Over the past 11 years, as her Parkinson’s disease has progressed, 68-year-old Thelma Davis has come to feel trapped in a body that will not move. The symptoms were unalarming at first. Davis told herself that the slight limp in her left leg was nothing serious, that the weakness in her left arm was just her imagination. But although the early signs of Parkinson’s disease are so subtle that they are often ignored by patients and misdiagnosed by doctors, the disease takes a relentless course. Uncontrollable tremors began to appear in Davis’s hands and legs. Because the disease affects movements of the jaw and mouth, speech became difficult for her. Little by little, her gait slowed to a flat-footed shuffle, and her face froze into the unblinking, unsmiling mask characteristic of Parkinson’s sufferers.
The cause of the disease, which afflicts an estimated 1.5 million Americans, remains unknown, and there is no cure. Scientists do know that Parkinson’s casts its imprisoning spell by slowly destroying a tiny section of the brain, the size and shape of a quarter, called the substantia nigra. The substantia nigra supplies the neurotransmitter dopamine to a larger area in the center of the brain, the striatum, which controls movement. As dopamine supplies from the substantia nigra to the striatum dry up, movements slow, become erratic, and finally grind to a halt.
Parkinson’s patients, like the rest of us, have plenty of dopamine elsewhere in their bodies; the conundrum is how to get it into their brains. Dopamine can’t pass through the blood-brain barrier, a membrane that guards the interior of the capillaries in the brain. Fortunately, the drug levodopa, commonly known as L-dopa, can pass through the barrier, and once it reaches the substantia nigra, cells there convert it into dopamine.
Thanks to L-dopa, Davis was able to lead a relatively normal life for several years, continuing to work as the chief financial officer of a Long Island, New York, mortgage bank. But L-dopa inevitably fails as Parkinson’s destroys substantia nigra cells, eventually leaving too few to convert the drug to the neurotransmitter. When her symptoms worsened, Davis reluctantly retired from her job. Now, despite a three-times-a-day regimen of short-acting and timed-release forms of L-dopa, she finds simple tasks like combing her hair and dressing difficult obstacles. She suffers from episodes of freezing when the drugs wear off, alternating with spurts of convulsive herky-jerky movements when they shock her system into overdrive- -the classic on-off symptoms of advanced Parkinson’s disease. Parkinson’s itself is not fatal, but many patients die from injuries suffered in falls. Others end up wheelchair bound, unable to move or speak, or succumb to pneumonia.
With her condition deteriorating, Davis has come to the Neural Transplantation Center for Parkinson’s Disease at the University of Colorado in Denver for what could be her last hope of recovery--a fetal tissue transplant. In the operation, transplant team leader Curt Freed and neurosurgeon Robert Breeze will implant brain cells culled from aborted fetuses through a thin needle into Davis’s brain. To make sure the dopamine reaches the cells that need it, the fetal tissue is grafted into the striatum, where neurons are alive but deprived of dopamine, rather than the substantia nigra, where they’re dying. Davis and her doctors hope that as the grafted cells grow and integrate into her brain, they will pump out enough dopamine to replenish depleted supplies and give her back some of her lost mobility.
The tissue for the transplant has been collected, with the consent of the mothers of the fetuses, from private clinics where abortions are performed. It consists of brain cells from the mesencephalon, an area that develops into the substantia nigra and other midbrain structures, dissected from half a dozen six- to eight-week-old fetuses. The cells must be collected within a narrow window that opens between six and eight weeks into the gestation of each fetus, just before they have fully differentiated into dopamine-producing neurons. Brain cells at this age can grow just like seeds, says Freed. They establish root systems in the form of neural connections, regenerating damaged brain circuits. (If the cells are any older, they break up and die during the transplant process.) Because these fetal cells have not yet developed the antigens that trigger an immune response, they also appear to grow without rejection. Over the past 20 days, the cells have been cultured, screened for bacteria and infectious diseases, and tested for levels of dopamine production. Twice during the last three months, Davis’s operation has had to be delayed because the tissue was less than perfect.
