Tissue Grafts May Ease Forms of Brain Disease

Buoyed by their early success at treating Parkinson’s disease in both animals and a small number of humans by transplanting adrenal tissues into the brain, researchers are accelerating brain graft experiments to treat diseases that involve brain degeneration.

Among their immediate targets are such common disorders as Alzheimer’s and Huntington’s diseases, researchers said at an international meeting on brain grafting here last week. Further in the future could be the treatment of epilepsy and birth defects.

But the work on these other disorders introduces many new complications. Parkinson’s disease is caused by the death of brain cells that produce one important hormone, dopamine.

Adrenal Gland Product

Lack of this hormone leads to tremors and rigidity of the limbs. Because this hormone is produced by the adrenal glands as well as the brain, each patient has his own source of transplantable tissues.

Alzheimer’s and Huntington’s, in contrast, are characterized by a more widespread degeneration of brain tissues. Huntington’s, which strikes in mid-life, is characterized by hyperactivity, tics (twitching) and emotional defects, and is fatal. Alzheimer’s is a disease of aging that is marked by a loss of mental function and memory, so that victims lose the ability to care for themselves.

These diseases are caused by the loss both of neural hormones that serve as messengers in the brain and of cells that have specific functions in the electrical circuitry of the brain.

Because no other organs in the body produce the hormones involved in these diseases, and because the implanted cells must be virtually identical to the lost cells if they are to be integrated into that circuitry, only fetal brain cells can be used.

But the use of fetal cells in humans presents both ethical and practical problems that have already delayed their use in Parkinson’s patients. Experts agree that human fetal cells will not be used for therapy of other diseases until they have been tested in Parkinson’s patients.

Animal experiments indicate that many of the symptoms of Alzheimer’s and Huntington’s can be alleviated with transplants of fetal cells and that the cells can become integrated. But researchers are finding that the mechanisms for recovery of function in damaged brains are more complicated than had previously been believed and that some earlier experiments may have been misinterpreted.

In animal models of Alzheimer’s, for example, the effects of the brain graft may be dependent upon how the brain has been damaged.

Neurobiologists Helen Barold and John R. Sladek of the University of Rochester studied a strain of rats whose ability to learn new tasks naturally declines with age. The animals were trained to locate an underwater platform in a six-foot diameter pool. Their memory was assessed by removing the platform and determining whether they swam to its original location or elsewhere in the pool.

The researchers then implanted in the rats’ brains fetal brain cells that secrete the neural hormone norepinephrine--which is believed to be deficient in Alzheimer’s victims. When the animals were then trained to new locations, their ability to remember the platform site was improved.

Reduce Learning Ability

But psychobiologist Carl W. Cotman of the University of California, Irvine, and psychologist Donald G. Stein of Clark University in Worcester, Mass., each produced learning deficits in rats by surgically severing a site in the brain that participates in forming new memories. Some of the rats received no further treatment, while others received grafts of tissue from the same area of fetal rat brains.

The animals who received no graft lost some memory function. They could not, for example, learn to run mazes as quickly as they could before.

Both investigators found that rats with the transplants could learn the mazes or other tasks almost as well as normal mice.

But when Cotman killed his rats and examined their brains, he found that a significant number of their own brain cells had died in those animals that did not receive transplants, while a much smaller number died in those that did. He concluded that the transplant secreted some unknown chemical, called a trophic agent, that kept the host cells from dying.

Stein proved this by repeating the experiments. This time, however, he removed the transplants before he tested the rats’ learning ability. He found that their learning abilities were still close to those of normal rats, indicating that the transplant had simply minimized brain damage from the surgery.

Can Be Misinterpreted

One conclusion, Stein said, is that scientists must be careful in interpreting their results when brain disorders are created surgically. The transplants may simply be minimizing the damage the researchers inflict.

“The more optimistic conclusion is that fetal cells can secrete trophic agents that improve the health of damaged cells,” he added.

Many scientists, in fact, believe that trophic agents are primarily responsible for the beneficial effects observed in brain grafts on Parkinson’s patients. They are now trying to isolate and identify these agents in the hope that they can be used as therapy in place of the grafts.

Several researchers presented evidence that brain grafts can alleviate symptoms of Huntington’s disease. Such symptoms are induced in animals by injecting chemicals that kill specific brain cells. After the cells die, the animals lose some control of their limbs and become hyperkinetic.

Neurobiologist Stephen B. Dunnett of Cambridge University in England, for example, found that chemically treated rats became less successful in reaching out of their cage to obtain food from a nearby bowl. Before the injection, they got food on 60% to 70% of such attempts; afterwards, they were successful only about 20% of the time.

Recovered Ability

When Dunnett grafted fetal tissues into the animals’ brains, however, the rats were eventually able to retrieve food nearly as successfully as healthy rats.

Other researchers, such as psychiatrist A. Wallace Deckel of the University of Medicine and Dentistry of New Jersey, also found that rats with grafted fetal cells became much less hyperactive, indicating an improvement in their condition.

One particularly intriguing report was presented by neurosurgeon Noel B. Tulipan of Vanderbilt University in Nashville, Tenn. He grafted fetal tissue into rat brains before he administered the chemical that induces symptoms of Huntington’s disease. Surprisingly, he found that the graft somehow protected the rat’s brain and that the symptoms never developed.

This finding is significant, he said, because many scientists believe that Huntington’s disease is caused by the action of similar chemicals on the brains of humans who are genetically susceptible to the disease. His results suggest, he said, that progression of Huntington’s might be halted by grafts of fetal cells.

Many experts believe that Huntington’s disease will be the next disorder in humans to be treated by brain grafting.

Overall, the most promising aspect of the meeting, co-organizer Don Marshall Gash of the University of Rochester noted, was the large number of people who have begun research in the field. At the first international meeting on brain grafting three years ago, fewer than 150 attended, he said. This year, there were more than 400.