Building better bodies (2008, March 22)


Building better bodiesSome athletes willing to use untested therapies that scientists are developing for patients

Curtis Eichelberger Bloomberg News

Saturday, March 22, 2008

Chris Rosa has spent 26 years in a wheelchair awaiting a treatment for his muscular dystrophy. Within the next five years, even before new drugs are approved for him, athletes may try using them to cheat, sports doping authorities and scientists say.

"I get angry about it," said Dr. Se-Jin Lee, the Johns Hopkins University scientist who discovered a protein being developed for diseases including muscular dystrophy. "The scientific potential to make people's lives vastly improved is incredible. And all we talk about is whether some athlete can use it to hit a baseball farther."

Wyeth, Amgen Inc. and closely held Acceleron Pharma Inc. are experimenting with spurring muscle growth by suppressing a chemical called myostatin, found by Lee in 1997. Doing so would reverse atrophy caused by wasting illnesses and aging -- and create a hard-to-detect, non-steroid shortcut for increasing the size of healthy tissues.

Agencies that police sports for performance-enhancing substances say myostatin blockers may reach athletes as soon as this year's Olympics and certainly by 2012. The World Anti- Doping Agency has banned them even before they have been fully tested. Meanwhile, that group and sports organizations including Major League Baseball are monitoring other treatments known as gene doping, in which cells are reprogrammed to enlarge muscles.

The Montreal-based anti-doping group, created in 1999, has already spent $6.5 million on finding ways to detect athletes using gene-altering technologies. The group plans to work with companies making myostatin inhibitors when trials are more advanced, according to Olivier Rabin, the agency's science director.

"We have to prepare ourselves for misuse in sport soon," Rabin said in a telephone interview. Some athletes might try to use the new muscle-building medicines as soon as the 2012 Olympic Games in London, he said.

The new drugs may be particularly difficult to detect because they are injected directly into the targeted tissues and could be designed not to show up in urine and blood tests, researchers say.

As a U.S. House of Representatives subcommittee probed the use of steroids in professional sports, witnesses at hearings in January and February warned that next-generation drugs may enable athletes to rewrite record books.

"When we think we have a problem solved, there are chemists creating new problems," said Bud Selig, the commissioner of Major League Baseball, told the House panel Jan. 15. Baseball "hired the best experts that we can" on gene doping, he said. Selig didn't address myostatin blockers.

Drugs to inhibit myostatin are being developed to help patients like Rosa, 40, who is the director of student affairs at City University of New York. He was diagnosed with muscular dystrophy at age 14. He remembers spending childhood summers playing stickball in the shadows of New York's Shea Stadium and the winters emulating St. John's basketball player Chris Mullin.

"I can't dream about my future without worrying about how this disease might skew my life expectancy," Rosa says.

In healthy people, muscle mass is determined by need. As exercise tears fibers, the cells instruct the tissues to rebuild themselves bigger and stronger to handle increased workload.

Patients like Rosa lose muscle and never rebuild it. The same process affects people with amyotrophic lateral sclerosis, also called Lou Gehrig's disease, after the New York Yankees Hall of Fame baseball player whose career it ended. Others lose muscle as they age, affecting stability when walking.

In 1997, Lee at Johns Hopkins in Baltimore created mice lacking a gene to make the protein myostatin and showed that they developed more muscle. He and other scientists later showed that the substance regulates growth of the tissues. Michael Bloomberg, the majority owner of Bloomberg LP, is a former chairman of the Johns Hopkins board of trustees, and the university's school of public health is named for him.

Wyeth, based in Madison, New Jersey, and Amgen, based in Thousand Oaks, California, are testing myostatin blockers in humans. Neither company would discuss the drugs' potential for abuse by athletes. "Amgen's mission is to serve patients," said spokeswoman Anne McNickle.

Wyeth, the fifth-largest U.S. drugmaker, is developing MYO- 029, an antibody molecule that attaches specifically to myostatin and blocks the signal instructing muscles to stop growing. The results of an early study, with more than 100 patients in the U.S. and the U.K., will be published this year, said Michael Lampe, a Wyeth spokesman.

Amgen, the world's largest biotechnology company, has started a safety trial for a myostatin blocker called AMG-745. McNickle declined to how say many patients are participating.

Acceleron, in Cambridge, Massachusetts, will begin safety trials this year for its myostatin treatment, ACE-031, said Steven Ertel, vice president of corporate development. Acceleron has reported that rodents given the substance had a 60-per-cent increase in muscle growth and primates, at least 10 per cent.

"What I care about are the five-year-old children diagnosed with muscular dystrophy who will be in a wheelchair by 12 and oftentimes dead by their early 20s," said John Knopf, Acceleron's chief executive officer."The focus here isn't on athletes."

Nonetheless, participants in sports are following the development of myostatin inhibitors. Lee, the Johns Hopkins School of Medicine molecular scientist, recalls putting down a test tube one day about two years ago to take a phone call from a Brazilian bodybuilder who had e-mailed for weeks with questions about the substances.

"I was explaining that we were still in the testing phases and that a drug Wyeth has in trials, and he interrupted me and said, 'MYO-029?' " Lee said during an interview at his laboratory. "He said, 'I have some right here. I just want to know if it's safe to take.' "

"I warned him against taking something that hadn't been thoroughly tested," Lee said. "It was a shocking conversation."

Geneticists Lee and Alexandra McPherron discovered myostatin when they were studying how cells send signals to each other. The material was one of the communicating molecules they identified. Lee later found that while the protein plays a predominant role in controlling muscle growth in mice, it is just one of many regulators in humans, and might not even be the most important, he says.

In Philadelphia, Dr. Lee Sweeney is developing a different, gene-based approach to increasing muscle mass. Sweeney, the chairman of the physiology department at the University of Pennsylvania's School of Medicine, recalls watching his grandmother struggle with muscular atrophy in her final years, until she was unable to care for herself.

In the late 1990s, he injected mice with a synthetic gene that produced IGF-1, for insulin-like growth factor 1, and saw a 30 percent gain in muscle. Later, rodents were genetically engineered to overproduce IGF-1 in their skeletal muscle. These sedentary mice experienced increased muscle mass of as much as 50 percent. The substance instructs the tissues to grow.

U.S. newspapers and magazines picked up on medical journal reports of his work, and football coaches started calling, Sweeney says. One offered his own athletes as test subjects.

"I kept telling them that my research had only been done on mice and that it could potentially kill a person," Sweeney said. "I finally had to hang up on some of them."

Sweeney's research has graduated to dogs from mice. It's a big step, because the dog's immune system is more similar to that of a human, he says. Treatments that safely alter the muscle mass of a mouse might trigger a canine's immune system to attack tissues injected with new genetic instructions.

That's why the medicines aren't yet safe enough for athletes or anyone else to try, Sweeney says. He worries that a rogue lab could be built for as little as $500,000 to turn out untested materials to meet athletes' demands, he says.

"You have athletes out there who want to become champions so badly that they are willing to risk their health and their lives," Sweeney says.