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Navigating the spinal cord

Once injured, the spinal cord cannot heal–at least that's what medicine has long believed. Now Yale scientists are mapping this terra incognita and providing real hope to people with paralysis.

Originating in the brain, stretching down the back and extending its reach through the peripheral nerves to every part of the body from the toes to the fingertips, the spinal cord is the body's information highway. Despite its importance, it is smaller than one might expect: just 18 inches long and about half an inch wide. It's also quite vulnerable. All it takes is a motor vehicle accident or a miscalculated dive into a swimming pool for the spinal cord to be compressed or twisted. In an instant, sensation and movement may cease altogether.

Each year in the United States, spinal cord injury deprives close to 14,000 people of the ability to walk, to use their arms and hands, or in some cases, to breathe unaided. Of the approximately 250,000 Americans who are paralyzed, a disproportionate number have been injured in the prime of their lives. Many, like actor Christopher Reeve, who was paralyzed from the neck down after falling from a horse in 1995, are traumatized at the peak of an active and vigorous life.

Although physicians have believed for thousands of years that an injured spinal cord could not be repaired, new scientific evidence indicates that this might not be true. "For about the past 10 years," says Stephen G. Waxman, M.D., Ph.D., professor and chair of the Department of Neurology, "we have had the sense that restoration of function after spinal cord injury is not an unrealistic goal." Applying new understanding of how nerve cells die and how they might be revived, Yale scientists have made important steps toward the goal of someday reversing paralysis.

Much of this work has been done in partnership with the Paralyzed Veterans of America and its largest chapter, the Eastern Paralyzed Veterans Association. In cooperation with the federal Department of Veterans Affairs, these two groups helped establish the PVA/EPVA Center for Neuroscience and Regeneration Research at Yale, which opened in 1988 at the VA medical facility in West Haven. In the decade that has followed, PVA/EPVA Center scientists have gained ground in several areas. They demonstrated that damage to the protective coating of nerve cells plays a key role in producing paralysis after spinal cord injury, and have focused their efforts on finding ways to restore nerve function where this myelin layer has been stripped away. They also uncovered the molecular mechanism by which remissions occur in patients with multiple sclerosis, a disease that also attacks the protective coating of nerve cells. And they have developed the basis for new treatments for pain and muscle spasticity specific to spinal cord injury. The major goal of the program is to restore total function in individuals who have sustained spinal cord injuries. Along the way, this research program is aimed at finding ways to improve quality of life for patients while the search for a cure progresses.

A decade of advances

These milestones and others were celebrated during a two-day program in late September marking 10 years of collaboration among Yale, the VA, and the PVA and EPVA. Speaking to more than 100 members of the veterans groups who came to New Haven for the event, Dr. Waxman said their support has provided not only funding but, through interaction between patients and scientists, motivation to work hard for a breakthrough. "We don't yet have a cure in hand," he told the group, "but we've made enough progress that I know we will come up with more effective treatments. A cure is now a realistic goal."

Because scientists thought that nerves in the central nervous system (unlike those in the peripheral nervous system) were incapable of regrowing after injury, they believed the only way to restore function would be to rebuild an entire spinal cord, surely a formidable task. Recent discoveries at Yale and around the world have changed that picture significantly. In 1988, Dr. Waxman put together two crucial pieces of information that, while previously known, had never been connected. One was the observation that among paralyzed patients, some nerve cells were found to survive at the site of injury—even in patients who had no function below the injury. The second was the knowledge that myelin was part of the puzzle in paralysis.

Myelin is a fatty sheath that insulates nerve cells and speeds the conduction of impulses along the spinal cord. When a spinal cord is damaged, some axons are severed. Others survive, but their myelin is stripped away. Dr. Waxman set out to find why the surviving axons were unable to function, and, in doing so, made the connection to the critical role of myelin in spinal cord injury. His research showed that nerve fibers within the spinal cord work somewhat like electrical cords—when their protective coating is removed, conduction is impaired. He discovered that it is this demyelination that prevents the surviving axons from properly carrying information. "In addition to the strategy of regrowing axons, this discovery opened up the possibility of repairing existing ones," says Dr. Waxman, the Helen Wilshire Walsh Director of the PVA/EPVA Center. "Damage to the myelin had been talked about even in 1906, but had been buried in the literature." This finding focused attention on the goal of restoring nerve impulse conduction in demyelinated axons, an approach to promoting functional recovery in spinal cord injury.