Davis begins her day by having a metal band bolted to her skull by four pins embedded in the outer layer of bone. A device that looks like a delicate geodesic dome is attached to the band, preparing Davis for her magnetic resonance imaging (MRI) scan. As a gurney inches her forward and back through a powerful doughnut-shaped electromagnet, a scanner detects radio signals emitted by hydrogen atoms in her brain. These signals are reassembled into three-dimensional images by the machine’s computer and projected onto a bank of monitors, which Breeze studies intently. From the images, Breeze calculates the angles and routes of the needles that will insert the fetal tissue implants into target sites while avoiding injury to arteries and vital brain structures. The domelike device provides a grid of reference points for plotting these routes.
After Davis is prepped for surgery and wheeled into the operating room, the dome is replaced with a stereotaxic frame, an awkward-looking device that resembles a large compass or sundial. The frame is a precision measuring tool. Its outer rim contains an array of small holes that can be adjusted to within a fraction of a millimeter to guide the needles delivering the fetal tissue.
Breeze drills four holes a shade smaller than the diameter of a pencil into Davis’s forehead and through her skull. As he carefully inserts the needle, Freed prepares the tissue, which has been transported to the operating room in a blue-and-white cooler. The tiny specks of tissue are suctioned into a syringe designed to extrude the tissue in fine, noodlelike strands. These are loaded into a hollow stainless steel tube called a cannula.
The operation is nearly bloodless and, since brain tissue does not register sensation, almost painless as well. Davis is sedated with a local anesthetic but remains fully awake. During stereotaxic procedures (which are most often used to obtain biopsy specimens of suspected brain tumors), it’s better to keep patients awake and talking, Breeze believes, to help guard against even the remote chance that the needles and catheters inserted into the brain could cause bleeding and precipitate a stroke. While general anesthesia would routinely be used for open brain surgery, when Breeze can see what he’s doing, during stereotaxic surgery he works blind, directing instruments into the brain based on computer calculations alone. If the patient were asleep and her brain began to bleed, by the time the doctors noticed, it could be too late. So the anesthesiologist keeps up a steady conversation with Davis throughout the operation, carefully listening for any confusion or slurring of speech.
The hollow needle is equipped with an inner stylet, to make it a solid probe that will not cut a core from her brain as Breeze taps the device gently forward. When the needle is in place, Breeze removes the stylet and replaces it with one of the cannulas that Freed has filled with fetal cells, and the infusion begins.
Two hours later, with two small bandages covering the incisions in her forehead, Davis is wheeled out of the operating room into intensive care. She’ll go home after four days, but it will be months more before she knows whether the transplant has worked. Fetal tissue transplantation for Parkinson’s disease remains highly experimental, and Freed cannot promise a positive outcome.
Thelma davis is only the twenty-second patient to undergo the procedure in Denver. Fetal tissue transplants for Parkinson’s disease are also offered on a limited basis at Yale, the University of South Florida in Tampa, and the Good Samaritan Hospital in Los Angeles, as well as in England, France, and Sweden, where some of the first experiments with the procedure were performed in the mid-1980s. Roughly 200 such operations have taken place worldwide since the technique was introduced amid a storm of political controversy over the source of the transplanted tissue-- electively aborted fetuses. In this country, despite the judgment of a National Institutes of Health advisory committee that fetal tissue transplantation was ethical and promising, government funding to test the technique in humans was banned during the Reagan and Bush presidencies. As a result, clinical studies were limited to a handful of patients. That ban was lifted by executive order during the first days of the Clinton administration, but now a new debate has surfaced, this time among scientists, over how well the transplants work.
The moratorium distorted the scientific discussion, says D. Eugene Redmond, the leader of a transplant team at Yale. To muster the political power to overturn it, the actual scientific accomplishments were somewhat exaggerated.
There was a presumption that it would work if the ban wasn’t there, adds William Freed (no relation to Curt Freed), an NIH researcher. People thought, ‘Well, it’s banned; it must be something really great.’
