Life on Wheels (76 page)

When people don’t walk for a number of years, their bones lose density, that is, they develop osteoporosis. This loss of bone density is another key question: whether the bones will be able to support the considerable weight of the body and tolerate the impact of walking.

Walking, as we’ve said, is not even the whole picture. What does all of this—nerve regeneration, myelin sheathing, establishment of blood supply, removal of scarring, nerve connections, muscle rebuilding, and bone strength—have to do with sexual function, bowel and bladder control, pain, and many other side issues related to various disabilities? Researchers gain insight into all of these areas when they perform research in basic science.

So this—extremely simplistically—is the puzzle that researchers face. One can understand the fascination of the challenge. With the availability of modern microscopes, laboratories, and computers, scientists can now study and engineer at the molecular level. They can see the processes, they can control them to some degree in the body, or they can reproduce certain aspects in the laboratory. They can attempt to reproduce some of the pieces through genetic engineering. How remarkable!

From this description, it could seem all but impossible to achieve a cure, but the progress made to date, if anything, answers what seemed completely impossible only a matter of years ago. The more researchers unearth the detailed physiology of what goes on with damage to the CNS, the closer we get to putting the impossible behind us, where therapies for acute—and even chronic—injury are a matter of course.

There is a huge array of research projects geared toward disability-oriented research. It would take many encyclopedia-sized books to list them and even begin to describe their work—much less how the research fits together. Particular studies and researchers will be mentioned here to give you a sense of the variety of studies, the immense complexity, the excitement of the progress, and the skill and dedication of the researchers. However, for each project or person mentioned, there are dozens who deserve equal billing.

The first attempt to understand SCI took place early in the 20th century, when a Spanish neuroanatomist named Santiago Ramon y Cajal conducted experiments with dogs and cats. He showed that the brain and spinal cord are made up of specialized cells, different from the rest of the body’s nervous system. He was the first explorer who mapped the structure of neurons and axons that make up the system and is revered today by anatomists as a pioneer. He observed that, when cut, CNS axons made a brief effort to regrow and then stopped. His work is the source of the long-standing belief that nothing could be done to regenerate CNS nerves.

In the early 1980s, a Montreal Institute of Neurology team led by Dr. Albert Aguayo became the first to demonstrate that spinal cord axons could grow more than the slight distance that had been observed by Cajal. Suddenly, the accepted dogma that spinal cords could not regenerate had to be reconsidered. But this demonstration was still a long way from getting damaged axons to grow enough to bring about a “cure.”

Dr. Wise Young, formerly at New York University and now the Director of the Neuroscience Center at Rutgers, State University of New Jersey, has been interested in spinal cord regeneration since well before it caught on in the neuroscience community. Early on, his attempts to get spinal cord research on the agenda at the Society for Neuroscience conferences met with little enthusiasm. But then Dr. Aguayo and his colleagues made the breakthrough that demonstrated that spinal cord axons could indeed grow. A few years later, Dr. Martin Schwab of the Brain Research Institute at the University of Zurich in Switzerland identified a growth inhibitor and began work on counteracting the inhibitor. Suddenly CNS research caught on, and Wise Young has been in the thick of it ever since.

The first assumptions about the inability of axons to regenerate were that something was missing. Then, in 1988, Dr. Schwab discovered that something is in the way. His team found a protein that inhibits CNS regrowth after a trauma. The team has been experimenting with ways to turn off this protein to allow axons to regenerate. In 1990, they discovered an antibody called IN-1 that appeared to block the protein. The team observed about 11 millimeters of growth in the spinal cord of a rat. This was a major step in the research.
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But the inhibitor protein discovered by Schwab’s team is apparently not the only one that exists. James Salzer, MD, PhD, at New York University discovered another inhibitor protein—a myelin-associated glycoprotein (MAG)—in the late 1980s. Actually, it was another researcher who found that the protein prevented axonal growth, and yet another who found that the IN-1 antibody had impact on it. At this early stage, it is hard to know if other molecules in Schwab’s test rats also had an effect on the experiment. Such is the complexity of this research and an example of how collaborative the process needs to be.

The inhibiting proteins reside in the myelin—the fatty tissue surrounding nerve axons—in very small quantities. It is very difficult for scientists to purify and analyze the proteins in order to generate enough to be used for research. Scientists must refine the molecules with absolute precision to develop a usable treatment. It is painstaking work and an example of why this research takes so long. The difficulties of getting a quantity of usable protein for research also limits multiple laboratories from being able to participate in the work. There is not enough to go around.

Another approach to turning off the inhibitors is being explored with cellular adhesion molecules (CAMs). CAMs reside on the membrane surface of nerve cells. They foster communication between the nerve cells. For instance, CAMs help nerve cells to recognize an axon so that they know where to go and do their job of creating myelin. CAMs also help override the inhibitors and, so, play a similar role to that of the IN-1 antibody.

