The New War On Parkinson's

He arrives late, unshaven and walking with a bowlegged shuffle. "I'm just waiting for the pill to kick in," says Michael J. Fox, extending a handshake and a request. "Could we wait a few more minutes? I'll be more human then." He ducks back into his office, and moments later, he's ready. In his black T shirt and jeans, Fox, 38, still looks very much like the open-faced teenager who stepped off the bus from Canada and into sitcom history 18 years ago. Which of course is the irony: the actor who became famous playing eternally youthful men on "Family Ties" and "Spin City" has been stricken by a disease known mainly for hobbling the elderly: Parkinson's. The actor has accommodated it gracefully for the past nine years, and he insists it hasn't much hurt his day-to-day quality of life. With the help of medication, and a brain operation he underwent quietly in 1998, Fox still skates and skis. He plays with his three kids and travels with his wife, actress Tracy Pollan. But like many Parkinson's patients, he has found that a decade is long enough to keep up appearances. On May 24, his TV series "Spin City" will air his final episode. "It's not that it was killing me," he says. "It's not that I couldn't have continued. It just seemed kind of pointless, given that I have an opportunity to help." From now on, he'll focus on the foundation he's starting to hasten the search for a cure.

Parkinson's disease is mercifully rare in people Fox's age, but his candor has helped create a new sense of urgency about the condition. It afflicts roughly a million Americans--including the likes of Billy Graham, Muhammad Ali and U.S. Attorney General Janet Reno--and it is growing more prevalent as the population ages. Parkinson's is a degenerative illness, in which the death of certain brain cells causes a progressive loss of muscle control, leading eventually to paralysis and death. Yet unlike the other major brain diseases--Alzheimer's, Huntington's, Lou Gehrig's--Parkinson's is highly treatable, even at fairly advanced stages.

Today's treatments are aimed more at easing symptoms than at repairing the brain, but that could soon change. Specialists are pursuing several techniques for replacing the very cells that Parkinson's destroys. Over the past decade, scores of Parkinson's patients have regained the use of their bodies after having fetal neurons implanted in their brains. No one expects to see fetal cells used on a mass scale, but the ongoing revolution in stem-cell technology could soon make them unnecessary. Stem cells can be cultivated endlessly. And as researchers learn to direct their development, brain repair could become a routine part of clinical medicine. "We're standing at the same threshold that we reached with infectious disease 100 years ago," says Dr. Abraham Lieberman, a neurologist at the University of Miami and the National Parkinson's Foundation. "The knowledge we're gaining could prove as revolutionary as germ theory."

Physicians have been diagnosing this syndrome since 1817, when the English physician James Parkinson first described it. The symptoms can range from impotence to depression and even dementia, but the cardinal features are tremors that occur in relaxed limbs; stiffness or freezing of the joints; bradykinesia, or slow, limited movement, and postural instability, a lack of balance and coordination. "With Parkinson's you don't have any control once you start to fall," says Pauline Kael, the celebrated film critic who left The New Yorker in 1992 after wrestling with the illness for a decade. "Your mind is working, but when you try to stop you can't. I fell flat on my face on the New York streets over and over. I broke my nose so many times I was embarrassed to go to the doctor."

Parkinson's also involves well-defined changes within the brain. Autopsies reveal a severe loss of neurons in the substantia nigra, a clump of dark, vinelike cells that originate near the center of the organ (chart). A healthy adult has roughly 500,000 of these nigral neurons. They help initiate voluntary movement by releasing dopamine--a chemical that nerve cells use to communicate with each other--into a nearby brain structure called the striatum. We all lose nigral cells as we age, but normal movement seems to require at least 100,000 of them. If the number drops below that critical threshold, the striatum ends up starved for dopamine and the patient's motor control deteriorates. The causes of this destruction are something of a mystery. Heredity is not a strong risk factor, but studies have implicated viruses and various environmental toxins. Dr. Donald Calne of the University of British Columbia speculates that these agents may destroy nigral cells as we encounter them, leaving us no cushion against age-related attrition.