Some patients have shown marked improvement on standard movement tests, such as touching a thumb and forefinger together or tapping their feet, and have resumed many daily activities that most people take for granted: tying their shoes or their ties, vacuuming or driving. They are able to reduce their medication by an average of 50 percent. One of Curt Freed’s patients, a California telephone lineman who had nearly lost his ability to speak and was embarrassed to eat with friends because he could no longer feed himself properly, celebrated the one-year anniversary of his transplant with a Thanksgiving dinner for 12. Another now enjoys cross- country skiing. About a third of the patients have had their lives revolutionized, says Freed. The problem is, the effects are variable.
One in three patients shows only moderate gains, and another third experience no long-lasting benefit at all from the operation. A few even get worse. There are other risks as well. The chance of something going catastrophically wrong during a transplant procedure is small--less than 1 percent that a needle will inadvertently strike an artery or a vital brain area. Nevertheless, in January 1994, Freed’s seventeenth patient, a 55-year-old man with an eight-year history of Parkinson’s, suffered a stroke in the operating room and died one month later--the first procedure- related fatality.
We knew this was an odds game, says Freed. Passing needles into the brain carries risk, and the risk of stroke is about 1 in 500 needle passes. At the time, we’d been doing 14 to 16 needle passes on each patient. With each operation, there was about a 3 percent chance of stroke.
Davis and other patients, many of whom have paid for the $40,000 operation privately, are willing to take that chance. No other form of treatment holds as much hope as this, says Davis. Neurologists who routinely care for Parkinson’s patients remain cautious about recommending the procedure without more proof, however. Parkinson’s disease is slowness of movement, not paralysis, points out Stanley Fahn, a Parkinson’s specialist at Columbia Presbyterian Medical Center in New York. Sometimes with enough excitement or stimulation, sudden movement can return. But this is only transient. Patients in advanced stages, who freeze when they try to cross doorways or are unable to walk across a room without holding onto the walls and furniture, can often negotiate a flight of stairs with ease, ride a bicycle, or catch a ball.
Fahn worries that some improvements observed in transplant patients may be the result of the excitement of undergoing the operation, the mystique of the transplant procedure, and the expectation of getting well. Parkinson’s patients may be particularly prone to such placebo effects. Studies of new drugs have shown that as many as 30 percent of Parkinson’s patients improve with placebo medications, albeit only briefly. Similarly, neurosurgical answers for Parkinson’s disease are also suspect.
In one such surgical technique, called pallidotomy, surgeons destroy a minuscule area in the movement center of the brain--the internal globus pallidus--which is located at the base of the brain, just above the spinal column. The procedure was recently reported on Prime Time Live to reduce tremor dramatically in Parkinson’s patients. But the New York Times followed up with a story detailing how the positive effects may not last, while the operation often leaves patients worse off than before. Skeptics also point out that tremor is only one among many symptoms of Parkinson’s. Before L-dopa became a standard treatment, lesion therapies, in which surgeons destroyed parts of various brain structures (usually the thalamus), were also observed to relieve Parkinson’s tremors, but these operations didn’t relieve slowness of movement in any lasting way.
Autologous transplants, using dopamine-producing cells from a patient’s own adrenal glands, also proved to be a disappointment. In the late 1980s hundreds of adrenal transplants were performed throughout the world (including about 100 in the United States) after Mexican neurosurgeon Ignacio Madrazo reported startling successes with the procedure. About 40 percent of the patients did experience some initial positive effects, but the benefits of the operation generally vanished before a year had passed. At least part of the problem, according to Freed, was that these cells produce mostly epinephrine and norepinephrine, with only a little dopamine. They’re just not the right kind of cell, he says. Also, they don’t survive well in the brain, because they don’t belong there. The tissue around them doesn’t provide a supportive environment.
