Repairing The Engines Of Life

David Ames was paddling out to sea on his surfboard in Cabo San Lucas in 2002, hoping to catch a huge wave when he realized that something was terribly wrong. The hard-core surfer, cyclist, and weight lifter, who was then 40, didn't have the muscle to even get out to the wave. Several months later, he was handed a cruel diagnosis: amyotrophic lateral sclerosis, better known as Lou Gehrig's disease. The illness destroys motor neurons in the brain and spinal cord, gradually robbing victims of their ability to move -- and ultimately to swallow or breathe. There is no cure, and patients are unlikely to survive more than five years.

Since receiving the news, Ames has tried everything from anti-inflammatory drugs to Chinese herbs. Still, he knows his best hope lies in something that has yet to be discovered: a way to regrow the lost nerve cells in his brain. Scientists are certain it's possible. But the effort to turn conviction into therapy has been stymied by research setbacks, funding shortages, and a political storm surrounding stem cells. These cells can be a universal source for growing the body's many tissues, and the most versatile ones are harvested from human embryos, drawing censure from some religious groups. "It's frustrating when you have a disease with a fast clock on it," says Ames, a San Francisco lawyer. "We'll get there. It's just a matter of when."

Ames's story captures the tragic collision of hope and promise that defines the nascent field known as "regenerative medicine." A growing cadre of scientists in academic and biotech labs across the world are pioneering a new approach to curing disease. Their goal isn't to develop drugs that slow down the brain's decline or to fight heart failure by formulating copycat cholesterol-lowering pills and telling people to eat fewer potato chips. Scientists on this frontier hope to reprogram the human body to heal itself.

Regeneration is biotech's Holy Grail -- and the ultimate scientific conundrum. Most living creatures are hard-wired for healing. But when it comes to regrowing entire body parts, humans are curiously deficient. Sure, if we scrape a knee, we sprout new skin. Our livers also can regenerate to some degree. Even a severed fingertip will grow back under the right circumstances. But that pales in comparison to, say, a lowly newt, which can regrow a leg, tail, jaw, intestine, spine -- even parts of an eye. Scientists wish humans could do the same.

Progress Abroad

Many researchers, as well as patients and their relatives, are certain that stem cells offer one route to regeneration. That's why so many are coming forward to protest tough funding restrictions that the Bush Administration has slapped on research into stem cells derived from embryos. "I just don't see how we can turn our backs on this," said Nancy Reagan at a gala event on May 8 to raise money for stem-cell research. "We've lost so much time already, and I can't bear to lose any more."

Therapies flowing from such research might one day help victims of Alzheimer's disease -- though it's unlikely any will arrive in time to help the former President, who was diagnosed a decade ago. What's noteworthy is the groundswell of bipartisan support for stem-cell work. Nancy Reagan's comments came just days after 206 members of the House of Representatives signed a letter to George W. Bush beseeching him to ease restrictions, which withhold federal grants from projects involving any but a very limited set of cells that were isolated before the government imposed the ban.

Academic activists have another reason to press for lifting the ban: Embryonic stem-cell research is progressing quickly in Europe and Asia, which means hamstrung U.S. labs could find themselves upstaged in an important branch of an emerging science. "The federal government walked away from a great opportunity. The U.S. could lose its competitive edge," says David T. Scadden, professor of medicine at Harvard University and co-director of a new stem-cell research institute there.

Much of the regeneration crusade is focused on the twin engines of life: the brain and the heart. Nowhere is the need for new treatments more urgent. Heart disease kills more than 700,000 Americans each year, making it the leading cause of death in the U.S. An additional 200,000 people die of stroke, Alzheimer's, Parkinson's, and other brain disorders. The cost of these scourges is a crippling $400 billion annually, at least $15 billion of which is spent on drugs that do little more than treat symptoms. That's all today's drugs can do. After all, when a swath of heart muscle is starved of oxygen during a heart attack, it dies. Nothing can revive it.

As the battle over embryonic stem cells rages on, several biotechs are uncovering promising regenerative therapies from much less controversial materials. Some companies are studying adult cells that can be plucked from muscle or bone marrow, then planted into patients to stimulate repair. Others are searching for proteins that might harness the body's innate ability to regenerate itself. The first such treatments could hit the market within five years.

Big Pharma is slowly realizing that regeneration is no longer a pipe dream. Johnson & Johnson (JNJ), Wyeth (WYE), and Eli Lilly (LLY) are among the companies making major investments in the field (table). "We believe there is great potential for innovative new medicines," says Rosamund C. Smith, a scientist at Eli Lilly & Co. Not to mention a grand opportunity to regenerate sales and profits: The market for treatments targeting heart and brain diseases could more than double, to $35.8 billion, in the next decade, estimates consultant Decision Resources Inc.

Where Are the VCs?