Parkinson's progresses at different rates in different people, but thanks to a 30-year-old drug called levodopa (L-dopa for short), virtually anyone can suppress the symptoms for several years. When Fox was diagnosed in 1991, his main symptom was a twitch in his left pinkie. But by 1993 his whole arm was shaking violently. Sinemet, an oral medication that combines L-dopa with a buffering agent called carbodopa, steadied him so well that audiences never glimpsed his disability. There were close calls, when he wasn't sure the drug would take effect in time for some public appearance. But with a little forethought, he could make himself presentable for anything. "I've varied the regimen," he says, "based on what I need to do."

L-dopa is closely related to dopamine--and unlike dopamine itself, it can pass freely from the bloodstream into the brain. When a Parkinson's patient takes L-dopa orally, her surviving nigral cells absorb it, then convert it into dopamine and fire it into the striatum to set the body in motion. The patient still lacks nigral cells, but the drug enables the surviving cells to perform heroically. Unfortunately, other brain cells are equally sensitive to L-dopa--and the doses required to restore motor control can overstimulate them, causing agitation and hallucinations. Kael was ambivalent from the moment she started taking the drug. "I stopped shaking and became much more alert," she says, "but I got agonizing hallucinations. It's scary, if you've always been a commonsense rational person, to have visitations in the night from animals and people. The bears were quite convincing."

The problems tend to worsen after three to five years, even as the patient becomes more reliant on the drug. Many sufferers experience dyskinesias, or wild, involuntary movements, whenever they're on L-dopa. The drug also starts to wear off faster, forcing them to dose themselves more often. And even when the treatment is working, its effects may wax and wane unpredictably, leaving the patient frozen one minute and twitching uncontrollably the next. "The side effects can almost be worse than the disease itself," says Dr. William Langston of the Parkinson's Institute in Sunnyvale, Calif. "You reach a point where you can't plan work, or your bridge party or when you go to Safeway."

One way around this problem is simply to avoid L-dopa as long as possible, and to use as little as possible. There are now several less noxious drugs that can augment or even replace L-dopa for a while. Eldepryl, a monamine oxidase inhibitor, helps preserve motor control by slowing the breakdown of dopamine within the brain. And drugs known as dopamine agonists can provide even stronger relief, by taking the place of dopamine within the striatum. The older agonists were generally used in combination with L-dopa, but SmithKline Beecham and Pharmacia & Upjohn have recently introduced stronger ones. These drugs, sold as Requip and Mirapex, can be taken alone for several years. They're not free of side effects--many users experience hallucinations and extreme drowsiness--but they're less likely than L-dopa to cause dyskinesias. "The benefits have been huge," says Fox's neurologist, Dr. Allan Ropper of St. Elizabeth's Medical Center in Boston. Fox takes Requip.

A well-calibrated drug regimen may give a patient 10 or more good years, regard- less of his age, but the miracles eventually cease. Dr. Dan Frost was a 39-year-old cancer surgeon in Los Angeles when he developed Parkinson's in 1989. He retired in 1993 and, with the help of medication, pursued his passion for restoring classic motorcycles. He still loves to run his elegant racing bikes down the mountain roads above Pasadena, but he's rarely able to do it anymore. "Just when you feel you can live with the disease," he says, "some new symptom comes along." But even Frost has yet to exhaust the treatment options. When the brain lacks a stable supply of dopamine, the cells governing movement start firing erratically. If drugs can't solve the dopamine problem, a surgeon can sometimes ease symptoms by disabling the errant cells.

Parkinson's surgery was common in the 1950s and '60s but fell from favor when L-dopa came along. Researchers in Sweden and France started experimenting with surgery again during the 1980s, and American physicians followed suit in the early 1990s. Until recently, the basic options were thalamotomy, which involves destroying part of a brain structure called the thalamus, and pallidotomy (which centers on the nearby globus pallidus). Fox underwent a successful thalamotomy in 1998, when drugs could no longer control the tremor in his arm. Unfortunately, these procedures can cause disabling weakness and slurred speech if they're performed on both sides of the brain. So the benefits are confined to one side of the body.

But techniques are rapidly improving. Surgeons have now hit upon a third brain structure--the subthalamic nucleus--that has similar effects on motor activity and can safely be altered on both sides. And researchers have recently found a way to disable neurons in any of these brain structures without destroying them. The procedure, known as deep brain stimulation, involves placing a small electrode in the brain and wiring it to a battery-powered stimulator implanted near the patient's collarbone. Errant cells can then be silenced by an electrical current. DBS isn't risk-free. The wire connecting the electrode to the stimulator can cause infection, and changing the battery requires minor surgery. But the current can be adjusted to suit the patient's needs--and turning off the stimulator reverses the effects.

