SiRNA – Building Better Bodies by Turning Genes on and Off

Even as the 2008 Olympics in Beijing are gaining momentum, the subject of doping is making its way into the coverage. That is to be expected. The prevalence of doping among athletes in professional, college and high school sports is well documented. And up till now, doping has always involved muscle-enhancing drugs such as steroids and recombinant growth factors.

Growth factors such as Human Growth Hormone, or HGH, and other new age drugs result from recombinant DNA technologies of the mid-1980s that a decade later led to drugs approved for human use to treat growth deficiencies.

In theory, these same growth-promoting drugs could be introduced into humans using gene therapy. However, gene therapy has been notoriously difficult to control, and once you introduce the gene, how do you take it back after its effect is no longer needed? After all, modern athletes who wish to cheat the system to achieve their athletic goals may wish to return to a normal life after athletic ambitions have been satisfied. With gene therapy there may be no way to reverse the unending effects of alien muscle-enhancing genes.

However, a new genetic solution is emerging that may solve the problem of uncontrollable long-term effects and offer a new, easier way to cheat the system.

In a 2004 Scientific American article titled, “Gene Doping,” H. Lee Sweeney describes the “Belgian Blue Bull” as the bovine version of the Incredible Hulk. The Belgian Blue Bull is a freak of nature because an inherited genetic mutation in the breed deactivates both copies of the gene that encodes myostatin, a protein that inhibits muscle growth so the organism can maintain a balance between muscles and skeleton. The absence of this protein not only allows unchecked muscle growth, it also inhibits fat deposition. As a result, this bull is incredible lean muscle bulk-a bigger, stronger, and, yes, faster bull.

In a recent paper in Trends in Genetics titled “Sprinting without myostatin: a genetic determinant of athletic prowess,” author Se-Jin Lee of Johns Hopkins University describes the occurrence of this myostatin mutation in mice, sheep and bully whippet racing dogs. In whippets, mutations in both copies of the myostatin gene lead to a dog with twice as much muscle mass. A mutation of only one copy of the myostatin gene results in about a 25 percent increase in muscle bulk with increased athleticism.

Among humans, a 2004 article in the New England Journal of Medicine reported on a child whose mutation affected both gene copies, meaning the child has no myostatin. The child’s mother, who was an accomplished sprinter, has one mutated copy of her myostatin gene. The child appeared extraordinarily muscular at birth and was noted to be unusually strong at seven months. At age 4 the child was monitored for cardiac function, but no cardiomyopathy was found.

Beyond naturally occurring mutations, the last five years have seen a new approach known as RNA interference to intentionally silence genes to treat diseases. The effectiveness of what is known as siRNA has been established for silencing genes , such as a gene in the liver of primates that causes high blood cholesterol.

Development of this technology has brought about rapid growth, creating a billion-dollar industry in just five years. In addition, large pharmaceutical companies such as Merck, GlaxoSmithKline, Novartis, Pfizer, and Hoffmann-La Roche are buying up or partnering with the smaller, innovative companies including Alnylam and Sirna Therapeutics, which own the patent rights to the siRNA technology.

It would take only a few weeks to design and synthesize an RNA interfering drug that could silence the gene that encodes myostatin, which is active only in muscle. Gene silencing of myostatin to produce a better athlete could, in theory, be accomplished by injecting siRNA into the area targeted for muscle building.

Indeed, researchers at Sirna Therapeutics have already produced siRNA’s that shut down myostatin expression, and Sirna has filed a U.S. patent application (US 20050124566) on the use of these compounds to increase muscle mass for increased strength, athleticism, bodybuilding, or cosmetic applications.

Targeting other genes has demonstrated lasting inhibitory effects of three to four weeks with a single siRNA injection. Since this is not classic gene therapy, this approach to muscle building can be reversed, avoiding problems associated with the life-long physiologic consequences of non-reversible myostatin deficiency.

A number of other human genes have also been mentioned as possible targets for gene doping in athletes. However, those muscle-enhancing genes would have to be introduced into the athlete with no guarantee of the lasting outcome. It seems more likely that siRNA will find its way to athletes who wish to cheat and the enablers who wish to exploit athletes to make money.

There may be no way to test for the type of genetic manipulation. Nevertheless, the US and International Olympic Committees should advocate for national laws to be enacted by all participating nations to make genetic manipulation of athletic traits unlawful. The ethical dilemma here is should athletes be denied the ability to acquire athletic traits that have been naturally acquired by others?

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