18thy December 2002
By Carey Goldberg, Globe Staff
Since ancient Greece, the accepted wisdom on paralysis from serious spinal cord injury has been: no hope. It is as if a bomb has gone off in a computer center, scientists say. How can all those connections ever be restored?
But these days, the field is racing forward. Christopher Reeve's exercise regime and recent remarkable finger wiggling may draw the most limelight. But more quietly, in laboratories around the world, mainstream scientists working on the basic biology of spinal cord cells have been making undreamed-of progress.
So great are their advances - closing in on the genes and proteins at work, getting injured rats back on their paws faster - that they are daring to say what they never would have said before: Significant regeneration of a human spinal cord, though years away, is possible. Even probable.
"Ten years back when I started researching this, it really was science fiction, the possibility of ever realistically being able to help a patient," said Dr. Clifford Woolf, professor of anesthesia research at Harvard and Massachusetts General Hospital. "And now I think it's doable. "
The greatest optimists are even predicting that with some luck, drugs aimed at restoring spinal cord connections and some partial function could start being tested in humans in three to five years.
Further down the line, researchers say, treatment for the estimated 250,000 Americans living with spinal cord injuries could involve a combination of strategies, including the implantation of stem cells and the construction of cellular scaffolds to bridge injuries. Reeve's progress in regaining a bit of sensation and movement is notable, they say, but they are setting their sights on much more radical effects, on actually getting people out of wheelchairs.
Already, growing numbers of researchers have been reporting for the last three years that they can take a rodent paralyzed by a spinal cord injury and, using a wide variety of methods, make it recover its ability to move much better than it would have without their help. They report only a few percentage points of improvement in cell growth and motor function, but that, they say, can be the difference between walking and not.
"It's gotten to the point that everybody has rats walking again," said Dr. Ron Cohen, president of Acorda Therapeutics, a biotech company based in Hawthorne, N.Y., whose strategic focus is therapies for spinal cord injuries.
All this momentum comes in large part from a series of scientific discoveries that began slowly about 20 years ago and, researchers say, have started to snowball in the last three or four years.
They point to a pivotal experiment, performed in 1981 by Albert Aguayo and Sam David in Canada, that cracked a central aspect of the central nervous system conundrum. It showed definitively that the problem with spinal cord injury was not that the nerve cells were incapable of growing again after the damage; it was that something was signaling them not to grow.
But what? Dr. Martin Schwab, now of the University of Zurich's Brain Research Institute, pinpointed the culprit, a protein called "Nogo" because it acts like a stop sign and tells the nerve cells not to grow. By 2000, researchers had found the gene in both rats and humans.
Then Dr. Stephen Strittmatter of Yale reported in 2001 that he had identified Nogo's receptor, the gate that must be unlocked for Nogo to be activated. And this summer, he reported success in blocking the receptor in rats, enabling them to recover better from spinal injury.
Blocking Nogo is not the whole story. "There's not complete restitution by any stretch of the imagination, which leaves open the idea that combining therapies would be more effective than any one therapy alone," said Strittmatter.
Still, Nogo is so promising as a drug target that Schwab is working with Novartis and Strittmatter is collaborating with Biogen to develop Nogo blockers for humans.
At Biogen, Michael Gilman, senior vice president for research, said the company has made some quick progress on Nogo. "If everything went really hunky dory top speed," he said, "we could have a molecule in the clinic in three years," beginning human trials.
Meanwhile, researchers are making progress on a panoply of other ways to restore spinal cords. Some are focusing on ways to keep many of the spinal cord cells from dying in the first place right after the injury. Many are focusing on how to get nerve cells to grow. Others also are exploring cell therapies, such as using cells from the nose or embryonic stem cells to build a bridge across the gap created by the injury.
Researchers are already testing in humans another approach: trying to repair damage to the myelin, a sheath surrounding the nerves that acts as insulation. A drug called Fampridine, made by Acorda, appears to help moderately in some patients, restoring some sensation or bladder control or sexual function. Fampridine could reach the market as early as 2005 .
"This is far from a cure," Cohen said. "It won't be getting people up out of wheelchairs." But, he emphasized, even a bit of added function can make a big difference in a person's life.
Cohen and others noted that the basic understanding gained from work on spinal cord restoration occasions extra excitement because it could ultimately be applied to other central nervous system problems, such as multiple sclerosis and stroke. Work in rodents already indicates that blocking Nogo could help recovery after stroke.
Now, more and more money is flowing into the spinal cord field from organizations such as the national Institute of Neurological Disorders and Stroke. "If the science is good, the funding will follow," said Dietrich.
For all their own excitement, scientists in the field tend toward extra caution when it comes to answering the inevitable "When?" from people in wheelchairs.
"You don't want to be the obstructionist scientist," Kleitman said, "but on the other hand you don't want to be the irresponsible Dr. Frankenstein, and finding the right balance is a real challenge for the field."
What if researchers induce nerve growth in a person, "and the growth we get is not the growth we want but in fact gives the person intractable pain?" she asked. "Or causes spasticity? Or gets in the way of the next great thing to come down the line?"
Kevin Gibson of Melrose, 32, a quadriplegic since he broke his neck in a diving accident 12 years ago, said he understands perfectly well that therapies are years away and that hope does not mean certainty.
Does he think, though, that he may walk in his lifetime? He paused, then said, "I think so." But, "I'm not guaranteeing it. I don't tell people I'm going to walk before I die. But the way things are going, I don't see why, in five or 10 years, they wouldn't have something to regenerate nerves."
One simple bit of advice, Cohen said, is for paralyzed people to maintain an exercise regime, keeping healthier and ensuring that their body will respond better when therapies do appear. Gibson said that some of his friends in wheelchairs seem to be emphasizing exercise more, spurred on by the prospect of clinical trials seeking healthy volunteers for spinal cord therapies.
For researchers, the advice is a different kind of persistence. "We've
gotten through the `gee whiz!' phase, which has given us the understanding
that, `Yes, it can be done,"' Cohen said. "Now it's time for the applied
science, for the heavy duty engineering where you get in there and grind
it out and try one thing after another until you get something that's right."
© Copyright 2002 Globe Newspaper Company.