Is the theory correct? To find out, scientists at Yale are experimenting with ways to mend the damaged myelin sheath in an injured spinal cord. Jeffery D. Kocsis, Ph.D., associate director of the PVA/EPVA Center and a professor of neurology and neurobiology, has carried out studies using the transplantation of glial cells to stimulate the renewed production of myelin and restore the conduction of electrical impulses through the nerve cells. Glia, whose name is derived from the Greek word for glue, are cells that fill in the spaces in the nervous system not occupied by nerve cells. Outnumbering nerve cells 10 to one, glia provide support for nerve cells, with complex functions ranging from producing myelin to regulating the metabolism.

Dr. Kocsis began work on the transplantation of cells four years ago. His interest was sparked by other research done in the 1980s in France and England showing that when glial cells were injected into the spinal cords of myelin-deficient rats, the cells produced anatomically correct myelin. "When I learned of the research, I wondered if the myelin would work properly," says Dr. Kocsis. To find out, he bred his own colony of myelin-deficient rats at the PVA/EPVA Center and injected two types of cultured glial cells–oligodendrocytes and astrocytes–into their spinal cords. He found that injecting glial cells not only produced myelin but restored impulse conduction.

Now, Dr. Kocsis is looking for ways to make this discovery useful to humans with spinal cord injuries. His research was spurred on by an important finding made by William F. Blakemore, D.V.M., a fellow collaborator in The Myelin Project. (This Washington-based organization was founded by Augusto and Michaela Odone of Fairfax, Va., after their son contracted adrenoleuko-dystrophy, a myelin-attacking disease. The 1992 film Lorenzo's Oil was based on their story.) Dr. Blakemore, of the University of Cambridge, found a way to demyelinate the spinal cord of a rat and this paved the way for Dr. Kocsis and others to experiment with the insertion of cells from the central and peripheral nervous systems, as well as genetically engineered cells. In these experiments, Dr. Kocsis found that extensive remyelination occurred when Schwann cells (from the peripheral nervous system) were mixed with astrocytes (from the brain).

The newest and most exciting aspect of this research is focused on the olfactory ensheathing cell, a peripheral glial cell located in the nose. "These cells are unique," Dr. Kocsis says. "Under different conditions, they can differentiate either into Schwann cells or astrocytes. We have found that they make myelin and migrate tremendously." This is encouraging because it may mean that only one type of cell is needed to restore myelin (eliminating the cumbersome process of mixing Schwann cells and astrocytes, as well as the need for the removal of astrocytes from the brain via a biopsy). Dr. Kocsis is also collaborating with Alexion Pharmaceuticals in New Haven to develop transgenic pig cells for transplantation into human spinal cords.

Clues about MS

Multiple sclerosis, a disease that affects more than 300,000 people in this country and an estimated 2.5 million worldwide, also results from neurological damage. As with spinal cord injury, the myelin surrounding the axons is destroyed, preventing them from transmitting signals to the brain. But unlike most neurological diseases, in which injury to the brain or spinal cord is generally irreversible, multiple sclerosis (MS) often includes remissions in which patients regain lost vision or movement spontaneously. Scientists have long been mystified as to the causes of these remissions.

A team of researchers, assembled by Dr. Waxman at the PVA/EPVA Center, has dissected nerve fibers molecule by molecule to identify the molecular basis for MS remission. They found that injured nerve fibers can heal themselves by inserting new sodium channels into the cell membranes. These sodium channels act like molecular batteries, powering the flow of impulses through the nerve fibers despite the absence of myelin at the site of injury. "We are trying to determine where the sodium channels are produced and how they are redistributed after injury," says Joel A. Black, Ph.D., associate director of the PVA/EPVA Center. The next step is to find a way to induce the insertion of these critical sodium channels into demyelinated nerve fibers. "My job," says Dr. Black, "is to tell the physiologists what I find so that they can design a drug." Success in this area may be applicable to those with paralyzing spinal cord injuries as well. "It's just a matter of time before we make significant advances that improve the lives of people with spinal cord injuries," says Dr. Black.

