One of the reasons the search for a cure for paralysis had never captured the public interest is that it had always been considered impossible. Even the Egyptians wrote in hieroglyphics 2,500 years ago that a spinal cord injury is a condition “not to be treated.” This belief became conventional wisdom. And, sadly, few victims of spinal cord injury survived long enough to attract much attention; most died of the pneumonia that inevitably sets in within days of the initial trauma.
Scientific interest was first sparked in the 1830s, when an anatomist named Theodor Schwann discovered evidence of cell regeneration below the cut nerve of a rabbit. This was very exciting because while the central nervous system seemed inexplicably unable to fix itself after an injury, the peripheral nerves apparently could. (Cells in the peripheral nervous system have been named Schwann cells in his honor.) What was preventing regeneration in the spinal cord?
For a long time it was assumed that the damaged nerves were simply, for some reason, incapable of regrowth. Then in 1890 Santiago Ramón y Cajal suggested that the central nervous system failed to regenerate because of an “inhospitable environment.” In 1981 Alberto Aguaya, a researcher at McGill University in Montreal, posited that the spinal cord could not regenerate because some vital ingredient was missing from its environment, and this theory became widely accepted. Researchers began focusing on nerve growth factors (NGFs), first identified in 1951 by the Nobel Prize winner Rita Levi-Montalcini, which were found elsewhere in the body but not in the spinal cord.
Aguaya demonstrated that a nerve taken from an animal's leg and grafted into the central nervous system allowed the nerve cells to grow along the transplanted nerve. This seemed to confirm that the problem did not lie in the damaged nerves themselves. It appeared that something in the central nervous system was impeding their growth.
Then, in 1988, there was a major finding: Martin Schwab, working on nerve regeneration at the University of Zurich, discovered two proteins that inhibit growth in a mammal's damaged spinal cord. This altered the assumption that the cord's inability to regenerate was due entirely to the absence of NGFs. Two years later Schwab was able to induce nerve regeneration in the spinal cord of a rat by blocking the inhibiting proteins with an antibody called IN-1. In 1994 Schwab achieved considerable regrowth of nerves in the partially severed spinal cords of rats after treating them with IN-1 and a growth-promoting factor called NT-3.
What excited me most about Schwab's work with antibodies and growth factors is that the regeneration he accomplished was through drug intervention, not surgery. In addition, he surprised scientists all over the world by demonstrating that as nerves regenerate they seem to have some kind of sense memory of where to go. Researchers had always feared that even if regeneration is possible, the new nerves might simply wander aimlessly or make inappropriate reconnections. You might end up thinking, “Move my left toe,” but have your right elbow move instead. The question would become whether the brain could learn to overcome this problem, as it can with dyslexia, for example. (Some scientists think that would be possible because the brain has an incredible ability to reorganize itself.) Schwab achieved regeneration of about 3 to 4 millimeters in his rats in an absolutely straight line. This linear regeneration was astounding in and of itself, but even more impressive was that the nerves made appropriate reconnections.
In 1988, the year of Schwab's breakthrough discovery of the two proteins that inhibit nerve cell growth, Wise Young organized the first center for the study of animal spinal cord injury. Today every researcher in the field agrees that regeneration is not only possible but within our reach. This has created real excitement in the scientific community and brought in many new investigators.
I've always been a practical person, not one to waste time in the pursuit of unrealistic goals or dreams. By the end of 1995 I was firmly convinced that the push for a cure was based on reality and not on unfounded optimism. It also seemed clear to me that scientists like Martin Schwab and Wise Young needed solid financial support so that they could progress as quickly as possible. I remembered the old adage that in business “time is money.” In scientific research money is time. On behalf of all of us with spinal cord injuries, I decided I wanted to do what I could to help keep the top researchers busy in their laboratories instead of having to waste valuable time begging the NIH or various foundations for more money.
