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By mid-morning, after her medicine has kicked in, Nancy Walls can easily fill a room with warmth and laughter. But when she first gets out of bed, when her feet resist like two wooden blocks, she has to use all her wits just to move. The auburn-haired 56-year-old was diagnosed with Parkinson’s disease about eight years ago, and in the past couple of years, she says, she really has begun to feel it. She shuffles as she walks, moving slowly, and each time her medicine starts to wear off, stiffness and fatigue set in. In Parkinson’s disease, neurons that make dopamine, a chemical that coordinates muscle movement, gradually stop working. By the time a doctor can diagnose symptoms such as tremors or poor balance, about 80 percent of these essential cells usually have shut down. “People try to be realistic, but it’s depressing, too,” Walls says, describing the Parkinson’s support group that she helps lead in Walnut Creek. A couple of participants, for instance, used to play tennis together. Now one man uses a walker and the other is losing his cognitive skills. “They just coasted along, and then the last year and a half, they’ve been on a friggin’ sled,” she laments. Walls can rely on Sinemet, a drug that is converted in the brain to dopamine, to control most of her symptoms. Over time, though, side effects overcome the drug’s usefulness, and ultimately nothing can stop the disease from progressing. Walls, who is a nurse, doesn’t deceive herself about the unproven and sometimes wild therapies that people bring to the support group. But when it comes to the possibility of advanced disease, she doesn’t hesitate: “If the drugs don’t work, honey, I’ll do whatever I can to move.” In the campaign for Prop. 71, people like Walls were promised a cure. With $3 billion from taxpayers in hand, its proponents pledged, the California Institute for Regenerative Medicine would fuel a medical revolution that would do away with 70-some diseases. Lower healthcare costs, a surge in jobs, and fat royalties for inventions would enrich the state, too. The foundation for this juggernaut would be embryonic stem cells, the body’s own powerful tools for building itself. The measure passed 59 to 41 percent, and now scientists, patient advocates, and the public are wondering exactly what they’ve done. Certainly, California Democrats thumbed their noses at President Bush and saluted the ideals of science. And citizens created a state agency for medical research that would be led by patient advocates with a sense of urgency. Yet the idea of embryonic stem cell cures, as logical as it seems, is built on a very young science—so far tried mainly in rodents. Even if we are certain that stem cells can give broken mice the ability to walk, can we trust that scientists will be able to harness these cells to mend human bodies? As the post-election euphoria dissipates, both the public and scientists have become wary. Two lawsuits question the institute’s constitutionality. Even supporters are pressing for more openness in its deliberations and for provisions that will ensure taxpayer access to royalties, revenue, and treatments once they come. Cell scientists dream of exciting new projects but fear that a demanding public will push embryonic stem cells into the clinic before they are safe or even might help. “Mouse physiology is different,” says Walls’ husband, Randy Schekman, a little wryly. “What you learn in a mouse may not translate [into humans].” Schekman, a cell biologist, is campus program director of Berkeley’s stem cell center. He’s excited about the new research possibilities, but when it comes to using embryonic stem cells to restore Nancy’s health one day, he stares down. He’s a rigorous scientist and can name a host of challenges before stem cell therapy will become clinically useful, particularly in the form of surgical transplants to help Parkinson’s sufferers churn out dopamine deep in the brain. “Right now, it’s remote,” he says, simply.
And to hear some scientists tell it, such cures really are close at hand. At one recent event, Thomas Okarma, president and CEO of Geron Corp., explained to entrepreneurs and investors that researchers at his Menlo Park company had produced eight types of specialized cells and had proven their power in four diseases. He predicted that the company would be testing embryonic stem cell-based treatments in people with spinal cord injuries sometime next year. “Is this hope or hype? You decide,” he challenged the audience. No one disputed Okarma on the dais—that would violate the polite society of science. But privately, many experts worry about the grand promises made in the campaign and a rush to the clinic that probably will come next. The embryonic stem cell studies in animals so far prove only the principle that they might work in people. Even the most enthusiastic stem cell biologists outline a series of difficult problems—including the real danger of cancer—that they must solve before these cells can become medical tools. They give reasons why therapeutic stem cells might not flock to their designated homes, or once they arrive, fail to integrate easily and do their jobs. Usually, new medicines must climb a ladder of careful testing—first in the petri plate, then in small animals such as rodents, next in creatures such as primates that might respond more like humans. Finally, experimental treatments must pass progressively larger trials in people to check safety, dose level, and only then, whether they really work. Embryonic stem cells may not become a treatment on their own at all, some researchers say. Instead, the information they deliver when scientists manipulate them in cultures may lead to other types of drugs and therapies. For many seasoned biomedical researchers, all this talk of “cures” triggers an unpleasant déjà vu. One after another brings up the disastrous claims made early on for gene therapy, which also had seemed so simple at first. Molecular biologist W. French Anderson was the