Online Extra: Regenerative Medicine's Slow Start

Scientists think proteins that spur the body to heal could make powerful drugs, but harnessing that potential has been tough

When Human Genome Sciences (HGSI ) announced in February that it would abandon an experimental wound-healing drug, the news dealt a blow to the emerging field of regenerative medicine. The product, called Repifermin, is a protein-based drug that HGS scientists believed would speed up healing by stimulating tissue growth. But when they tried it on three different types of wounds, it just didn't work.

What makes this failure particularly poignant is that HGS's founder, William Haseltine, has long been one of the most vocal boosters of regenerative medicine. While Repifermin hasn't quite turned him into a pessimist, "I'm a realist," says Haseltine, who plans to retire as HGS's CEO later this year. "Regeneration is where medicine is going. But we must temper our enthusiasm. It's going to take a lot of careful work to sort out what's going on here."

Indeed, what science understands about proteins is still rather elementary. It's well known that cells contain genes that produce proteins that stimulate growth and repair. Stem cells -- the master commanders of development -- give rise to all the other cells in the body. But implanting cells into patients to promote regeneration is risky and controversial.

"THE PLACEBO WORKED GREAT."

  So, many scientists are now asking these questions: Is it possible, instead, to identify the proteins key to regeneration, grow them in factories, and then inject them into patients to regrow damaged tissues? Or even better, could drugs be developed that would prompt the human body to make more of these proteins when it needs them?

While the concept is appealing, the actual execution has been littered with failures. Biotech giant Genentech (DNA ) has been wrestling for years with a protein called VEGF, which promotes blood-vessel growth. Genentech did succeed in blocking VEGF: Its new colon cancer drug, Avastin, inhibits the protein, which in turn cuts off the blood supply to tumors.

Then the company tried to do the opposite -- boost VEGF -- in patients with angina, in the hopes of improving blood flow through the heart's oxygen-starved regions. Nothing happened. "The placebo worked great," jokes Charles Semba, Genentech's associate group director of vascular medicine and neurology.

MULTIPLE HEALERS.

  One drawback of proteins is that they don't linger in the body for very long. Semba believes that the VEGF cleared out of patients before it could do them much good. So now Genentech is trying again -- this time in a setting where the protein will stay put. It's working on a VEGF booster that can be topically applied to diabetic ulcers, which are painful wounds that patients with diabetes often develop on their feet. Because the drug can be applied as a gel, "the VEGF will sit on the wound and linger," Semba says. Genentech is now planning clinical trials.

A growing body of scientific evidence suggests that in some diseases, however, one protein might not be enough. In March, scientists at New York-Presbyterian Hospital/Weill Cornell Medical Center announced that when they added two proteins to VEGF and then injected the cocktail into rats' hearts during heart attacks, they decreased the damage to the heart by 40%.

Of course, injecting proteins directly into the heart may not be feasible in an ambulance or emergency room. That's why scientists are now trying to identify molecules that will stimulate the body to make more of these proteins when it needs them -- ideally something that could be given to patients as a pill or by intravenous drip. "We're looking forward to the day when we can tickle the body to do this itself," says Dr. Jay Edelberg, assistant professor of medicine at Weill Cornell Medical College.

"IT'S EARLY DAYS."

  Figuring out which cocktails will spur regeneration could take decades, and the task will be complicated by safety concerns. Already, early studies have shown how dangerous it can be to alter the body's natural chemical balance.

In two separate studies, brain tissue from aborted fetuses was transplanted into patients with Parkinson's disease in the hopes of boosting their levels of dopamine -- a vital neurotransmitter that's depleted in people who have the disease. In some patients, the tremors that characterize the disease actually worsened, possibly because the transplanted cells were emitting too much dopamine. "If we don't get a handle on how to control these therapies, we're going to continue to have problems," says Dr. Alan J. Russell, director of the University of Pittsburgh's McGowan Institute for Regenerative Medicine.

Despite the hurdles, the biotech industry is pressing ahead in the hunt for therapeutic proteins and for effective ways to deliver them to patients. The possibilities range from injecting genes to implanting tiny machines that would churn out the necessary proteins nonstop. "It's early days," says Chris Fibiger, chief of neuroscience research at Amgen (AMGN ). The biotech, the world's largest, is studying the use of proteins in neurodegenerative disease.

"It's very promising. But there's still a lot of biology and molecular engineering to be done," says Fibiger. And many more hurdles to clear before the restorative power of proteins can be fully realized.

By Arlene Weintraub in Los Angeles

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