Monday, March 20, 2006

Stretching the Limits to Heal Spinal Cords

For years, scientists have been trying to make injured spinal cords grow back, with limited success.

Lying awake in bed one night, neurobiologist Douglas H. Smith came up with an offbeat alternative:

Instead of trying to regrow the damaged nerves, how about taking nerve cells from elsewhere in the body and getting them to stretch? After all, he reasoned, a similar process must be going on when whales and giraffes grow their spinal cords to tremendous lengths.

So far, it's working. Smith and his University of Pennsylvania colleagues have taken clumps of nonessential nerve-cell bodies from rats, stretched them very slowly - a millimeter or two a day, in specially constructed stretching boxes - and successfully implanted them into other rats with injured spinal cords.

Still to come are tests to show if the implanted nerves actually "work." Any trials on humans are years away.

But the research is seen as promising, and is just one of several dramatic recent advances in science's quest to reverse the irreversible.

Some scientists are using drugs to limit the harmful inflammation and other secondary damage that arises within hours of a spinal injury. Others, including Drexel University's prominent spinal-cord group, have restored some muscular function in lab animals by using neural stem cells.

Still others are using drugs to stimulate neural regrowth. A variety of clinical trials are under way or about to begin.

The breadth of activity reflects what some see as a coming of age of spinal-cord science. It has been helped along by a shift in federal spending priorities and an increase in private funds - attributed in part to the lobbying efforts of the late actor Christopher Reeve and his wife, Dana, who died earlier this month.

"I think we have a lot more hope for clinical research into whether some of the things in labs are going to have an impact on patients," says Phillip Popovich, a spinal-cord researcher at the Ohio State University College of Medicine.

Partial recovery

Scientists caution against raising the hopes of those with spinal-cord injuries, of whom there are an estimated 250,000 in the United States, according to the University of Alabama, Birmingham.

There are no immediate expectations that paralyzed people will walk again, and researchers say that right now, that isn't even the primary goal.

In surveys, many patients suffering from spinal-cord injury say they become used to living in their wheelchairs, and are more interested - at first - in smaller advances that can make them independent. Among these are regaining bladder or bowel control or partial movement in paralyzed limbs.

"Seemingly small things can make such an incredible difference in quality of life," says Oswald Steward, director of the Reeve-Irvine Research Center at the University of California in Irvine.

Lately, scientists at the Reeve Center, named for the late actor, have used neural stem cells to replenish the myelin sheaths around damaged spinal nerves in laboratory rats. That process - akin to replacing the insulation on electrical wire - enabled the rats to get back some mobility.

At Drexel's College of Medicine, scientists have transplanted another type of neural stem cell into the spinal cords of injured rats, resulting in the partial restoration of bladder control.

The cells did not replace the damaged circuits, says Drexel's Itzhak Fischer, chair of the school's Department of Neurobiology and Anatomy. Rather, they seem to have encouraged compensatory "sprouting" in adjacent, uninjured cells.

But demonstrating a technique in rats is one thing. In people it's quite another.

Rats are hardy, resilient animals, with redundant capability built into their nervous systems. After technicians in Smith's Penn lab cut out centimeter-long notches from rodents' spinal cords, for example, the animals could still walk.

Yet the initial experiments have shown promise, Smith and his co-authors reported in the January issue of the journal Tissue Engineering.

When stretched to the right length and implanted into the injured spinal cords, the replacement nerves - nicknamed "jumper cables" - took hold.

Four weeks after implantation, the new nerves not only survived, but grew into the damaged spinal cords.

A true test will involve transmitting electrical signals along the length of repaired spinal cords. That research is scheduled to begin during the coming year.

Stretching nerves

Smith, 46, the boyish director of Penn's Center for Brain Injury and Repair, got the idea one night while thinking about the harmful stretching of brain cells that occurs in a concussion.

Could stretching be adapted to repair spinal cords? he wondered.

A review of the literature revealed almost no research into how spinal cords grow.

Which is when he decided to grow them himself.

The lab started by extracting the cell bodies from rats' peripheral nerves - the conduits that relay sensory information from the legs and other body parts back to the spinal cord.

Researchers then placed clumps of nerve-cell bodies onto two adjacent plastic membranes, each coated with jelly-like collagen. The cells were then immersed in a soup of liquid nutrients.

Tiny branches - the beginnings of the nerve fibers known as axons - soon sprouted from the cells until the adjacent membranes were connected.

Then, slowly and steadily with the use of computers, the two membranes were pulled apart. The pulling takes place in little boxes that might call to mind a torture instrument.

"Torquemada would be proud," Smith quips, referring to the Spanish Inquisition's grand inquisitor.

But contrary to the experience of torture victims, the nerves seem to like the stretching just fine. They absorb nutrients from the surrounding growth medium and grow thicker even as they are pulled.

Smith thinks the process is not much different from what occurs in the growth of a real spinal cord.

"We're just kind of copying that from nature," he says, adding that his approach could be used in conjunction with other techniques, such as stem cells.

Drexel's Fischer, who was not involved in the stretching research, calls it "an engineering triumph."

If tests show that stretched nerves are truly functional after implantation, human trials could begin soon after.

Smith, like most in his field, is wary of making predictions, given that bold statements have backfired before. In the 1980s, for example, one prominent researcher is said to have predicted that the problem of spinal-cord injury would be solved within a decade.

Yet Steward, the Reeve-Irvine Center director, understands the need to hope, citing his experience with the actor.

At one point during the course of lobbying for more research funds, Reeve was optimistic that stem cells would benefit him personally, Steward says. Eventually, the actor told Steward, he realized he would not live long enough.

"He certainly realized that what he was doing was for later," Steward says. "But did he hope? You bet."

By TOM AVRIL - Philadelphia Inquirer