first to win regulatory approval to try the idea in 1991, as a means to correct a 4-year-old girl’s barely functional immune system. Five years later, he predicted at the time, gene therapy would be used to manage cancer, AIDS, hemophilia, and Tay-Sachs disease. Instead, two children developed leukemia after receiving the experimental treatment and one, 18-year-old Jesse Gelsinger, died when his body reacted violently to the injection. “After that, they said gene therapy does not cure people, but it’s killing them,” says Inder Verma, an expert on gene therapy at the Salk Institute. “We underestimated the difficulties.” Verma believes that both gene therapy and embryonic stem cells will eventually work. But right now, he says, “There’s too much hype.” Lorenz Studer, director of the laboratory of stem cell and tumor biology at Sloan-Kettering, fully expects to see the treatment tested in people before it is ready. “You have the pressure on the scientists to deliver and that’s not a very healthy situation,” he says. Their caution resonates with Walls, who turns to poetry for comfort and encouragement—not the latest findings in the medical literature. When she was diagnosed, she got excited about each “cure” announced in the morning paper. Over the years, her enthusiasm has become more measured. “There’s still hunks missing from the puzzle,” she explains. Walls has watched dramatic videotapes showing people with advanced Parkinson’s who try one or another experimental treatment, then miraculously walk with ease. She and Schekman, her scientist husband, also have seen friends try invasive new therapies and get no better, or even worse. The two have held off any methodical examination of their long-term medical choices. After all, Walls still works part-time for the Sutter Visiting Nurse Association, they hike together regularly on the coast, and she travels without much trouble. If the drugs stop working, the most successful treatment so far has been a procedure called deep brain stimulation. Surgeons implant a battery-operated device into the brain, where it sends out electrical impulses that interfere with wayward signals between cells. Although it helps many people turn back the clock several years, it can cause severe complications. One friend went through many exhausting hours getting the equipment adjusted, but his Parkinson’s got worse. Another person died of infection. “It’s pretty hit and miss,” says Schekman. “But at a certain point, that may be our only option.” In discussions about embryonic stem cell research, Parkinson’s nearly always is mentioned as one of the reasons to move as quickly as possible, along with spinal cord injury, juvenile diabetes, and Alzheimer’s. For each of these conditions, there are good reasons to imagine that embryonic stem cells might help (see sidebar). Yet for each, the same set of problems stands in the way. Before embryonic stem cells can become medical treatments, scientists must learn how to create and grow them easily, efficiently, and predictably. Every cell must be identical and free of contaminants. Right now, no one is certain how to reliably push these pliable entities to grow into most types of cells, and then to stop them from reproducing on cue. Finally, there’s still a question as to whether even healthy therapeutic cells can survive and do their jobs in a patient’s body without the disease eventually shutting them down as well.
Science moves forward in fits and starts, though, and in May, a team in South Korea leaped ahead in one important technical step. They took skin cells from a variety of patients 2 to 56 years old and transferred the nucleus from those cells into eggs donated by fertile women. Then they coaxed the new combination into growing into the beginnings of an embryo. In all, they created 11 human embryonic cell lines that had the same characteristics as those in people with spinal cord injury, juvenile diabetes, and genetic immune deficiencies. These cell lines could prove enormously useful for research. The cells also had their donors’ immune markings, so if researchers were able to correct the genes or other mechanisms that had caused their disease, the cells likely could be returned to the patient safely. The report both stunned and thrilled scientists around the world because the Koreans had created embryonic cell lines ten times more effi-ciently than ever before. Studer, who specializes in Parkinson’s, is one of those leading the way toward discerning how to make embryonic stem cells transform reliably into a desired type. He uses a 50-day process to coax them into becoming the nerve cells that make dopamine. Right now he can get 70 percent to turn into the ones he wants. The cells behave normally but don’t seem to survive very long inside the animals that have stood in for humans so far. “It’s proven more difficult than expected,” Studer says. “You do get behavioral improvement, but it’s not as extensive as we’d like to see.” Fortunately, in the 200 or so rats and monkeys he has tested with his nerve cells, Studer has not seen the cancerous growths that often show up in other studies.When Harvard researchers implanted mouse embryonic stem cells into rats, one in every five developed tumors. A study in diabetic mice with cells grown to make insulin failed after three weeks for the same reason. This remains a major worry, because embryonic stem cells, by definition, continue to divide unless a developmental signal tells them to stop. Studer thinks the answer is to make sure that every cell has matured into some type of adult form before it goes into the patient. He worries about other side effects, though. When dopamine-producing neurons from fetal tissue have been implanted in people with Parkinson’s, the signaling system inside the brain sometimes has gone completely haywire. And even if the fetal cells work for a while, most don’t survive longterm. Schekman hopes that when he gives talks to his wife’s support group about embryonic stem cells, he doesn’t hype the potential. “I don’t want