Searching for a therapy that repairs.

Everyone hears about the end result of MS: how a fatty material called myelin, which insulates nerve fibers, is attacked and eaten away by body defense team gone awry. Thus, the nerve's ability to transmit impulses quickly, evenly, or even at all, is foreclosed.

Teams of scientists worldwide work at the questions of why and how these attacks take place, and how the process might be stymied. Meanwhile, other teams work at another set of questions: Could lost myelin be restored? Could the damage done by MS be reversed?

This search is encouraged by new knowledge in the field of glial-cell biology, the life history of a family of non-nerve brain cells. Two types of glial cells are familiar to people who read up on MS--the astrocytes, which normally support the nerve-cell fibers or axons, and the oligodendrocytes, oligos for short, which produce that essential myelin.

Since the 1980s, scientists have known that oligos repair some damaged myelin in adults, but the effect is weak and incomplete. Scientists were surprised that remyelination took place at all; mature oligos in the adult nervous system appear to be retired from active myelin-making. That is done by young oligos. Mature oligos don't divide and replace themselves with new young ones either. Instead, these cells develop in stages from glial stem cells, which are active early in an individual's development--no one is sure for how long. Then the stem cells apparently disappear.

Today, however, some researchers are working with the hypothesis that a few glial stem cells survive in adults. One strategy for replacing lost myelin involves trying to edge those quiescent stem cells back into action.

Another strategy is transplantation.

Suppose it were possible to inject active oligos into an area damaged by MS--a lesion. Would the cells live? Would they produce normal myelin? And would that myelin wrap itself properly around the unprotected nerve fibers? Over the past several years, studies in laboratory animals with spontaneously inherited myelin disorders have s yes. But do such remyelinated nerves function normally?

Two NMSS grantees--Dr. Ian D. Duncan in Wisconsin, and Dr. Jeffery D. Kocsis in Connecticut--are heading two of the perhaps half-dozen research groups around the world that are trying to find out if transplantation has a chance of helping people with MS. Their collaboration recently resulted in publication of a paper entitled "Transplantation of Glial Cells Enhances Action Potential Conduction of Amyelinated Spinal Cord Axons in the Myelin-Deficient Rat." [Proceedings of the National Academy of Science, Vol. 91, pp. 53-57, 1994.]

In plain language, this means that the studies provided the first demonstration that transplantation of oligos can restore nerve function in the limited area of the transplant.

Dr. Ian D. Duncan is a neuroscientist with a long-standing interest in MS. This interest brought him from Scotland to Canada to the University of Wisconsin-Madison. Along the way, his research has been supported by the MS Society of Canada, The Myelin Project, the NIH, and the National MS Society.

His part of this collaboration has involved the growth and culture of transplantable oligos and transplantation techniques for use in very unusual animal models. His group successfully transplanted oligos into a mutant rodent strain called the md (for myelin deficient) rat.

Dr. Jeffery Kocsis is associate director of the Neuroscience and Regeneration Research Center at Yale--via Stanford University, Harvard Medical School, and the biology department at Boston's MIT, among others. With funding from the National MS Society, he and his colleague, Dr. Stephen Waxman, have been studying drugs that might restore function to demyelinated nerves.

Their research led to important questions about whether a remyelinated nerve would work properly.

Drs. Kocsis and Waxman studied drugs that manipulate the function of potassium ion channels on nerve cell surfaces. Together with sodium channels, these structures are the batteries of the nervous system, for electrical current is created as charged sodium and potassium particles move back and forth through these gaps. ,

The two investigators learned that ion channels relocate when a nerve fiber loses its myelin. This sometimes restores a bit of nerve function but it's a phenomenon that might spell a dead end to remyelination hopes. Replacing myelin on an axon that has been without it might not help at all, for the number and location of critical ion channels is almost certain to have altered in the meantime and new myelin might plug up the channels.

"Instead of restored function, you could get what we biophysicists call an impedance mismatch," Dr. Kocsis said. "The remyelination might look beautiful, but the nerves could function even less well than before!"

With their history of studying basic nerve conduction properties for their drug project, Dr. Kocsis's group was well-primed to study the function of remyelinated nerve fibers, but they were miles behind Dr. Duncan's team in transplant techniques.

"Instead of spending the time to learn how to do this delicate work, we established a collaboration with lan. He's the master of it," Dr. Kocsis said. "The md rats Ian sent us were a wonderful model, a clean slate. We knew that their myelin had to be produced by transplanted cells because they have none of their own."

Within two weeks of transplant, it was easy to see long white streaks of myelin in the rats' spinal cords, "robust myelin" Dr. Kocsis called it. He and his group went to work recording the conduction properties of axons both inside and outside of the transplant zone. Then they correlated the amount of myelin in specific areas with their results.

"We found the remyelinated axons were conducting impulses within normal limits. The conduction velocity (the speed) was nearly normal. And the axons were able to follow very high frequency stimulation, meaning impulses didn't stumble or stutter as their number increased, as they do in demyelinated nerves. They moved along in a smooth pattern. And impulses entered and left the transplanted zone without problems....

"We think this study has some very interesting things to say about functional recovery, perhaps in spinal cord injury as well as in MS, for we've managed to establish on a cellular level that an axon without myelin can reorganize its structure in response to being wrapped in myelin," Dr. Kocsis said. "Now, to the next level: can we do this in an adult animal?"

Dr. Duncan is already working with a candidate adult model, the taiep rat, which loses myelin over its lifetime, perhaps because it lacks one critical gene. If the new model passes muster and Dr. Duncan's team demonstrates that myelination occurs after transplant, Wisconsin animals will again be ferried to Connecticut for nerve-function studies.

"We're able to do very fine correlations at this point," Dr. Kocsis said. "We can study the functional effect of myelination on a a single axon. And there are subtle issues we will miss if we don't look with this degree of detail."

While Dr. Kocsis continues this work, Dr. Duncan has begun studying the possibility of culturing glial stem cells for transplanting, because these cells have the ability to migrate.

"There is some evidence from Dr. Annick Baron van-Evercooren's group in France that immature oligos will migrate into areas of demyelination," Dr. Duncan said. In other words, it might be possible to culture cells for transplant that will home in on MS lesions wherever they are. In the work done so far, remyelination occurs only at the site where oligos were injected.

The two scientists are excited about their results and simultaneously cautious. Years of work lie ahead.

For example, so far, no one has studied oligo transplantation in lab animals that have an inflammatory disease--such as EAE--which more closely resembles the situation of people with MS. Would remyelination work on nerve fibers that have been demyelinated for many years? This, too, more closely parallels the human situation. (Researchers at Albert Einstein College of Medicine in New York City have done some very early work that suggests it might.) And could transplants work in the presence of scarring and gliosis--the overgrowth of astrocytes? This also is a feature of MS.

"Not only do we need to invent experiments to answer these and other questions," Dr. Kocsis said, "but, in many cases, we also need better animal models. Transplantation for MS is in its infancy."

The most basic obstacle is this: Transplantation doesn't change the underlying disease. Thus, as long as MS is uncontrolled, repaired myelin would probably be vulnerable to the disease that damaged myelin in the first place.

But if scientists develop treatments to slow or stop the MS process--and the success of Betaseron is encouraging--then transplantation might provide an answer for the many people who have disabilities caused by demyelination.

"I'm convinced that therapy for MS needs to be two-pronged," Dr. Duncan said. "In Betaseron, we have the first drug to affect MS attacks, and others are under development. By the time MS is more controllable, we want to be absolutely ready to treat people who have been affected by loss of myelin. Research needs to address both issues."

Martha King is the director of publications at the National MS Society--and editor of INSIDE MS.