Despite such tantalizing prospects, the struggle to regrow hearts and brains is sure to be long and agonizing. Nearly every advance so far has come with a battery of setbacks, from contradictory test results to dangerous side effects suffered by patients in early trials. These sobering developments, coupled with the outcry over embryonic stem cells, has frightened off some investors. "We know this is going to be big," says Alan G. Walton, a senior general partner in the Westport (Conn.) office of venture capital firm Oxford Bioscience Partners. "But we're waiting for someone to make a major breakthrough before we pile on."

Are breakthroughs on the horizon? Nature provides reason for optimism. In a tiny lab at Children's Hospital Boston, 3,000 zebrafish are charting a course to the future of cardiac medicine. Two years ago, the Harvard scientists who work here made a startling discovery: Unlike mammals, zebrafish can regrow their hearts. After slicing out 20% of the heart tissue from each fish in the study, the scientists were amazed to see that heart cells multiplied around the wounds and began generating replacement muscle. Soon the fish had new hearts that worked just as well as those they were born with. The next step is to identify all the genes and proteins that touch off this automatic repair process.

While scientists labor to translate the zebrafish phenomenon into something useful for humans, many biotechs are searching for other ways to fix a broken heart. Two miles away from Harvard's zebrafish lab is Genzyme Corp. (GENZ) -- the world's fourth-largest biotech, with $1.7 billion in annual sales, and one of the pioneers of regenerative medicine. Genzyme's experimental process involves removing hunks of thigh tissue, each roughly the size of a small rubber ball, from patients who have had heart attacks. Muscle cells called "myoblasts" are teased out, grown, and injected right into the damaged areas of those patients' hearts. These aren't stem cells, so they can't morph into myriad types of tissue. But Genzyme scientists believe the cells prevent the heart's wall from thinning out over time -- a devastating aftereffect of a heart attack that inevitably leads to congestive heart failure. In early trials in France, 10 patients saw an average 35% improvement in their hearts' pumping efficiency.

Myoblasts aren't quite ready to debut in cardiac-care wards, though. Some of the patients in Genzyme's trials suffered irregular heartbeats, and the cells might have been to blame. Furthermore, all the patients received the myoblasts during bypass surgery, so no one knows how much of the patients' improvement can be credited to the cells vs. the operation. "We can't make too much of any of this yet," says Earl M. "Duke" Collier Jr., a Genzyme executive vice-president who heads its cardiovascular research. "Does this prolong life? We're anxious to know." Genzyme has launched a large study to find out.

What is clear is that myoblasts are just the first step toward biotech's grandest ambition: real regeneration, à la zebrafish. Thigh cells don't give birth to heart muscle and thus will never be more than mere imposters. That's why scientists at Genzyme and elsewhere are experimenting with stem cells, which haven't yet formed their final identities. Many scientists hope they'll be able to prompt them to evolve into heart muscle -- or something with equal potential. And a growing stack of evidence suggests that the adult stem cells our bodies cradle throughout our lives might provide rich raw material for refurbishing damaged body parts.

Bone marrow, the golden core of the body's immune system, could be a wellspring of regeneration. In a study at the University of Pittsburgh's McGowan Institute for Regenerative Medicine, patients with congestive heart failure had two types of adult stem cells removed from their bone marrow and then buried in their hearts during bypass surgery. On Apr. 25, the university announced that after six months the hearts of the patients who got the cells pumped 24% more efficiently than those of people who only had surgery. Tissue samples suggest that the cells lodged in the patients' hearts and then churned out a protein that signaled new muscle was being produced. "Some of these people couldn't work, and now they've gone back to work," says Dr. Amit Patel, who led the study. "It's very promising."

Such optimism about adult stem cells always comes with a side order of worry. Scientists have yet to determine that these cells produce bona fide heart or brain tissue. And it's unclear if the cells stick around in the body long enough to do a complete enough repair job. Many stem-cell supporters remain convinced that only embryonic stem cells will be truly regenerative. They are, after all, the seeds from which the entire human body grows. Conceivably they could be harvested from early embryos, grown in labs, and given the signals they need to turn into heart muscle, neurons, or any other tissue for patients who need them.

For now, a political furor has quashed those hopes. The ban on research funding that President Bush imposed in 2001 was designed to placate supporters who abhor the destruction of embryos and others who object to techniques in which embryos are cloned for the harvesting of stem cells. American scientists cannot derive new strains of such cells, or even study those found overseas, using grants from the National Institutes of Health -- a crucial funding source. That infuriates stem-cell supporters such as the actor Michael J. Fox, who suffers from Parkinson's disease. "This research should not be treated as a political football. It's a potential breakthrough that could have a huge impact on people's lives," he says.

Filling a Gap

Some stem-cell researchers are fighting the law. In March, Harvard University professor Douglas A. Melton announced that he had created 17 new lines of embryonic stem cells with privately donated money. Harvard then unveiled plans to raise $100 million in private funds to create a stem-cell research institute. "We're not a political organization," Melton says. "We don't have to be concerned with election results. Our only concern is that scientifically this is the right thing to do."