Another strategy has emerged from the work of Drs. Kocsis, Waxman and colleagues. They have furthered the development of a drug called 4-aminopyridine (4-AP), which improves impulse conduction in damaged nerve fibers. The drug, now in Phase III clinical trials for multiple sclerosis, works to reverse symptoms such as weakness and visual loss in MS patients. Early clinical trials have started to test 4-AP's benefits for patients with spinal cord injury. These initial studies suggest that treatment with 4-AP may reduce pain and spasticity. "The patients who have responded to 4-AP know it is not going to cure them, but it appears to improve the quality of their lives," says Dr. Kocsis. These inquiries into pain and spasticity were prompted by discussions with members of the PVA, who had approached Dr. Waxman's team several years ago in search of answers.

Although it is not a cure and despite side effects that may include trembling and seizures, 4-AP has been met with enthusiasm. "We feel that science is on the verge of a breakthrough, especially with 4-AP, which has really meant a lot to those of us with spinal cord injuries," says Kenneth Huber, president of the PVA, which funded early studies on 4-AP. "The return that some people have experienced has given us a great deal of hope."

Scientists at the PVA/EPVA Center and in Yale's Department of Pharmacology played an important role in the development of 4-AP by identifying the molecules that prevent nerve impulses from traveling through the spinal cord in the aftermath of an injury. In axons, nerve activity is modulated by specialized molecules called potassium channels, which were discovered in the 1950s by Nobel prize winners Alan Hodgkin and Sir Andrew Huxley. Hodgkin and Huxley did their research on squids, which have very large nerve fibers. Three decades later, Yale researchers showed that, in mammals, the potassium channels are located beneath the myelin, which covers and masks them.

Working in separate laboratories at Yale but communicating closely, the PVA/EPVA Center's team and J. Murdoch Ritchie, Ph.D., the Eugene Higgins Professor of Pharmacology, showed that when axons lose their myelin, these potassium channel molecules are exposed and halt nerve conduction, acting as "locked brakes." This discovery provided a target–if the potassium channels could be turned off, the brakes would no longer be locked. The drug 4-AP turns off these unmasked potassium channels, thereby improving transmission of impulses and restoring some lost functions.

Stopping cell death

One of the latest and most innovative investigations at the PVA/EPVA Center involves the prevention of nerve cell damage before it occurs. When the spinal cord is traumatized, nerve cells die, but not all at once.

Research at the PVA/EPVA Center has indicated that cell death is caused by a process akin to sabotage. The initial blow to the spinal cord kills some cells instantaneously and then sets off some secondary processes which cause the body to attack itself. An abnormal influx of calcium, a byproduct of the first round of cell death, gnaws away at nearby nerve cells. Death occurs in waves, taking hours or even days to complete. The timing of cell destruction, however, leaves a window of opportunity in which damage might be limited. Yale scientists have targeted the specific molecules that release calcium to the axons and are working to develop the foundation for drugs which will inhibit these molecules and stem the tide of calcium at the time of injury. If this research is successful, scientists may be able to prevent a spinal cord injury from resulting in paraplegia or quadriplegia by intervening in the process of cell death and "rescuing" nerve cells.

In the last decade, advances at the PVA/EPVA Center at Yale and other research institutions around the world have been made on such a broad front that the field of neurology is undergoing a dramatic change. "Traditionally, neurology has been an intellectually beautiful discipline, but we did not have therapies," says Dr. Waxman. "A neurologist would go through a meticulous mental exercise and arrive at a diagnosis. But, we would have nothing to offer the patient, and that has to change."

Dr. Waxman believes that neuroscientists will very soon be able to help patients in ways that were once thought impossible. He is optimistic that within the next decade researchers at Yale or elsewhere will find a vaccine for MS and a cure for spinal cord injuries. "We're approaching a new—and much more hopeful neurology of the spinal cord," Dr. Waxman says. "The goal of repairing the injured spinal cord, at least in some patients, is a realistic one and we're moving as fast as we can in this direction." YM