefficient, because the modified gene affects only the injected area and it would have short lasting effect due to cell death and gene loss. The most controllable mechanism is the introduction of a modified gene to an extracted muscle cells and culturing the cells in the lab before reintroduction, however, it is limited to cell type and it is a more complicated process. Since the virus is the most efficient mechanism, scientists proposed that they could further control the gene, to eliminate side effects, using engineered promoters that would only respond to certain triggers. Therefore, the gene will be integrated in the genome forever, while having a controllable amount and position of the gene product (6).

Too perfect right?

Well, it can’t be, because as we all know, the immune system does not tolerate artificial DNA and will therefore, trigger and kill the cells that acquired the artificial DNA. It could take months, but the immune system will win at last.


The possibilities of gene doping

Sky is the limit! But here is a couple of the most potential gene doping possibilities.

Blood doping

Erythropoietin (EPO) is a hormone that controls the production of oxygen-carrying red blood cells (hematocrit) and it is produced in the kidneys. The use of EPO started with gene therapy for patients with kidney failure that lacked EPO production and therefore, had severe anemia and low levels of oxygen in the blood. The gene therapy was a success, where it requires the injection of EPO several times a week, as the EPO levels decline rapidly.

Here the misuse started.

By the early 1990s, scientists saw the potential of EPO in another direction, and therefore, started EPO gene doping on mice. The results were astonishing, where they observed an increase in the hematocrit levels from the normal 40% to 70% that lasted for over six months. The experiment was replicated on monkeys and showed the same increase that lasted for a longer period of time, and not far after, athletes in endurance sports such as cycling started doping on EPO (Figure 2) (6).

Figure 3. The changes in hematocrit levels in mice and monkeys, after a single injection of a virus containing a modified EPO gene.

Figure 3. The changes in hematocrit levels in mice and monkeys, after a single injection of a virus containing a modified EPO gene.

Again, too perfect! Athletes doping on EPO are at high risk of heart failure, because a hematocrit level of 60%, increases the viscosity of the blood, DANGEROUSLY.

Muscle doping

Gene doping for strength athletes is not as easy and available as it is for endurance athletes, due to the complications involved in inducing the production of a non-protein substrates like steroids by gene therapy. However, the possibilities exist, unfortunately.

Insulin- like growth factor1 (IGF-1) is an essential endocrine in childhood growth and important in anabolic processes in adulthood, as it induces organs and tissues growth. Researchers demonstrated the potential of IGF-1 in gene doping, by inserting an active promoter to an IGF-1 coding region, and inserting the gene to mice muscle tissues, where the mice showed an increased muscle mass and strength (6).

IGF-1 has not been misused yet, but there are many cultures that use deer antler for medicinal uses and as growth tonic for children because it is a rich source of IGF-1. Early doping!!

At last, are we ready for this?

Is it right?

Is it detectable?

No, no, and unfortunately no.

Gene doping is a dangerously new technology, and no smart athletes should risk their career and health for it. With side effects as bad as heart failure, immune diseases, and cancers, it is too early and too foolish to take that path.

The World Anti Doping Agency and the International Olympic Community have banned gene doping, which is a great start ahead, but how useful is that in undetectable gene alterations!

So, Be Dope, and don’t Dope! 😉

Athletic Genes

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“Uzbekistan Uses Genetics to Find Future Olympians”

                                                                        The Atlantic, Feb 2014

 “Olympic athletes have the right genes for their sport”

                                                                        CBC NEWS, Feb 2014

 “Gene doping test for athletes in the works”

                                                                        CBC NEWS, Jun 2013

 “Gene tests for child athletes add pressure”

                                                                        CBC NEWS, Mar 2011


Olympians and high performance athletes have been filling the headlines in the recent years because of their genetics rather than their medals!

But why the sudden interest in their genes? Is that what makes them really good at their sports?


Some might say that determination and training is all that matters to make a Michael Phelps or a Usain Bolt.

YES, but that is only half of the story.

Many researchers around the world are now looking for the genetic code in high performance athletes to detect the exact gene(s) that makes them “elite” athletes in their sports. Researchers have discovered many “sport genes” and alleles and here we’ll discuss some of them, and wonder why we’re not in the Olympics even though we train hard!


Can you run a marathon, or sprint to the first place?

After the 2012 London Olympics Sean Hogan, from the strength and conditioning blog, noticed, as many of us did, that “athletes of an Afro-Caribbean ethnicity dominated the sprint events while athletes from the northern and eastern African continent continued to dominate the endurance events”.

The first thing that comes to my mind is evolution, but before we jump to that we have to know what differentiates athletes from these two groups, physically and genetically, because it is not about where they come from, but about the variations in their genes they inherited that makes them the best.


Speed athletes are generally muscular, and able to start sprinting with speed and power in a matter of seconds or less! It’s the fast twitch muscles, which are a type of skeletal muscle fibre, that provides the burst of speed and power  using glucose for the large amount of energy required before quickly fatiguing when energy resources run out.

 On the other hand, endurance athletes have a higher rate of the slow twitch muscle, which are dependant on oxygen for energy, giving them the longevity to be active but with less speed.

 Ok, but how is that related to your genes?

Let me explain!


The fun stuff

A Few years ago, scientist began testing high performance athletes, and comparing their genetic material with active individuals from the general population as a control, to detect sport genes that could be used to distinguish future Olympians.

And according to the headlines they were successful.