The results suggest the patients were experiencing a placebo effect, but the side effects of the open brain surgery were real enough: respiratory problems, pneumonia, urinary tract infections, sleeplessness, confusion, and hallucinations. Patients had also suffered strokes and heart attacks while undergoing the surgery; about one in ten patients died.
To put the effectiveness of the fetal tissue operation to the test, Freed and Fahn have joined forces on an unprecedented and controversial study. Forty patients, screened by Fahn at his clinic in New York, will undergo transplants in Denver. But to assure that whatever improvements the patients enjoy can legitimately be attributed to the procedure, the study will follow a double-blind, randomized design, similar to a drug trial, in which half the patients will receive a sham operation. Researchers will give the control patients an MRI scan, prep them for surgery, fit them with stereotaxic frames, and drill holes in their skulls; then Breeze will fake the rest of the procedure. Neither the patients nor Fahn, who will be evaluating their progress, will know who has actually received an implant.
The pacing and atmosphere will be nearly identical to the true tissue implant, says Freed. The strategy is to do things exactly the same way, maybe even have some tissue set up in a dish so there’s time involved in picking up the tissue. We’ll drill holes in the skull, the needles will be inserted into the stereotaxic apparatus, all the calculations will be done, the timing will be exactly the same, but the needles will not drop the last 5 centimeters into the brain.
After the operations, Fahn will evaluate the patients by methods ranging from rating their performance on tasks like getting out of a chair to computerized analysis of their videotaped movements. Researchers will also perform positron-emission tomography (PET) scans to evaluate how well the tissue has survived and grown in the patients.
Members of the control group will be eligible to receive real transplants later--providing the procedure passes the test. We’ve promised them the treatment. But if it’s a bust, they’re better off having the sham surgery rather than the real operation, says Fahn.
The four-year, $4.8 million trial is being funded by the National Institutes of Health. This is the first grant awarded for a study of fetal tissue transplantation since the research moratorium ended. A second $4.8 million NIH grant has recently been approved for a similar controlled study of 36 patients who will undergo transplants at the University of South Florida in Tampa.
Freed hopes the studies will provide an unbiased estimate of the value of the procedure. The sham operation presents no additional risk, he says. As an added precaution, the NIH has assigned a Data Safety Monitoring Committee to oversee the studies. The committee has the option of stopping the studies if there are signs of any unexpected complications.
What you don’t want to do, especially with something as dramatic and publicized as fetal tissue transplantation, is put yourself in a position where you’re not sure that what you’re seeing is real, says C. Warren Olanow, a neurologist at Mount Sinai Hospital in New York. Olanow heads the consortium of investigators that will conduct the second NIH- funded trial. Is it better to expose a small number of patients to placebo than to forgo a control group and potentially expose hundreds of thousands to a procedure that may not work?
However, other researchers consider the double-blind studies dangerous and therefore unethical. There’s a one in a hundred chance that performing craniotomies on the surgical controls could result in the formation of blood clots. If one of those patients dies, it could set the field back several years, argues neuroscientist John Sladek of the Chicago Medical School.
Controlled trials of fetal tissue transplantation will remain premature, at best, critics believe, until gaping methodological differences between the transplant teams are resolved. The teams disagree on such crucial details as in which of the two sections of the striatum-- the putamen or the caudate nucleus--to implant the tissue. The putamen appears to be responsible for a wider range of Parkinson’s disease deficits, such as freezing and the inability to walk, but the caudate may govern a number of subtle functions, including eye movement. Researchers also disagree about how much tissue is needed (one to nine fetuses), how to prepare it for transplant (in suspensions, cultures, or cryogenically frozen and thawed specimens), and whether to place large quantities in a few locations or skewer the brain with 15 to 20 micrografts. Even the key question of whether patients should be treated with the immunosuppressant drugs used in organ transplant operations remains undecided.
