HARVARD GAZETTE ARCHIVES

Pig Transplants Aid Parkinson's Sufferers

By William J. Cromie

Gazette Staff

Cells from the brains of pigs transplanted into human brains are helping to relieve the rigidity and uncontrolled movements of Parkinson's disease.

Nine successful transplants have been done by Harvard-affiliated surgeons and researchers. They were performed at the Lahey-Hitchcock Medical Clinic by James Schumacher, who is also a research fellow at McLean Hospital. Eight of the nine patients have shown improvement.

The ninth person died seven months after surgery of an unrelated clot in the main artery to his lungs. An autopsy revealed that the fetal pig cells had connected themselves properly in his brain and begun to function as they should.

"This is the first direct evidence that fetal pig cells will adapt to life in a human brain and work to lessen the symptoms of Parkinson's," said Ole Isacson, director of the Neurogeneration Laboratory at McLean Hospital. "At eight months, this is, as far as I know, the longest survival of a xenograft [animal graft in a human] in medical history."

Tony Johnson, 57, of Taunton, Mass., underwent the first transplant in April 1995. His movements have become much smoother and his speech is clearer. However, without looking inside Johnson's brain, there is no direct evidence that the implants directly caused his improvement.

The first transplants of pig cells into the brains of Huntington's disease sufferers have also been done by a Schumacher-led team at Lahey-Hitchcock in Burlington, Mass. The surgeons hope to relieve the jerky, involuntary movements and progressive mental deterioration caused by degeneration of brain cells different from those involved in Parkinson's. These implants were performed too recently to determine if the patients will be helped, and Schumacher plans to do 10 more such operations in the coming months.

The results with Parkinson's patients, taken together with many years of research on animals, leads Isacson to state that "we can now repair brains. Only 10 years ago, this was science fiction."

Human-to-Human Implants

Human fetal cells have also been used as implants, but that surgery remains controversial. In 1988, the Reagan administration banned the use of federal money for transplanting fetal tissues obtained through abortions. However, such research continued with private funds.

President Clinton lifted the ban in 1992, but practical, legal, and ethical concerns still dog the procedure. Isacson, who is also an associate professor of neuroscience at the Medical School, estimates that "about a hundred of these transplants have been done worldwide. However, different surgeons used different techniques. The fetal cells came from varied gestation ages; some were frozen, some were not. As a result, there are no good data on how effective the transplants can be."

To find out, the National Institutes of Health funded two studies. In one, 20 Parkinson's patients will have small holes drilled into their skulls and human fetal cells will be injected into their brains through a small needle. Twenty other patients will undergo sham surgery. Then the two groups will be compared over an extended period.

Whether successful or not, Isacson doesn't think use of human fetal cells can solve the problem of long-term treatment of Parkinson's. "Morality aside, it's unreasonable to develop a medical technique based on abortion," he insists, "because there will never be enough tissue available. You need up to 12 fetuses for one patient. And if the abortion pill, RU 486, comes into wide use, it will not provide any usable tissue."

Debilitating Move Swings

No one knows how many people suffer from Parkinson's, but Isacson and others put the number at about 1 million in the U.S. alone. It effects 1 percent of people over age 50, including such luminaries as Attorney General Janet Reno, former world boxing champ Muhammad Ali, and Pope John Paul II.

The disease is caused by a progressive loss of cells in a part of the brain called the substantia nigra, which lies at the base of the brain just above the spinal cord. These black cells make a chemical messenger called dopamine that travels, via nerve fibers, to areas of the brain where movement is initiated.

When 85-90 percent of the dopamine cells die off, the symptoms of Parkinson's appear -- stiff posture, unstable gait, trembling, muscle weakness, and speech disturbance. The most common treatment consists of drugs that contain levodopa (L-dopa), which the brain converts to dopamine.

After more than five years, however, response to the drug becomes erratic. Despite giving constant levels of the L-dopa, the drug can, for unknown reasons, suddenly stop working. During such "off" times, the person freezes up and has great difficulty trying to move. During "on" periods, movements become excessive and uncontrolled.

"These on-off swings are very debilitating," Isacson notes.

So debilitating, in fact, that neurosurgeons advocate cutting out part of the brain to provide relief. Encouraging results with a procedure called pallidotomy has led to about a thousand such operations this past year.

But experts say that pallidotomy will only help 5 to 10 percent of those suffering from Parkinson's. Also, Isacson and Schumacher say they have difficulty with the idea of further damaging brain circuits to correct a problem due to loss of brain cells in the first place.

"Reconstruction is better than deconstruction," Isacson says.

Pig-Headed Rats

In 1989, Isacson began transplanting pig cells into rats with the equivalent of Parkinson's. "The results convinced me that the immature cells will grow and release dopamine," he comments. "The implanted cells possess all the mechanisms to regulate themselves, secreting dopamine when it's needed and turning off when it's not. All the rats improved, and that was very exciting to see."

Last year, Schumacher's group received permission from the Food and Drug Administration (FDA) to test the technique on people. "It's a concerted effort, involving Lahey-Hitchcock, Boston University, Massachusetts General Hospital, and Diacrin Inc. [a biotechnology company]," Isacson explains.

One concern focused on the possibility that pigs cells might harbor a virus or microbe that would damage human brains. Most scientists considered that unlikely, but the FDA and the U.S. Centers for Disease Control and Prevention have monitored the surgery closely.

Tony Johnson, the first implantee, notes that millions of people eat pork every day. "I eat it, too, so I thought that I might as well try this."

Before the transplant, he had difficulty using the phone, couldn't write, and used a wheelchair to get around. Afterwards, "he has greatly reduced his medications," says his wife, Mildred. "He still takes L-dopa but in lower doses. His speech has improved, he walks better. Overall, Tony's doing very well. Recently, he went golfing."

Brain scans of Johnson and seven other surviving transplantees indicate dopamine activity where there was almost none before. The patients also report quality-of-life improvements that began as soon as three months after surgery.

"This makes us feel confident enough to expand our study to the next phase," says Schumacher. He recently did two additional transplants and will do one more during the present phase of work, a privately financed test for safety that ends in 1998.

The next phase would involve more patients and more institutions, including Brigham and Women's Hospital in Boston and Rush Presbyterian Hospital in Chicago. It will focus on the most effective doses and placements of implants.

Simultaneously, the Schumacher-Isacson group is increasing its research and experiments on Huntington's disease. The first transplant of human fetal cells into a Huntington's patient was done recently in Los Angeles Memorial Hospital. Schumacher followed this with the first implants of pig cells, which he did in the past few months. He has FDA approval to do 10 more such transplants.

Isacson also works on the potential of implanting genetically engineered cells to treat both Parkinson's and Huntington's.

"Such gene therapy is not yet a reality," Isacson adds quickly. "We have yet to master how new genes transferred into the brain would be turned on and off. But we see both cell transplants and gene therapy as useful treatments for repairing the brains of those suffering from Parkinson's, Huntington's, and other degenerative diseases of the nervous system."