While watching the news broadcast of President Schwarzenegger’s speech, Martin looked at a reflection of himself in a mirror across the room. He marveled at his own physique, with his 23-inch arms and 22-inch, well-defined calves. At a height of 6’, Martin carried 325 pounds of solid muscle, with a bodyfat level of a mere 5 percent. Martin was in the midst of training for the International Galaxy bodybuilding show, the premier professional bodybuilding contest. The Galaxy contest had superseded the old Mr. Olympia event that Arnold had won so long ago.
Just a few years earlier Martin had been an average competitor, hardly good enough to compete in a national contest, much less an international professional event. Even though he indulged in the gamut of available anabolic drugs, it seemed he didn’t have the genes to compete with the big boys at the pro level.
Then Martin discovered gene doping. The first thing he used was an injected form of the gene for insulinlike growth factor-1 (IGF-1). Although the therapy had been developed solely for use in treating muscle-wasting diseases, such as muscular dystrophy, athletes had jumped at the chance to use gene therapy for athletic enhancement. In fact, the last Olympic games said to be untainted by gene doping was way back in 2004, at the Summer Games in Athens. A short time later gene doping made its way into sports.
Martin responded spectacularly to the IGF-1 gene therapy. His bodyweight rose from 240 pounds to more than 300, and the gain was all muscle. He soon added other gene therapies. One was a highly active cleavage product of IGF-1 called mechano-growth factor. Although he wasn’t blessed with great calf development, when Martin injected the MGF gene into his calves, they grew to massive proportions overnight.
Dieting used to be difficult for Martin. Those low-carb plans made him dream about ice cream and pizza orgies. The days of hunger, however, ended with the advent of the new fat-burning drugs. One worked by inhibiting the gene for an enzyme called acetyl coenzyme-A carboxylase, which synthesized another chemical called malonyl-coenzyme A. Now Martin burned fat 24 hours a day. He was burning fat as he listened to Arnold once again thank everyone for the grass-roots campaign that had led to the constitutional amendment permitting him to run for president.
Martin’s reverie was broken by the sound of his phone ringing. His doctor was calling. “Martin, your tests came back, and I have some bad news for you.”
While the above scenario may seem farfetched, most scientists who monitor the athletic-drug world say that gene doping is just around the corner. Drug use in sports has long been a cat-and-mouse game, with many athletes seeking performance-boosting substances that can’t be detected and sports authorities trying to keep pace by developing new tests to find them. The great concerns about gene doping are that there isn’t any known way to detect it and that detection tests won’t be available for the foreseeable future—if ever.
Gene doping involves the insertion of artificial genes into muscle cells.1 An inserted gene then produces RNA, which dictates the synthesis of specific proteins by the cell. At present the most familiar technique for manipulating genes involves a protein, myostatin. Discovered in 1997, myostatin inhibits muscle growth. Animals born without genes that code for it usually show unprecedented muscular size, with a concomitant lack of bodyfat. Scientists then tested how myostatin works—in animals—by breeding special “knockout-gene” rats, in which the genes that code for myostatin were knocked out. As expected, the rats showed muscles about two to three times the size of normal rats.
The New England Journal of Medicine recently described a five-year-old German boy who was born without myostatin genes. His mother, a track athlete, has only one gene for myostatin, which makes her look exceptionally muscular. But her son is something else. At the tender age of five he already shows signs of unusual muscle mass and strength. In all other ways, however, he appears completely normal. Is he a future Mr. Olympia or some other world-class athlete?
To answer that question, consider how myostatin works. Special stem cells called satellite cells are normally recruited after muscle injury (including that induced by exercise) and contribute nuclei that result in the thickening of existing muscle cells by adding a buffer to them. We recognize this as added muscle size. The satellite cells are stimulated primarily by locally produced—that is, produced in the muscle itself—insulinlike growth factor 1 (IGF-1). Myostatin works by blocking satellite-cell function, and that inhibits muscle growth. Get rid of the myostatin, and you get rid of the impediment to muscle growth.
Some scientists think that the supply of satellite cells is finite. Indeed, one reason for the weakness and loss of muscle that accompanies aging is that the body somehow loses the ability to adequately recruit satellite cells for muscle recovery. One scientist has suggested that since the German child produces no myostatin, he may exhaust all his satellite cells by about age 30. What happens after that is anyone’s guess.
