The hulk gene

Scientists have unlocked the code for unlimited muscle growth, a breakthrough that has the potential to save millions of lives—and create lots of really muscular people.

IN 1997 Se-Jin Lee, M.D., a professor of molecular biology and genetics at Johns Hopkins’ Institute for Basic Biomedical Sciences, with the assistance of thengraduate student Alexandra C. McPherron, made a groundbreaking discovery. While studying cell growth and differentiation in mice, Lee and company found that by knocking out a previously unidentified gene in embryonic mouse cells, they could create “mighty mice”—animals that carried twice as much muscle mass as their normal siblings. Lee dubbed the previously undescribed gene “myostatin,” after the protein whose release it is coded to trigger.

Myostatin protein limits muscle growth in a number of animals during the developmental and adult stages. The myostatin gene regulates it in much the way a spigot regulates the flow of water. Normally, the spigot is left open, myostatin is released into the bloodstream, and skeletal muscle growth is kept in check. When the spigot is turned off, however, as in the case of Lee’s mighty mice, muscle growth is unimpeded. McPherron et al. described the phenom enon in the May 1997 scientific journal Nature. A startling photo of a transgenic mouse side by side with its genetically unaltered brethren reveals that the genetically altered mouse sports bulging calves, round sweeping thighs, and knotty back muscles, but the control mouse is typically mouselike. In describing his muscular subjects, Lee was quoted in Johns Hopkins Magazine as saying that “they look like Schwarzenegger mice.”

It wasn’t long before Lee noted that his heavily muscled mice bore a close resemblance to a couple of other Mr. Olympias of the animal kingdom, namely the Belgian Blue and Piedmontese breeds of cattle. Like the mice, the beefy bovines are the result of genetic manipulation, but not the kind done in a lab.

In the early 1800s, Belgian livestock breeders noticed that some of their cattle possessed much more muscle and less fat than others. Seeing the upside to lean, meaty stock, they crossbred the biggest of the big to create a lineage of super muscular cattle, commonly referred to as “double-muscled.” The half-ton-plus, marathon-runner-lean animals became highly prized for their rich meat.

Gregor Mendel may have become famous as the “father of genetics” for his cross-pollination of pea plants, but the cattle breeders were unwittingly conducting a form of genetic research all their own and in many regards as significant as that done by Mendel.

What the Belgian breeders didn’t consider at the time, but Lee would confirm two centuries later through gene analysis, was that they’d managed to breed cattle that carried a mutated version of the myostatin gene. The result was oversize muscles due to both hyperplasia (the creation of new muscle cells) and hypertrophy (the expansion of existing muscle cells).

With evidence mounting, it became apparent that the myostatin gene might be the key to unlocking the mysteries of muscle-wasting diseases, such as muscular dystrophy, in humans and may even offer hope for a day in which muscle degeneration would no longer be an inevitable by-product of the normal aging process. Of special note to researchers is the fact that myostatin suppression shows a dramatic effect on skeletal muscle but little, if any, effect on smooth muscle and cardiac muscle: The internal organs, as well as the hearts, of the transgenic mice, like the cattle’s, remained normal in size.

Of course, altering genes in the embryonic stage of development is a technique that can’t be applied to MD patients, even if myostatin were found to play the same role in humans that it did in mice. “ ‘Knocking out’ the myostatin gene isn’t possible for treating patients,” Lee said in a 2002 interview quoted in Science Daily, “but blocking the myostatin protein might be.”

1. THE IGF-1 ANGLE

At around the same time Lee and his co-workers were conducting their experiments, University of Pennsylvania professor H. Lee Sweeney, Ph.D., was leading a team of researchers investigating a different form of gene therapy to increase muscle mass, also in hopes of mitigating the effects of muscular dystrophy. Rather than using a method of subtraction (myostatin protein), Sweeney’s group focused on increasing the production of a hormone known to influence the production of muscle—insulinlike growth factor-1 (IGF-1)—with rats as the test subjects. IGF-1 is secreted by the liver and produced in other tissues, such as muscles, and promotes growth via several different means.

The team injected the hind legs of the rats with a modified virus containing a gene that would trigger increased production of IGF-1. Then the rats were put on an intensive training regimen of ladder climbing to exercise their leg muscles. The result was a 15–30% increase in the size and strength of the rats’ legs. Even those not put through this experimental rat race displayed a muscle mass increase of 15–20%.

One potential downside to the IGF-1 therapy, however, is that, unlike myostatin, the hormone affects an array of tissues besides skeletal muscle. Although no negative side effects were reported in the study, questions remain as to whether ancillary tissue growth could be a by-product of the injections.

Although the results of the IGF-1 study didn’t yield the same kind of muscle-mass gains as the myostatin project, the upside was that the therapy was performed on mature animals, rather than embryonic ones. The implication was that injections directly into mature muscles could result in significant growth on a site-by-site basis.

Still, neither approach had been tested on humans, and it was unclear whether such genetic tampering would even yield similar results. Although the lab mice and rats showed no visible side effects, the question remained as to whether unrestricted skeletal muscle growth would prove safe in people.

Then, in 2004, news broke of a toddler in Germany whose existence would advance muscle-building science as much as all the hypermuscular mice, rats, and cattle combined.