My first step into raising public awareness and money for research had been asking Paul Newman to host the APA dinner. The event brought in close to a million dollars; previous benefits had raised only about $300,000. I was asked to give a speech that night. When I had the audience's attention, I began by saying, “I want to tell you about the wall of my room at Kessler. A fascinating subject, don't you think?” (I could feel them wondering where this was leading.) “But on it there was a poster, a picture of the space shuttle blasting off at night, signed and sent to me by all the NASA astronauts currently in training. Written across the top was, âWe found anything is possible.'”
I reminded the audience that in 1961 President Kennedy had issued the challenge to land a man on the moon before the end of the decade. At the time scientists thought the goal was impossible; no one had yet envisioned a vehicle that could make a successful landing on the moon and then take off again. Many considered Kennedy's speech irresponsible because he had delivered it without consulting the experts. Yet the vision was so captivating, to both scientists and the American public, that it became a reality. It took the combined efforts of 400,000 workers at NASA and dozens of companies that made component parts, but in July 1969 Neil Armstrong took that giant step for mankind.
I reminded the audience of another extraordinary chapter in our history of missions to the moon. As the crippled
Apollo 13
craft was returning to earth, dangerous levels of carbon dioxide were building up inside the command module, and the astronauts had less than thirty minutes to live. At mission control engineers who were used to doing everything by the book had to rely on their experience and ingenuity to solve the problem. As Eugene Kranz, the flight director, states in Ron Howard's film
Apollo 13
: “Failure is not an option.” The challenge, in effect, was to fit a round peg into a square hole. They improvised a solution with cardboard and socks. Instructions were relayed to the spacecraft, and the astronauts survived.
I suggested that it was time to propose a similar challenge to medical science. This time the mission would be the conquest of
inner
space, the brain and central nervous system. I had no doubt that an all-out attack would produce dramatic results. To create a sense of urgency, and to give the quest a human face, I declared my intention to walk by my fiftieth birthday, only seven years away.
As I came offstage, I realized that I had just taken on a new responsibility. I would have to back up this speech with action. From my work with The Creative Coalition, I had access to Washington and friends like Senators Paul Simon, Jim Jeffords, Patrick Leahy, and John Kerry, who could help guide me. I even had a working relationship with President Clinton, having campaigned for him in 1992. I also knew it was important to reach out to the other side of the aisle, because any real progress would have to come from a bipartisan effort.
Everyone at APA was delighted with the evening. A few weeks later I was elected chairman of the board.
The mission of the American Paralysis Association is to find a cure. Nothing less. One of its goals is to speed up the pace of research by convincing some of the world's leading investigators to work together. I learned that the APA funds scientists at the Miami Project to Cure Paralysis, Wise Young (now at Rutgers), Lars Olson in Sweden, and Martin Schwab in Zurich, as well as young researchers with innovative ideas who would probably not receive funding from the National Institutes of Health. This wide-reaching approach seemed sensible to me. Just as it took forty or fifty scientists working together to develop the polio vaccine, the hope for speedy progress in the search for a cure for paralysis lies in the pooling of scientific information and financial resources.
The Miami Project is a major center for research. Dr. Mary Bartlett Bunge, a cell biologist there, is working on the problem of getting an adequate amount of regeneration with enough length for fibers to reach their appropriate target. Bunge's group has focused on Schwann cells in the peripheral nervous system because they produce and secrete elements essential for nerve growth. Schwann cells can be cultured, so if Schwann cell transplants work, researchers will be able to create millions of cells that can be transplanted to an injured area without immune rejection. Only 10 percent of the cells need to “catch” to achieve movement.
At the Weizmann Institute in Israel, Michal Schwartz has been working with compounds taken from fish brains. She came to visit me in Bedford not long after I got home from Kessler and has kept in touch. Her approach is to culture fish brain compounds and inject them into the injured site, bridging the gap across the scar tissue and making new connections.