them to think something’s around the corner,” he says. In 10 years or so, maybe some cell lines with restorative properties could be available in banks organized by broad immune types. His friend Robert Tjian, a biochemist at Berkeley known for his groundbreaking research on the signals inside cells, thinks there are 15 to 20 years of research ahead before embryonic stem cells become readily available, off-the-shelf treatments. For instance, even if researchers can grow the right cells for Parkinson’s, Tjian asks, how do you get the neurons always into the right spot in the brain? How do you tell them to stay there? Once they’re positioned there, what signals do they need to begin making dopamine? “All those signals, we almost don’t know anything about,” says Tjian. Some of Tjian’s own research is aimed at juvenile diabetes. He is studying the signaling process in beta islet cells, which make the insulin necessary to process blood sugar. When people develop juvenile diabetes, their immune system has mistakenly destroyed these cells. Islet cell transplants from cadavers have restored sugar processing in hundreds of patients. But the supply of cells is extremely limited and recipients must take powerful immune suppressants for the rest of their lives. And Tjian says the adult-onset version of the disease, which is far more common and develops for different reasons, probably will never become a candidate for embryonic stem cell-based therapy. Neither Tjian nor Schekman have much hope that embryonic stem cell therapy will prove useful in another very common and high profile disease, Alzheimer’s. The disease wreaks massive damage throughout the brain, making it difficult to correct with individual cells or tissue. But embryonic stem cells would be a wonderful tool to reproduce and observe the disease in process. Schekman would like to find out whether brain cells’ mishandling of a protein called the amyloid precursor might underlie what goes wrong. When part of this protein is clipped off, the fragments build up into the plaques and tangles associated with Alzheimer’s symptoms. If Schekman could reproduce this mistake using embryonic stem cells, he could test chemicals that might stop it. Indeed, this approach could be considered the fall-back position of embryonic stem cell science, and not a bad one at all. Researchers could create cell lines that duplicate their disease of choice, then search for the processes that go off track. Then they could try to correct the problem at the molecular level. Drugs could be tested cheaply in the petri dish before huge sums of money are spent for clinical trials. Scientists are thrilled with the prospect of using these cells to understand human development and to decipher the underpinnings of all kinds of health problems. But this kind of fundamental work is probably not what Californians envisioned when they voted to provide $3 billion for embryonic stem cell studies. With cures in their hopes, patient groups lobbied hard for the initiative. And its primary author, Robert Klein, built in features likely to push the science out of the lab and into the clinic quickly—perhaps, some scientists fear, with the wrong focus or before it is ready. When the Institute for Regenerative Medicine begins doling out money for research, grant proposals will be ranked for their therapeutic potential. Patient advocates dominate the oversight committee that has final approval. Klein, whose son suffers from diabetes, says his intent was to accelerate and streamline the scientific process, but researchers point out that their path is rarely linear. A “patient imperative” might constrain and hinder their work. Tjian acknowledges that having patients involved helps keep scientists focused on the reasons they are doing their research—that is, beyond the pure pursuit of knowledge. “But when the science is so new, so uncharted, for me to think about using it in patients is out there,” he says. The solution to a scientific problem sometimes comes from an entirely unexpected direction. And, he adds, non-scientists may not be promoting the most sensible things. That could happen, concedes Jeff Sheehy, an AIDS activist who works for the UCSF AIDS Research Institute and sits on the Institute for Regenerative Medicine’s oversight board. But it may not always turn out badly. He points out how patient advocates changed the timetable for research on HIV and dramatically speeded up access to experimental drugs. “We’ve gotten bigger progress, not just on HIV, but in breast cancer, too,” Sheehy says. Schekman himself knows the frustration people feel as they watch scientists insist on understanding the details, not just whether these cells seem to do the job. “I can assure you, when you’re on the inside, as I am now, progress seems excruciatingly slow,” he says. Walls, who tends toward the cautious side, has come to believe that patients bring an essential realism into the picture. She reminds her husband that scientists don’t have the corner on objectivity about science. The brainpower, ferment, and creativity flooding into both Parkinson’s research and embryonic stem cells, pushed forward by real dollars and real people who know these diseases intimately, has got to be helpful in the long run, she believes. But Walls also reminds herself that the fundamental mechanisms for a cure simply are not yet in hand. She tries to stay focused on the here and now, the day to day. But in the corner of her mind, even though she doesn’t really want to say it out loud, “There’s a little jump-for-joy kind of guy, cheering stem cells on. I let him keep jumping,” she says. “We’re getting there; we’re getting there.” Sally Lehrman is an award-winning reporter and writer on medical and science policy for national media, including Scientific American, Nature, Health, The Washington Post, Salon.com, and The DNA Files distributed by NPR. She is a former Knight fellow and co-winner of a 2002 Peabody, as well as many other awards. |
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