Improved tissue processing and implantation techniques could also resolve another major concern of researchers, the poor survival of fetal tissue. Recently, when one of Olanow’s patients died (of unrelated causes) a year and a half after his surgery, an examination of his brain revealed that hundreds of thousands of fetal cells had survived and formed connections with surrounding brain tissue. But a handful of other autopsy reports and numerous animal studies, showing that up to 95 percent of the transplanted cells die, reinforce the need for further progress. Although even a few surviving transplanted cells may be enough to produce clinical effects, poor survival may account for variability in the results we’ve seen so far, says Freed. People doing kidney transplants were able to get better results simply by improving their surgical techniques and their handling of the organ.
Another problem is the needle-in-a-haystack task of gleaning usable dopamine-producing cells from 2-centimeter-long fetuses often smashed beyond recognition during abortions. The difficulty, Freed once told a Senate subcommittee, is so great that it should be an adequate safeguard against any potential abuses of fetal tissue transplants. Problems with tissue availability may also continue to limit the number of fetal tissue transplants that can be done in Denver and other centers.
To overcome these obstacles, researchers elsewhere are exploring a number of new technologies, including new versions of autologous transplants. This time the cells used would be the patient’s own skin and muscle cells, genetically engineered to produce tyrosine hydroxylase, a chemical the brain uses to make dopamine, as an alternative source of tissue. From a skin biopsy the size of a quarter we can produce as much tissue in two weeks as you could harvest from a hundred fetuses, says Krys Bankiewicz, who is working with the California biotechnology company Somatix Therapy to perfect methods of mass-producing cells for transplant.
In April, doctors at the Lahey Hitchcock Clinic in Burlington, Massachusetts, began trials of cross-species transplants, inserting tissue from five fetal pigs into the brain of a Parkinson’s patient. Porcine fetal brain cells are similar to human fetal cells but are more readily available. Experiments are also under way to test encapsulated dopamine- producing cells sealed in semipermeable plastic capsules. Because this delivery system is designed to allow dopamine out of the cells while preventing immune destruction, scientists hope unmatched adult tissue or even animal tissue could be transplanted into patients without immune suppression.
But dopamine may not be the whole story. Some researchers believe the fetal transplants may also produce growth factors--chemicals that stimulate nerve cells to sprout. In a recent article in the Journal of Neurosurgery, Bankiewicz describes experiments he conducted at the NIH in which he transplanted a variety of fetal cells--none of which produce dopamine, but all rich in growth factors--into rats and monkeys. The result was nearly as good as fetal transplants of mesencephalic tissue, producing a measurable improvement in the animals lasting 7 to 12 months.
According to Bankiewicz, the healing powers of fetal tissue grafts stem from a dual effect of dopamine and growth factors. Future studies may include trying to boost the effectiveness of fetal tissue grafts by infusing additional growth factors or injecting growth factors alone.
For the time being, however, patients seeking a transplant to relieve their Parkinson’s disease have only one option--fetal tissue. The field is still in its early stages. But I’m very optimistic that as our techniques improve we will have a chance of curing Parkinson’s, says Freed. The patients are desperate, and we have no other means of helping them. If they could wait five years, we could probably do it better. But some can’t.
Despite the risks and unknowns, there’s no lack of volunteers for the trials. Enrollment has been completed in the 40-patient Denver study, and though the 36 patients for the Tampa trial have not yet been selected, Olanow has had no trouble finding willing subjects for the study’s preliminary stages. The Denver patients range in age from their early fifties to 75; Olanow expects the Tampa patients to start as young as 35. In both studies half the patients will be under 60 to see whether the patient’s age alters the effectiveness of the procedure.
Olanow warns his patients that they must have realistic expectations. We need people who are absolutely committed to seeing it through. If a patient is unrealistic and he doesn’t have a great result, you won’t see him again. We need to be able to follow these patients, especially the bad results, because you’ve got to know what went wrong as well as what went right.
For Thelma Davis, as she recovers at her home on Long Island after the long flight back from Denver, waiting to see if the transplant worked is going to be tough. You try to rationalize the situation, the facts, that it’s going to take months and may not be a cure. But it’s not logical, she says. I just hope I have the patience.