The white mice scrambling over one another in plastic cages in Dr. Evan Y. Snyder's laboratory at Children's Hospital in Boston look like standard-issue research animals. But they represent a new frontier in the manipulation of life. In a series of recent experiments, Snyder injected living human neurons into the mice's soft, tiny skulls. The neurons survived and spread, sending out connections until they were fully wired into the mice's brains. The mice now negotiate their world with brains that are part human.
Snyder's mice offer the promise of a new treatment for Alzheimer's, Parkinson's disease, strokes, and spinal cord injuries, all of which lead to the destruction of brain cells. "We are looking for ways to repair those neurons, replace those neurons, and restructure the brain," said Paul R. Sanberg, a neuroscientist at the University of South Florida. He and Snyder were among a group of scientists who described the latest developments--including new research on humans--at a seminar on Jan. 25 at the annual meeting of the American Association for the Advancement of Science in Anaheim, Calif.
The notion that neural-cell transplants might treat brain damage was first explored nearly two decades ago. Then, fetal neurons were injected into several Parkinson's patients, but the improvements in symptoms were modest and fleeting, and researchers went back to the lab to figure out why. "The reason they stopped is because they weren't confident they knew what they were doing," said Ronald McKay, a molecular biologist at the National Institutes of Health in Bethesda, Md., who has been working on neural transplantation since the early 1980s. Now, however, "the whole thing is booming," said McKay. "The pharmaceutical industry is all over our work--they really want to do this." According to Sanberg, a dozen or more research teams at universities and biotechnology companies have jumped into the field in the past few years.
NEW WAVE. The early experiments with fetal neurons are being replaced by what might be called a second wave of brain-cell transplants. In November, Snyder reported that he had isolated human neural stem cells--the immature precursors that grow into all the neurons and related cells found in the brain and nervous system. "They are really the seeds of the brain," Snyder said. (McKay and others have worked with similar cells, and there is disagreement over who was first to isolate stem cells.)
Most of the neural transplant work so far has been done in rats, mice, and monkeys, but human tests are beginning. In one of the most ambitious studies so far, Dr. Douglas Kondziolka, a neurosurgeon at the University of Pittsburgh, has treated nine stroke victims by injecting human neurons directly into the parts of their brains that were damaged. The hope is that the neurons could help restore memory and speech lapses and other debilitating consequences of strokes. The first report on the transplants will be presented on Feb. 4 at the American Heart Assn.'s annual stroke meeting in Nashville.
Kondziolka is using neurons produced from a testicular cancer tumor called a teratocarcinoma. The tumor arises from the germ cells that generate sperm, and, like sperm cells, it can change as it grows to form many kinds of tissue--including nerve cells. The neurons, grown by Layton Bioscience Inc. of Atherton, Calif., were originally produced for use in drug testing and other experiments.
SMART CELLS. Sanberg, who did the scientific work to prepare the tumor cells for the University of Pittsburgh trials, had originally focused his research on Parkinson's disease. That changed a few years ago. "My father had a stroke," he recalled. "I watched his therapy, and there hasn't been anything new in the past 20 years. I thought, `Isn't there something we can do to help this man?"'
The animal studies have revealed an amazing new discovery: When neurons are transplanted into a living brain, they seem to know just what to do. The cells don't spread randomly through the brains, grabbing on wherever they can. Instead, they begin to develop into various types of brain cells. Each type migrates to the place it belongs and wires itself up in the proper way--just as if Nature had done it herself. Something in the mice's brains is cueing the injected cells to do what is needed to repair damaged brain parts. This works even when human cells are injected into mice brains--suggesting that mice and human brains use the same cues.
Snyder has also shown that the neurons can be used to correct inherited disorders. He grew mouse brain cells that carried the mutant gene responsible for Tay-Sachs disease, a fatal disorder that poses a special risk to Ashkenazi Jewish populations. He then added human neurons with the normal form of the Tay-Sachs gene. The new genes smoothly took over, supplying a missing enzyme, and the problem was corrected.
Dr. Mark H. Tuszynski of the University of California at San Diego described another approach using gene therapy to carry a substance called nerve growth factor into the brain. The addition of the growth factor, he says, should help slow and reverse damage associated with Alzheimer's disease before brain cells are destroyed and a neural transplant becomes necessary.
In a few months, Tuszynski will seek approval to use the technique for the first time in humans. He plans to take small samples of patient's skin cells, genetically engineer them to produce nerve growth factor, and inject them into patients' brains. If this were done even several years after the diagnosis of Alzheimer's, it might prevent the loss of mental functions, he says.
"LEAP OF FAITH." Several biotech companies have entered the race to develop brain transplant techniques, Sanberg says. They include Diacrin in Charlestown, Mass., and Genzyme Corp. in Cambridge, Mass., which are collaborating on human experiments with fetal pig cells to treat Parkinson's and other disorders. And two scientists from McKay's lab at the NIH have left to form a company called Neural Stem in College Park, Md., to try to advance some of McKay's findings.
Part of the excitement arises from the fact that cells transplanted into the brain do not seem to face rejection by the immune system, as is the case with, say, liver or kidney transplants. The reasons are not entirely clear, but the finding is significant. It means brain-cell transplants are likely to survive a long time--which is essential if they are to correct brain damage. It also means that cells will not have to be matched to individuals, as is done for blood transfusions or other organ transplants.
McKay believes the current research could one day lead to treatments even for the slow, steady brain deterioration that occurs with old age. "When you look at old people, you think they're just losing it--they're running down," he said. "But that's not right. All the cells are still there. What's changing is the nature of the conversation between the cells.... And I know that these processes can be slowed, stopped, corrected."
Of course, whether the success in mice will be repeated in human beings is an unanswered question. "We always believe that what we're doing in animals will have relevance to humans," Snyder said. "But it's a leap of faith." Within a few years, researchers should find out whether that leap is justified.