States will also try to fill the funding void. Activists in California collected more than 1 million signatures in support of a state ballot initiative to allocate $3 billion for stem-cell research over the next 10 years. If it passes in November, lobbyists say it will put California on par financially with many countries that have prioritized such research, including Britain and South Korea.

Volunteers such as John Ames are working hard to keep the initiative in the public eye. The father of Lou Gehrig's patient David Ames, he spent many days on street corners collecting signatures. His concern is tinged with anger over the lack of progress in research that he believes could cure his son. "I'm appalled to see science governed by religious beliefs," says the elder Ames, 70. "I'm an activist now. I'm in your face."

In the San Francisco labs of biotech company Geron Corp. (GERN), activism takes a purely scientific form. Geron is working on turning embryonic stem cells into microscopic factories of regeneration. In November, Geron announced that one of its experimental products helped partially paralyzed rats with spinal cord injuries regain much of their ability to walk on all four legs. The trick involved forcing the embryonic cell to "differentiate" into an adult cell that produces myelin -- a protective coating that blankets the nerve fibers and allows them to transmit electrical signals from the brain. The destruction of myelin is the culprit in several neurological disorders.

While stem cells have received the most attention, many scientists are impressed with the restorative power of the bare proteins such cells produce. The key to regeneration could turn out to be as simple as a protein, or perhaps a cocktail of proteins, chemicals, and cells. Biotech giant Amgen Inc. (AMGN) is testing a molecule called GDNF. It stimulates the growth of neurons that make dopamine, a neurotransmitter lacking in patients with Parkinson's. At a meeting for Wall Street analysts in March, Amgen showed videos of patients who struggled to get out of a chair and walk across a room. After GDNF was injected into their brains, their ability to complete the simple task improved dramatically.

Still, protein-based drugs have drawbacks that could make them impossible for some patients to tolerate. Because they're large molecules, they don't easily penetrate or spread through the brain. That means they have to be squirted through a surgically implanted device right into the damaged regions. And the drugs don't remain in place for long, so they have to be infused continuously to have any effect. "GDNF is a baby step," says Amgen's executive vice-president for research and development, Roger M. Perlmutter. "We need better ways to do this."

Biotech startup Titan Pharmaceuticals Inc. (TTP) is placing its bet on cells that are normally found in the back of the human eye. After obtaining the cells from tissue banks, the company purifies them, grows them in a lab, and then places them on gelatin beads. When the beads are planted in the brain, the cells stay put and emit dopamine nonstop. In early studies, Parkinson's patients who underwent the procedure experienced a 48% improvement in motor function.

Many biotechs are pursuing a more controversial delivery method: gene therapy. The idea is to insert therapeutic genes directly into a patient's cells, using viruses or other agents as delivery vehicles. Research nearly ground to a halt in 1999, when 18-year-old Jesse Gelsinger died while receiving gene therapy to correct a rare metabolic disorder. But many champions of regeneration forged ahead, convinced that genes may be the most effective carriers of repair-promoting agents to the brain and heart. Genzyme is experimenting with a gene called HIF -- thought to spur cardiac repair by stimulating robust blood vessels to grow in a damaged heart.

Still, the Gelsinger tragedy proves just how dangerous it is to mess with the body's natural tendencies. And even after safety issues are solved, the biotech industry will face yet another daunting question: How will anyone perform such "cell therapies" on an industrial scale? Working with cells is extraordinarily difficult. They must be surgically removed from a patient, then delicately processed before they can be reimplanted. A busy heart center can do 25,000 procedures a year, estimates Dr. Nicholas Chronos, medical director and chief scientific officer at American Cardiovascular Research Institute in Atlanta. In contrast, a bone-marrow transplant facility that might double as a stem-cell center typically can handle only 150 patients a year. "It's a different order of magnitude," says Chronos.

One workable solution might someday be found in the cells themselves. Startups Osiris Therapeutics Inc. and Neuronyx Inc. are experimenting with sub-populations of adult stem cells that may be harvested from donors and administered to any patient without touching off an immune response. That, at least, is the hope. "Every hospital pharmacy would be able to have frozen bags of cells available for every heart patient," envisions Mark F. Pittenger, vice-president for research at Osiris.

What if regeneration could be achieved with a bottle of pills? That dream drives scientists at Curis Inc. (CRIS) in Cambridge, Mass., which is studying "signaling pathways," the molecular master switches that produce a torrent of proteins vital to regeneration. One pathway is called Hedgehog, for the bristly look of fruit-fly embryos used in early research. Curis is developing drugs designed to flip on Hedgehog after, say, a heart attack or stroke. In animals, the molecules mobilize stem cells to grow in damaged tissue. "We're taking the body's own ability to repair itself and enhancing it a little," says Chief Scientific Officer Lee L. Rubin.

Such innovations will never be risk-free. And they may not come fast enough for those in the grip of degenerative disease. But neither politics nor funding hurdles are likely to dam the swelling stream of knowledge in regenerative medicine. By Arlene Weintraub

With Michael Arndt in Chicago

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