Transplants From Fiction to Reality
Richard A. Knox,
New York Times Syndicate
© 1999; The Boston Globe
October 6, 1999 -- Brain transplants? Not whole brains, of course, but grafts of brain cells, derived from animals or humans, to repair damage long-assumed irreversible. After all, the dogma goes, brain tissue does not regenerate. Implausible as it sounds, scientists report tantalizing new evidence in scattered human trials that brain-cell grafts can work, sometimes dramatically. Researchers, biotech companies, and Federal officials are encouraged enough that they're shifting human experiments into a higher gear, enrolling more patients who suffer from a lengthening list of disorders.
Patients such as Ms. Maribeth Cook, 39, of Saratoga Springs, NY, who was struck down five years ago by a massive stroke, ending her career as a dental hygienist and leaving her with partial paralysis and severe weakness on her left side. A month ago, Boston neurosurgeon Dr. Julian Wu of Beth Israel Deaconess Medical Center guided a needle deep into the base of Cook's brain to the dead area marking the stroke damage. Once in the target zone, Wu injected 30 million cells, taken from the brains of a half-dozen or so fetal pigs.
Fetal cells are used because they are in a vigorous growth mode; pig neural cells are chosen, among other reasons, because they are "functionally indistinguishable from human fetal neural cells," according to a spokesman for Diacrin, Inc., a Charlestown biotech firm that provides the cells and sponsors the study.
In a process developed by Diacrin, the pig proteins on cell surfaces are masked by antibodies to prevent the immediate rejection that would otherwise destroy such cross-species "xenografts." The masking technique appears to sidestep the need for long-term immune-suppressing drugs. Patients are carefully monitored for any evidence of activated pig viruses; so far, none have been found, researchers say. Cook and her physical therapist think her chronic muscle stiffness and spasms have already lessened. Her neurologist, Boston stroke specialist Dr. Louis Caplan, is skeptical of such an immediate effect. "They told me it would be a couple of months to six months before I see anything," Cook says. "When I see my fingers and toes moving I'll know for sure it's working."
Cook is the first person to receive fetal pig cells to treat stroke, but Pittsburgh researchers have just completed a similar study in which a dozen stroke patients got injections of human neural cells. Eight of the 12 Pittsburgh patients have reported subjective improvement in their disabling stroke symptoms, and about half have improved measurably on neurologic tests, the study leader reports. "People have described improved walking, better arm function, and return of feeling in the face and arm. Several people have noted improved memory," says neurosurgeon Douglas Kondziolka of the University of Pittsburgh Medical Center, who is planning a larger trial involving up to 60 stroke patients.
There is no shortage of willing volunteers. Every year 700,000 Americans suffer a stroke and 200,000 or so are left with severe disabilities. The Pittsburgh researchers have screened several thousand volunteers for the next study.
Stroke is only the most recent application of brain-cell transplants. In the last 12 months, Boston researchers have found that fetal pig-cell brain grafts reduced severe seizures in patients with frontal-lobe epilepsy in two cases by as much or more than conventional surgical treatment. Surgery for frontal-lobe epilepsy works in 60 percent of cases, at the maximum. An anti-seizure medication can usually win federal approval if it reduces seizures by 30 to 50 percent. By comparison, the pig-cell brain grafts reduced the frequency of patients' seizures by about 75 percent. "If this were a drug, it would be considered high-potency,'' says Dr. Donald Schomer of Beth Israel Deaconess Medical Center, who is conducting the epilepsy study with colleagues at Brigham and Women's Hospital, in conjunction with Diacrin.
The most encouraging brain-cell transplant results, and the most experience in this young field, come from experiments on patients with Parkinson's disease, a common, progressive disorder that robs victims of their ability to move normally, among other effects. In severe, late-stage cases, patients can be virtually "frozen" and unable to initiate voluntary muscle movement. For unknown reasons, in Parkinson's disease the brain cells that produce the neurotransmitter dopamine gradually die off; by the time symptoms appear about 80 percent of such cells have perished.
Scientists have amassed a decade of experience with brain grafts for Parkinson's disease. According to Olle Lindvall, a leading Swedish researcher in the field, more than 200 patients have received implants of dopamine-producing cells derived from the brains of aborted human fetuses. Most showed long-term improvement of symptoms up to eight years, but there were no cures.
In this country, such experiments have been hampered by a federal ban on human embryonic cell transplants, but researchers in Colorado and Florida launched studies, with federal funding, after President Clinton lifted the restriction. Recent reports parallel those from Europe; most Parkinson's patients have benefitted modestly, and some have experienced remarkable improvement. Recent transplants of fetal pig cells for Parkinson's Disease show similarly encouraging results, although researchers still don't know why some patients benefit dramatically, others modestly, and still others not at all.
Fifty-one-year-old Jim Finn of Newport, RI, is one of the showcase examples. Diagnosed with Parkinson's when he was only 30, Finn could barely walk (and on his worst days had to crawl). Feeding himself was an ordeal. Fatigue was constant. "It was obvious that I was entering the 'end stage' of this hideous condition," he recalls. "And I was told there was precious little else that could be done." In mid-1996, a Lahey Clinic neurosurgeon injected 12 million fetal pig neural cells into the right side of Finn's brain, in a motor-control area most affected by Parkinson's disease. Three months later doctors began seeing measurable results.
Gradually Finn improved to the point where he could do things he thought were lost to him forever -- walk without a cane, navigate stairs, cut food and butter bread, give speeches, cut down drastically on medication, and even drive his beloved taxi-yellow TR-7 sports car. "One thing that was interesting with Jim Finn," says Dr. Samuel H. Ellias of Boston Medical Center, Finn's neurologist, "is that we put the cells in the side of the brain that controlled his left side -- his worst side. In three to six months, using a device to measure the speed of arm and hand rotation, we found that his worst side had become his best side. We were aware of it before he was."
Another interesting, and unexplained, phenomenon is that the pig-cell transplant ultimately benefitted both sides of Finn's diseased brain. "We've seen this in animal experiments too. The mechanism is unknown," says Jonathan Dinsmore, a Diacrin scientist. Diacrin is working on cell transplants for a wide range of other disorders, including Huntington's Disease, chronic pain, spinal cord injury, liver damage, heart disease, and blindness-causing macular degeneration.
At this point, though, cell transplants are still somewhat of a "black box." Researchers put the cells in and cross their fingers that they will survive, thrive, crank out nourishing growth factors, and make new connections with the recipient's cells. They're still somewhat at a loss as to why. But they're increasingly impressed that it happens at all, and convinced they can learn to manipulate the system better. "It's not definitive, but the evidence suggests that this stuff works," says Ronald McKay, a neuroscientist at the National Institute of Neurological Diseases and Stroke in Bethesda, MD.
One reason for the excitement is that the dawning success with brain-cell transplants comes at a time when scientists are learning how to steer human precursor cells, called Embryonic Stem Cells, into desired developmental pathways promising someday to grow large quantities of virtually any desired tissue.
Ultimately, these "engineered" stem cells may overtake the use of animal cells, so-called xenografts as the source of spare parts and restorative tissues, drawing on the lessons being learned through xenografting. "That's the scenario we anticipate," says Dinsmore, the Diacrin scientist. "We're collaborating with stem-cell researchers because in the long-term we recognize that this probably represents the next generation of therapeutic products."
McKay agrees. "The past decade we've seen the dominance of the gene and DNA technology,'' he says. "The next step is cell engineering. In five years it's going to be radically different. This concept of cell engineering will be in every part of medicine and biology.''