Nicole Stedman struck gold with this technique. Three years ago the 61-year-old California piano teacher had hit the limits of drug therapy. She couldn't function without L-dopa, but whenever she was on it she writhed and twitched violently. "It was awful," she recalls, "and it was getting worse and worse." Dr. Alim Benebid, the French neurologist who pioneered DBS, happened to give a speech in Los Angeles in March of that year, and Stedman wrangled a meeting with him. A few months later she traveled to his clinic in Grenoble, where she had electrodes implanted in both sides of her subthalamic nucleus. The effects were dramatic. She still required medication, but she needed only a fraction of her usual dose--and cutting the dose put an end to her dyskinesias. "It was all quiet," she says. "Right away. It was like being another person."

Bigger breakthroughs are conceivable. The ideal therapy wouldn't merely ward off the symptoms of Parkinson's. It would reverse the condition by replacing the dopamine-producing cells of the substantia nigra. Swedish and American researchers have pursued this dream since the 1980s. Over the years, they have grafted nigral cells from aborted fetuses into the brains of about 250 Parkinson's patients, and despite years of bitter controversy, they've achieved some remarkable successes. Dan Stewart of Maumee, Ohio, had run the gantlet of Parkinson's drugs in 1994, when he went to the University of Colorado Health Sciences Center to have cells from four fetuses implanted in his striatum. The cells took, and within 16 months he was able to drop all his medication. He's still drug-free six years later, and suffering only minor symptoms.

Unfortunately, fetal-cell implants don't always work this well. In one carefully designed study, researchers led by Dr. Curt Freed of the University of Colorado and Dr. Stanley Fahn of Columbia University followed 40 patients. Half of them received brain grafts containing 2 million fetal cells, while the other half underwent sham operations (a hole in the skull but no cells) to control for the placebo effect. The surgery itself went well; imaging tests showed that 16 of the 19 graft recipients incorporated the fetal cells into their brains. But the clinical benefits were largely confined to patients under the age of 60. For some reason, the older cell recipients did no better, on average, than those receiving sham operations. "The challenge," says Freed, "is to make the results more predictable and uniform."

That's the first challenge, anyway. The next one is to find a better source of implantable cells. A single brain graft requires tissue from four or more electively aborted fetuses. And though federal policy permits the use of fetal tissue for research purposes, no procedure that requires large amounts is likely to find wide clinical use. So scientists are racing to develop alternatives. At the biotech companies Genzyme and Diacrin, researchers are working with fetal brain cells from pigs. In one preliminary experiment, published this spring, the scientists transferred pig cells into 12 advanced Parkinson's sufferers and gave them immunosuppressant drugs to prevent rejection. A year later most patients had adopted at least some of the grafted cells, and three had experienced clinical improvements. A larger study is now in the works.

But pig cells are at best a stopgap. Ideally, physicians would not have to dissect several fetuses for every patient needing help. Instead they would cultivate huge populations of undifferentiated stem cells in laboratory dishes, and use various signaling molecules to guide their development. Because stem cells reproduce in culture, a small supply can generate many more. "Fetal-cell transplantation is the hunter-gatherer phase of this technology," says Ronald McKay, a research scientist at the National Institute of Neurological Disorders and Stroke. "Cultivating stem cells is more like settled agriculture." McKay and his colleagues have already succeeded at turning embryonic stem cells into dopamine-producing neurons in lab experiments. And they've shown that the neurons can take root, and relieve symptoms, in Parkinsonian rats. Will these tricks work in people? Human trials could begin within the next few years. "There's a lot of practical work to be done," says McKay, "but we're growing cells in clinically useful quantities."

Michael J. Fox is nearly a decade into his own battle with Parkinson's, but he's unabashed in predicting he will live to see a cure. "I'm not a scientist," he says. "I haven't even played one on TV. But things are going to start happening very quickly. If there's a concentrated effort, this is done in 10 years." Few researchers would make such a bold promise. Turning stem cells into replicas of human nigral cells will take work, luck and money. But there has never been more cause for optimism.