Several muscle diseases are the result of birth defects involving the lack of essential muscle proteins, such as dynorphin in some forms of muscular dystrophy, that lead to extensive muscle weakness. To combat it, one form of gene therapy injects an IGF-1 gene directly into muscle. To get into the muscle, the gene must be packaged with a vector, or delivery vehicle—typically an inactive virus, which shunts the IGF-1 gene into the muscle cell. The cell then starts pumping out IGF-1, which in turn promotes the activity of satellite cells. If it all works out, you wind up with bigger and stronger muscles.
A study with mice showed that IGF-1 gene therapy worked perfectly, with the treated mice experiencing gains in muscle size that amounted to hypertrophy, or growth, two to three times normal. Injecting the gene for mechano-growth factor, which is a derived form of IGF-1, made the mice double their muscle size in only three weeks.
Gene therapy uses a magic bullet approach to seek and destroy cancer cells. It may also enable the body to produce substances that are in short supply due to illness or aging. For example, hormones can theoretically be boosted by gene therapy. People born with defective genes that amount to biological time bombs could perhaps have their defective genes replaced.
While it all sounds great and one day will likely change the face of medicine, it is new, and all of its ramifications are unknown. The possible dangers of gene therapy became evident in a case reported in 1998: An 18-year-old patient with a rare type of liver disorder—not life threatening—was offered the chance to serve as a human experiment in gene therapy to treat the condition. The patient readily agreed, but he died from multiple organ failure.
Several possible gene therapies appear attractive to athletes, despite the dangers. One involves injected gene-encoded viruses for erythropoietin. EPO increases the volume of red blood cells, which in turn, increase oxygen delivery to cells. Blood doping was based on increasing the number of red blood cells. It was superseded by using recombinant-DNA drugs based on EPO. Use of the technique was popular with all types of endurance athletes and led to a scandal at the 1998 Tour de France, when an entire team was found to be using EPO-based drugs.
Gene therapy for EPO, however, cannot be detected. In a 1997 study mice and monkeys got EPO gene therapy that resulted in an 81 percent increase in the level of hemoglobin, the protein that carries oxygen in the blood. But the animals’ blood got so thick from all those new blood cells that they had to have their blood diluted to prevent heart failure and stroke.
One advantage of injecting the IGF-1 gene is that it stays localized to the muscle. The problem with systemic IGF-1 is that it stimulates all types of cellular growth, including cancer. Keeping it sequestered in muscle should prevent that problem, but scientists remain uncertain of the ramifications of injecting what amounts to an IGF-1 production plant in muscle.
Another type of gene therapy with potential athletic uses is the gene for vascular endothelial growth factor. That gene is inserted into the body with the same virus that causes the common cold; the activity of the virus is blocked. VEGF works by promoting the growth of new blood vessels, which means increased blood and oxygen delivery to muscles, lungs, liver and other tissues. On the other hand, cancer cells also spread throughout the body by promoting the production of new blood vessels. Will overproducing VEGF promote cancer? Who knows?
Two other growth factors linked to increased muscle-satellite-cell activity—fibroblast and hepato—are candidates for gene therapy. Another therapeutic idea is to manipulate genes that lead to muscle catabolism, such as the ones for myostatin and a protein called ubiquitin. Blocking them alone would lead to considerable muscular growth. Deleting the gene for cytosolic phospholipase A-2 also promotes increased muscle growth.2
Make no mistake: Gene therapy is the wave of the future in sports doping. You’ll know when it’s here by the number of world records that fall and by the appearance of athletes who use the growth-promoting gene therapies, such as those involving IGF-1 genes. The unanswered question is the fate of the athletes who turn themselves into human clinical experiments. Perhaps those contemplating using gene therapy might pause to consider the classic case of an experiment gone wrong: Dr. Jekyll and Mr. Hyde. Or better yet, Mary Shelley’s Frankenstein.
References
1 Unal, M., et al. (2004). Gene doping in sports. Sports Med. 34:357-62.2 Haq, S., et al. (2004). Deletion of cytosolic phospholipase A2 promotes striated muscle growth. Nature Medicine. 9:944-51.
©,2012, Jerry Brainum.Any reprinting in any type of media, including electronic and foreign is expressly prohibited.
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