In June 1996, just a few months after I'd returned home, a group of researchers working under Dr. Lars Olson at the Karolinska Institute in Stockholm succeeded for the first time in growing nerves across gaps in the spinal cords of rats. These cords had been completely severed, yet after a cell transplantation across a gap of about one-fifth of an inch, the rats started to flex their hind legs. A year after the surgery they could support their weight and move their legs.
This experiment received a great amount of publicity. It was regarded as a milestone because it showed that something that had been regarded as impossible is possible. But I was very skeptical about its viability in humans. The nerves that had been grafted onto the rats' spinal cords were from the peripheral nervous system, which does regenerate, but they would probably be incompatible with the central nervous system in humans and thus unlikely to produce motor function. In addition, many of the rats did not survive the surgery. Also, they were originally injured at the thoracic level, where the spinal cord is relatively wide. An operation on a high-level injury in humans, where the spinal cord is very thin, would be extremely dangerous. And the rats in the experiment had their cords completely severed, which is almost never the case in an injury to humans. Building a bridge across a complete transection is a very different procedure from bridging a partial gap. It was hard to imagine that any neurosurgeon would be willing to completely sever a section of a human spinal cord in order to apply the Olson bridging technique. Even if the patient were to survive, I believe that would be a serious violation of the Hippocratic oath, which states, “First do no harm.”
That fall, Wise Young came to visit. He brought me up to date on the work in his laboratory, then dropped a bombshell: the next day he was going to Brazil to see six patients who, without Olson's participation, had undergone the Olson procedure. A year earlier all six patients (who had suffered complete spinal cord injuries and/or transected cords) had peripheral nerves grafted into the sites of their lesions. But several weeks later Wise reported to me that there had been no recovery of function. The one improvement the patients experienced was decreased spasticity: their bodies no longer moved uncontrollably at unpredictable moments. I concluded that Lars Olson's work was not yet suitable for humans, but that it was a promising example of a radical approach, the sort of bold step that is needed if you want to go to the moon or to cure paralysis.
A few years ago researchers knew only that it was essential to preserve as many nerves as possible in the early stages of an injury. They believed that whatever nerves were lost were lost permanently. Ramón y Cajal had even won the Nobel Prize back in 1906 for “proving” that nerves in the spinal cord cannot regenerate. When Paul Newman learned this, he said, “If that guy were still alive, we'd have to find him and take the prize back.”
Today, with scientists convinced that regeneration is imminent, preserving nerves is only one aspect of spinal cord research. I've learned that it now centers on three approaches: preserving the intact nerves; restoring function in the surviving ones; and the most exciting possibilityâregenerating nerves in the spinal cord.
To preserve intact neurons, researchers have to catch them before they decay. Stroke research has shown that chemicals flood in to kill nerve cells after a trauma. This is known as
apoptosis
, or programmed cell death. To a spinal cord victim, this can seem like a cruel joke of nature: not only do you suffer the original injury but healthy cells near the site seem to commit suicide anywhere from a month to six weeks after the initial trauma. A drug has been developed to block this process in stroke victims, and others are on the way. This may have a crossover benefit for spinal cord patients. Dennis Choi at Washington University in St. Louis specializes in programmed cell death. He claims, “We have a good sense of the cascade that destroys nerves after impact, and there is a lot of commonality between the brain and the spinal cord in this respect. Many of the same approaches that work in the brain work in the spinal cord.”
In the second main area of researchâgetting damaged nerves to function againâresearchers focus on restoring connections that are intact after an injury but for some reason no longer work. Research with animals has shown that a lack of myelin, a fatty substance found on healthy nerve fibers that allows conductivity, is significant in the loss of muscle control. Multiple sclerosis is a disorder in which immune cells strip spinal cord nerves of their myelin sheath. Decades ago researchers working on MS began testing 4-AP (4-aminopyridine), a derivative of coal tar, to help MS patients gain as much use of their existing nerves as possible. The drug works by temporarily acting as a myelin coating, allowing impulses to travel through the nerves. Paralyzed animals given intravenous 4-AP have shown improved muscle reflexes. Many scientists believe that 4-AP holds real promise for the future.