Researchers discovered performance-enhancing polymorphisms (PEPs), which are a genetic variant, that could be as small as one nucleotide, that can improve the athletic performance in the people carrying it. So, we all have a copy of the gene, but a small variation in the sequence may make some people perform better at certain sports.

Since 2007, over 200 autosomal PEPs and 5 X-linked PEPs have been reported. Here, I will discuss two of the first (and most studied) PEPs to be identified and have been found to have different effects on processes like blood flow and muscle formation.


 The Angiotensin-converting enzyme (ACE) is a fundamental component in regulating blood vessels constriction and blood flow, and it is triggered by decreased blood pressure.

When we run, the blood vessels in our muscles dilate and acquire greater blood flow, causing a decreased blood flow to the other tissues and organs, and eventually a decreased blood pressure. The decreased blood pressure leads to the release of renin from the kidneys that cleaves the Angiotensin released from the liver, making Angiotensin I. Afterwards, ACE is  secreted from the lungs where it further cleaves Angiotensin I to make Angiotensin II that causes vasoconstriction and increases the blood pressure by regulating body fluid levels (Figure1).

Screen shot 2014-03-21 at 1.10.10 PM

Figure 1. The Renin Angiotensin system. Angiotensin is secreted from the liver and cleaved by renin (which is secreted from the kidneys following decreased blood pressure), making angiotensin I. The ACE is secreted from the lung where it cleaves off the residues, making angiotensin II that increases vasoconstriction.


But that happens to everyone, so what’s so special about the ACE gene?

There are two polymorphisms detected in the ACE gene, called D (for deletion of a 287 base intron) and I (for insertion). Studies found that that the I allele is associated with lower ACE activity, therefore, less vasoconstriction and more blood flow to the rest of the body leading to enhanced performance in endurance sports. While the D allele is associated with higher (than normal) ACE activity, therefore, excessive vasoconstriction in the tissues and organs, but more oxygenated blood flow to the muscles, leading to enhanced performance in sports requiring a great amount of energy in a short amount of time.


To put this in prospective

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The Jamaican sprinter Usain Bolt(who’s the fastest person EVEEEER), and the American swimmer Michael Phelps, both probably have homozygous D alleles, because they are the best short distance sports. SPEED!

Screen shot 2014-03-21 at 1.26.20 PM

On the other hand, the championof Tour de France,Chris Froome, and the champion of the ITU Triathlon World Championships, Francisco Javier Gómez Noya, are most likely homozygous for the I alleles, because their bodies are using the blood flow more efficiently for a long time and distance.ENDURANCE!

Analyze and predict, whether you are team D or team I, or both!


Now let’s talk about the big guns that we’re working really hard for, and what affects them!

We have three types of muscles and one of them is skeletal muscle that supports our bones and affects our skeletal movement. Skeletal muscles are divided between slow twitch muscles, which are rich in capillaries and mitochondria causing efficient use of oxygen for energy, and fast twitch muscles, which are divided into three subtypes that generate short bursts of speed and power and are dependent on glucose for energy.

Actin-binding proteins, primarily ACTN-2 and ACTN-3, are essential components of a superstructure including structural, contractile and machinery proteins that generate contractile force in muscle fibers. While ACTN-2 is expressed in all skeletal muscle type, ACTN-3 is found in only the fast twitch muscles where it connects to actin filaments to control muscle contraction (Figure 2).

Screen shot 2014-03-19 at 5.19.14 PM

Figure 2. The ACTN-3 proteins stabilize the actin filaments, in the fast twitch muscle fibers, to the Z-line with the help of other mechanical and structural proteins. The ACTN-3 protein increases the integrity of the fast twitch muscle fibers.


So what’s so special?!

Researchers found that the ACTN-3 gene is highly associated with elite athlete performance, and that the gene has two alleles, a null 577X allele and a functional 577R allele. The null allele is caused by a premature stop codon, where the functional allele has an arginine instead of the stop codon.

While both alleles can be found in in everyone and still be associated to high performance athletes, it is the higher than “normal” frequency of the alleles in elite athletes that makes it a PEP. 

By comparing between elite athletes and controls, researchers have found that “Speed” athletes like sprinters have a very low frequency of the null phenotype (6% for sprint athletes and 18% control), and higher frequency of homozygous functional 577R phenotype (50% vs.30%). Therefore, demonstrating that a higher ACTN-3 (a homozygous 577R allele) increases the amount and efficiency of fast twitch muscle.  When comparing between endurance athletes and controls, researchers found the opposite results, where endurance athletes had higher frequency of the null allele and lower frequency of the functional allele.

Athletes with the null ACTN-3 genotype have a great advantage in endurance training, where the lack of ACTN-3 is compensated by the expression of ACTN-2, leading to more efficient use of energy and oxygen and displaying the characteristics of slow twitch muscles.

 So it’s a win win!!


 HOWEVER, you have to keep in mind that this is not random at all… it’s all evolution.

Yup, I used the E word.

Human beings are one complex organism, so it’s not as easy as having certain PEP or not. Many of the polymorphisms discovered have been associated to certain ethnicities, where they mean nothing in other populations! And that’s why Uzbekistan and Australia, for example, started testing PEPs in their athletes years ago, to know what works for them, and not depending on researches from the U.S. or China.


 Anyhow, think about it; what alleles could you have, and let us know maybe!

And ask your self again, can you run a marathon, or sprint to the first place?

Personally, (according to my trainer) I’m better at endurance sports, which is not a surprise with two soccer player brothers in defense and center midfield position. But, what about the sprinter?! He might be heterozygous or mutated…


– References to the post are found in the References page