A CAM known as L1 has been shown to play a role in the regeneration of axons. Another Swiss researcher, Melitta Schachner, showed that L1 stimulates growth and does so in the presence of the inhibiting protein discovered by Schwab. L1 is known to be present in the developing brain and spinal cord but goes away after birth. L1 that is found in rats is 99% similar to that found in humans, making animal studies more reliable as indicators of what might happen in humans.

L1 is found on Schwann cells—which produce myelin in the peripheral system but not on oligodendrocytes—which create myelin in the CNS. This makes Schwann cells of great interest because they not only might remyelinate the spinal cord, but could promote regrowth of the axons. And, since IN-1 is so difficult to produce, L1 might prove to be a more practical solution, if only because it is easier to synthesize.

Factors like IN-1 and L1 can clear a path by overriding inhibiting proteins, but something more is needed to really get things growing. Dr. Naomi Kleitman, Director of Education at the Miami Project to Cure Paralysis, says:

The job for researchers is to create that right environment for regeneration to take place.

Neurotrophins feed nerves and, so, stimulate growth. The brain and spinal cord already produce these growth factors but not in sufficient quantity to repair a trauma. There is quite a list of growth factors being studied by researchers. Nerve growth factor (NGF) was discovered in 1951 by Italian researcher Rita Levi-Montalcini and Viktor Hamburger of Washington University in St. Louis. Others include basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF). Among many others, these growth factors are commonly referred to in research literature. According to Wise Young:

Dr. Kleitman talks about the presence of up to 50 growth promoters present in the PNS.

The one that has shown the most promise and has earned the most research attention is called NT3. In 1994, Dr. Schwab and his team used NT3 along with the inhibitor antibody, IN-1. They got nerve fibers to grow the entire length of a rat’s spinal column—another groundbreaking step.

In the July 15, 1997, issue of
The Journal of Neuroscience,
researchers at the University of California, San Diego, reported an early success in axonal regrowth using gene therapy. They managed to get injured rats’ own cells to produce growth factor right at the injury site. They used normal skin cells from the rats and altered them genetically to get them to produce NT3. When grafted back into the animals, these new cells secreted NT3, which produced axonal regrowth. Some rats recovered a degree of walking ability.
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Another good piece of news in the study is that the cells continued to produce NT3 for several months. This means that the cells were able to produce enough NT3 to be effective, yet were not what researchers call immortal cells. Such cells can cause cancer, since they continue to reproduce and ultimately spread where they are not wanted. Wise Young summarizes his optimism about future progress:

When nerve axons die, so does their myelin. So, if axons are regenerated, the myelin must also be regenerated. In the PNS, Schwann cells promote growth of myelin and regeneration of injured nerve axons. In the CNS, oligodendrocytes perform the job of myelin production. However, says Dr. Kleitman:

Oligodendrocytes in the CNS also have a tendency to cross over between axons, whereas Schwann cells have the ability to myelinate along the length of a single axon.

Since Schwann cells are not naturally present in the spinal cord, researchers are particularly interested in bringing them into the CNS and using them there as a possible tool for spinal cord repair. It is already well proven that Schwann cells are also able to regenerate myelin in the CNS for both sensory and motor nerves. The challenge remains to find how to create the conditions in which Schwann cells can accomplish this regeneration in a compromised spinal cord.

Schwann cells have the ability to create a connective framework that holds cells in place as they regenerate. This framework is a latticework of proteins called an extracellular matrix. The extracellular matrix looks like a blanket that wraps around the axon and the Schwann cells. This matrix— different in some respects from the extracellular matrix found in the CNS— is a key characteristic of Schwann cells and has growth-promoting features of its own. Its major component is a protein called laminin, which is also a promoter of growth. Kleitman states:

Schwann cells contribute to the regeneration of the nerve as well as the myelination and, so, perform a double duty. They help the nerve to grow and provide a myelin sheath in a controlled fashion along the nerve, and the matrix generates a structure that keeps the whole thing in place. Kleitman explains:

At the Miami Project, researchers are working with Schwann cell “bridges.” The bridges are based on work from Brown University, which produced a hollow polymer tube that can be wrapped around nerves. (Remember that the scale is microscopic.) According to Kleitman:

This little pathway serves as a guide for nerve growth between two damaged axonal ends.

Schwann cells alone will not be the magic solution. Dr. Mary Bartlett Bunge of the Miami Project led a study in which Schwann cells were engineered to produce the growth factor BDNF. In the first set of studies, the researchers completely transected a spinal cord and laid down a trail of half a million Schwann cells. They found a lot more growth with BDNF and Schwann cells in combination than with Schwann cells alone.
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Dr. Kleitman observes: