Innovators 2001 - SAMUEL DAVID
By Josh Fischman
The mouse shouldn't have been able to move its legs, let alone take a step. A deep cut in its spinal cord had slashed nerves between its brain and lower body. Thousands of people each year are paralyzed by this kind of damage, and it left the mouse in no better shape. Then neuroscientist Samuel David reached out to tickle the top of the rodent's foot. The mouse lifted its leg and carefully put it down again.
David turned to another injured mouse, and then another, and tickled both into steps. "I was really thrilled days later when we looked at the spinal cord through the microscope," recalls David, who works at the Montreal General Hospital Research Institute in Quebec. "You could plainly see the nerves had regrown past the damage. There were lots of nerve fibers, hundreds! A decade ago, people said this regrowth was impossible."
The impossible has started to appear very real. At last month's meeting of the Society for Neuroscience in New Orleans, David's research, presented in a huge convention hall, seemed like part of a nerve regeneration bazaar. Right next to him a scientist was talking about success using a leg nerve to reconnect a severed optic nerve in a rat. Another researcher was showing that rodent brain cells can be transplanted from one brain region to another, take root, and function.
David's work–a vaccine-type injection–holds special promise for treating people after a crippling injury, though he's years from realizing that promise. The vaccine, oddly, gets the body's immune system to attack myelin, a sheath surrounding nerves. But myelin's embrace can also block new nerve growth, almost like a suit of armor that restricts movement.
Signs of movement. "David's immunizations have one big advantage," says the man who first discovered myelin's dual nature, Martin Schwab of the University of Zurich. "We don't know all the separate myelin components that inhibit nerve growth. So broad immunizations against all of myelin can even block ones we haven't identified. That could have a strong impact." The disadvantage, he cautions, is that the effect could be too strong, damaging myelin and the nerves it shelters elsewhere in the body. "After all, multiple sclerosis is an attack by the body on this myelin, and no one wants to cause that."
Certainly not David, who's spent his career helping people move their bodies. Born 54 years ago in Bombay, India, and trained as a physical therapist, he worked with spinal-cord-injury patients. He kept this up when he moved to Canada in 1969. "I saw all kinds of injuries. I remember one guy who was pulled into a machine in a tire factory; it snapped his spine. Then there was a young girl paralyzed from the waist down in a car accident."
David felt he was making a difference, but not a big one. Severed spinal nerves never recovered, nor did body control. But in the limbs, unlike the spine, damaged nerves do regrow. So David knew growth was possible. "I wondered if there was a way we could do more," he says. In the late 1970s, he got a neuroscience doctorate and then, at McGill University in Montreal, he experimented with nerve grafts into the spinal cord. In the 1980s, Schwab showed that myelin, the sheath, actually got in the way of nerve growth."For the first time that gave us someplace specific to look," David says.
Myelin first appears before a baby is born, but only after a developing nerve tendril reaches a target in the spinal cord. The sheath helps channel nerve signals down this tendril. And it may prevent the nerve from connecting helter-skelter elsewhere, so a signal to bend your knee won't also make your toes twitch.
But what helps new nerves hit targets would hinder severed adult ones trying to reconnect. Researchers set out to identify molecules within myelin that stunted nerve growth and found a few, like the aptly named Nogo. David and lab mates Lisa McKerracher and Peter Braun found one called MAG, and hints that there were likely to be more. The wide field of candidates led the team to try an immunization approach.
Raising an army. The idea rests on antibodies, the immune system's advance guard, which glom onto molecules that could be dangerous to the body. Over a three-week period in 1999, David injected mice with cow myelin. The injections raised an army of antibodies. Then the scientists cut the cord.
Three weeks later, many of the mice were hoisting their feet. Another group, not primed with myelin, couldn't move theirs. David thinks the antibodies in the immunized mice bound up myelin at the injury, keeping it away from regrowing nerves.
"We all thought that was amazing," David says. "But there was one big problem. You can only use this priming approach to treat injuries before they happen." That's little help to accident victims.
So this year David's group developed an after-injury therapy. They raised myelin antibodies in mice as they did in the first experiment. But this time, they took the antibodies out of the mice, injured a second group of animals, and then injected the antibodies into the injured spinal cord. Again, the antibodies seemed to gunk up enough myelin to permit nerve cells to grow right past the injured spot.
One small step for
a mouse, however, is no giant leap for mankind. "We need to figure out
a way to do this safely in people," David says. Mouse immune systems didn't
attack the myelin of other, uninjured nerves. But there's no clear safeguard
to prevent that from happening in humans, and with it the risk of a multiple
sclerosis-like disease. "I can't go up to Christopher Reeve this week and
say, 'We have a cure for you,' " David admits. But if scientists gain control
over myelin for the first time, patients may once again gain control over