2. THAT’S MYO BOY

When pediatric neurologist Markus Schuelke of Charité University Medical Center in Berlin, Germany, took his first glance at a particularly jittery newborn in 1999, the doctor immediately noticed a startling physical anomaly. Like those of Lee’s mice, the boy’s limbs were bulging with well-developed muscles. He looked as if he had been pumping iron for years, despite being fresh from the womb. Only weeks earlier, an associate of Schuelke’s had read the report by Lee and his colleagues and suggested that the boy might have a naturally occurring mutation to his myostatin gene, as in the Belgian Blue and Piedmontese cattle.

Using a special device, Schuelke discovered that both copies of the boy’s myostatin gene were inactive, meaning he produced no myostatin at all. He was essentially a muscle-making machine without an “off” switch. Other than muscle size and strength about twice that of an average baby, however, Super Baby showed no abnormalities or health issues as he aged. Most important, the absence of myostatin protein in his system did not affect the size of his heart muscle.

Upon testing the boy’s 24-year-old mother, who was naturally muscular, it was discovered that she, too, had the myostatin gene mutation, although only in a single copy of her myostatin gene. The other mutated gene almost definitely came from his father, but no information about him was disclosed. Interestingly, it was reported that the men of the woman’s family were unusually strong, with her grandfather being said to manhandle 330-pound curbstones as a construction worker.

At last, definitive proof existed to support the theory that myostatin affected humans in the same way as animals. “It’s a huge step,” Lee told The Seattle Times. “Based on animal studies, we thought it worked in humans. But there was lingering uncertainty.

“Now we can say that myostatin acts the same way in humans as in animals,” commented Schuelke, as reported by the Associated Press. “We can apply that knowledge to humans, including trial therapies for muscular dystrophy.”

3. EDGE OF REALITY

In December 2005, a report was published in the Proceedings of the National Academy of Sciences citing the development of an agent by Lee’s group that trumped all others in producing muscle. The new myostatin inhibitor, called ACVR2B, worked far better and faster than even Lee had anticipated.

“The soluble form of the myostatin receptor is by far the most potent agent that’s been described to date, and we showed in that paper that just two injections of this agent spaced one week apart can increase muscle mass by 40–60%,” Lee says.

That means that only two weeks after the first of two injections of ACVR2B into a mouse muscle, there can be up to a 60% increase in mass. For researchers, as well as victims of muscle-wasting diseases such as MD and AIDS, Lee’s latest discovery holds exciting promise. For bodybuilders and strength athletes, it could mean an advantage so great that it would leave steroids, growth hormone, and insulin in the dust. What’s more, unlike those ergogenic drugs, gene therapy would be, for practical purposes, undetectable.

It’s inevitable that Lee’s ongoing myostatin research, and possibly Sweeney’s IGF-1 project, will soon yield therapies that will save the lives of millions of people afflicted with muscle-wasting diseases. Aging will no longer mean a default loss of muscle size and strength, and seniors will suffer far fewer falls due to unsteady limbs. Recovery from injury or disease will not be hampered by muscle atrophy, and even astronauts spending prolonged periods in orbit can return to Earth without any loss of strength. All this may be possible and sooner than you might think.

This past October, researchers in China announced that they had engineered brother and sister beagles (named Hercules and Tiangou) with disruptions in both copies of their myostatin genes. Consequently, the siblings look like canine versions of the Incredible Hulk and the She-Hulk. Another dog breed, the whippet, has seen a gene mutation among its ranks without human intervention.

“Bully whippets” have one or both copies of their myostatin genes mutated, causing the normally wispy dogs to be loaded with rippling muscles.

Presently, Pfizer is conducting a Phase 2 study of an intravenous myostatin blocker on 6- to 10-year-old boys with Duchenne and Becker muscular dystrophy to see if it will help restore muscle mass and strength lost to the diseases. As of this writing, however, no results of human testing have been reported.

“There is every expectation that we will see the same effects in humans that we do in mice, given that myostatin plays a role in regulating muscle mass in humans, but we just don’t know,” says Lee. “There’s no data ddressing that as of yet. That will be answered to some extent by the clinical trial being run by Wyeth Pharmaceuticals. Of course, it’s not yet known what the longterm effects of living a life without myostatin will be.”

One potential long-term downside to quieting the myostatin gene function has to do with the source of new muscle growth—satellite stem cells. It appears that myostatin exists to regulate growth, which it does by ensuring that muscle cells do not overdraw from the store of satellite stem cells kept in reserve. What happens when stem cells are constantly being called into action is anyone’s guess. Do stem cells replenish indefinitely, or is there a finite supply? Another potential risk is the long-term effect on involuntary muscles, like the heart. The hearts of bully whippets and Piedmontese cattle aren’t especially large, but could long-term use of a myostatin inhibitor lead to heart-muscle growth?

Regardless of risks, unknowns, or medical caveats, it’s a sure bet that athletes will be hurdling over one another to be among the first in their sports to take advantage of myostatin treatment. treatment. Unforeseen long-term effects notwithstanding, myostatin blockers already appear to be more effective and safer than anabolic steroids, growth hormone, and insulin, the three most prominent ergogenic drugs used by athletes today. In addition, testing for genetic mutation would be a far less practical and reliable affair.

The questions that should most concern bodybuilders and other athletes are not scientific in nature but moral. If a treatment is created to benefit the diseased and dying, what are the ethical ramifications of using it for personal glory?

On a sliding scale of morality, how does genemutation therapy compare with steroid use, fixing a game, or corking a bat? Certainly, it would become illegal to administer such therapy without the consent of a physician, so how does one justify breaking the law in the name of athletic performance?

With any new technology comes debate over how it should be used, regulated, and harnessed. The current state of genetic testing in the area of muscle growth necessitates that the time for such discussion is now.

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