BUSINESSWEEK ONLINE : DECEMBER 11, 2000 ISSUE
SCIENCE & TECHNOLOGY

Rebuilding the Spinal Cord
In the lab, treatment methods for back injuries are advancing by leaps and bounds

Purdue University and Indiana University are about to embark on an experiment that, until a few years ago, would have been tackled only in a science-fiction novel. In November, the two institutions announced that they were planning the first human trials to see if weak electrical charges can regenerate nerve fibers in injured spinal cords. The technique, which uses an implantable device developed at the Purdue School of Veterinary Medicine, has already helped dogs suffering paralysis regain some functions, and the researchers hope for the same results in humans.

This clinical trial is hardly a sure bet: Experimental spinal cord treatments have had far more failures than wins. Still, these efforts represent a revolutionary change in thinking about such injuries. For decades, it was a firmly held belief that the neurons, or nerve cells, of the brain and spinal cord were unable to regenerate after injury, unlike cells in the body's other tissues. But over the past decade, scientists have come to realize that the body can create neurons if the circumstances are right. Now, they are figuring out just what some of those circumstances are and how to induce them.

PROMISING. While many doctors believe it may be 10 years before the discoveries benefit human patients, they are starting to envision what a successful treatment strategy might entail. Particularly promising approaches include efforts to transplant stem cells into the spinal cord, where they may be able to repair or replace damaged neurons. Antibodies have also been developed that encourage the regrowth of nerves. And researchers are exploiting the recent discovery that the spinal cord is able to retrain itself after injury, shifting tasks to the undamaged nerves.

Such advances have supercharged the whole area of research on spinal cord injuries. At the November annual meeting of the Society for Neuroscience in New Orleans, seminars on spinal cord advances were packed. Some of the presentations featured monkeys that had regained the use of their forelimbs and rats able once again to walk and swim--in the wake of catastrophic spinal damage. ''Man, to be a rat right now,'' said Christopher Reeve, the paralyzed actor who cannot breathe without a respirator, and who spoke at the meeting. ''I never thought I'd be jealous of a rodent.''

Of course, it is a big leap from rats to humans--and there are huge obstacles to clear before any doctor will take that leap. Still, in an October review article in Nature, leading neuroscientist Fred H. Gage of the Salk Institute for Biological Studies in La Jolla, Calif., wrote that ''the first rational, functional therapy for regeneration, probably for spinal cord injury, may be in the clinic just 10 years from now.''

Sadly, that will likely be too late to help people such as Reeve who have lived with spinal cord injuries for years. In such cases, researchers suspect that there will be too much scar tissue and atrophy around the site of the injuries to allow repair. Plus, scientists are quick to point out that even those patients who can be helped are not likely to regain full functionality. Nevertheless, ''going from complete paralysis to some movement would be a huge improvement in the quality of life of these patients,'' says Dr. Evan Y. Snyder of Harvard Medical School. ''Just to get that patient off a respirator would make a huge difference.''

BROKEN LINK. It could also be a huge cost savings. The National Institutes of Health estimates that about 11,000 Americans suffer spinal cord injuries each year, with 47% becoming paraplegic and 52% quadriplegic. There are some 250,000 permanently paralyzed persons in the U.S., and the cost of caring for them is $10 billion a year. One reason: People aged 16 to 30 suffer 55% of all spinal cord injuries, and they require massive amounts of care for the remainder of their lives.

Spinal injuries are so disastrous because they interrupt communications between the brain and the rest of the body. The spinal cord contains two long bunches of nerves known as axons. The descending pathway carries signals from the brain that control voluntary movements, while the ascending pathway carries sensory information to the brain, such as sense of touch, temperature, pain, and body position. These two pathways are connected to a large network of peripheral nerves that exit and enter at each vertebra and control specific areas of the body. When the axons are crushed or severed, connections to the peripheral nerves are lost, and the regions they control are paralyzed. In general, the higher up the spinal column the injury occurs, the more severe the ensuing paralysis.

Spinal cord injury research today breaks down into three different approaches: replacing the damaged nerves, repairing them, or retraining undamaged nerves to take over their function. The replacement, or regeneration, track has gotten the most attention since a major breakthrough in 1996, when a team of researchers at the Karolinska Institute in Stockholm grafted tiny bridges made of cells taken from peripheral nerves into rats with sections of their spinal cords removed. Some axons regrew into the bridges, and the rats were able to move their hind limbs and support body weight.

The regenerated axons, however, never reconnected with peripheral nerves, sending scientists searching for a better cell-transplant source. The most promising so far are fetal stem cells, also called precursor cells, which have the ability to turn into any kind of tissue. At the Neuroscience meeting, Dr. Hideyuki Okano of Osaka University's Graduate School of Medicine highlighted this versatility. His report, on stem cells extracted from the spinal cords of rat embryos and transplanted into adult rats, showed that the rats had regained the use of their front legs within five weeks. Autopsies revealed that the transplanted cells had not only turned into several types of neurons but had also reconnected with peripheral nerves.

RIGHT CELLS. When it comes to obtaining adequate supplies of fetal stem cells, however, there are considerable obstacles, both practical and political. George W. Bush has said, for example, that he would stop federal research using fetal cells. But adult stem cells might also do the trick. For years, adult cells were thought to be less malleable than embryonic versions, but this notion seems to be falling by the wayside. ''Our work shows that bone marrow cells from mature individuals...can be changed by environmental signals,'' says Dr. Ira Black, chairman of neuroscience at New Jersey's Robert Wood Johnson Medical School. In Black's lab, adult stem cells bathed with growth hormones were induced to convert to nerve cells within minutes or hours. Black says these converted cells were then transplanted into the brains and spinal cords of normal rats, where they continued to survive.

It remains unclear whether stem cells from any source will consistently turn into the right kind of nerve cells, once transplanted. To get around that problem, some researchers hope they can get damaged nerves to repair themselves. Martin E. Schwab of the Brain Research Institute at the University of Zurich is a leading advocate of this approach. Ten years ago, he discovered the ''stop'' signals in the spinal cord that prevent damaged nerves from regrowing. In January, his lab isolated the gene for one of these inhibitors, called Nogo. Schwab's team has developed antibodies that block Nogo, allowing uninjured axons to sprout and extend to peripheral nerves that have lost their original connections. Rats tested with the antibodies were able to recover full functionality, Schwab says.

It is likely that antibodies and stem cells will eventually be combined into one therapy. But a more immediate treatment may also be in the offing: Researchers have discovered that the spinal cord has the ability to process some sensory information and make decisions on its own, without help from the brain. ''We are just beginning to realize that spinal intelligence and plasticity is far greater than had been previously realized,'' says V. Reggie Edgerton of the University of California at Los Angeles.

As a result, there are numerous efforts to retrain spinal cord nerves, so that patients can regain motor skills on their own after injury. Edgerton notes that some patients can dramatically improve their ability to step when trained on a treadmill. Animals have also been trained to bear their full weight--although the ability declines once training is stopped. Edgerton is now conducting human trials with a robotic step-training device, hoping to identify types of injuries that respond to treatment.

All of these breakthroughs are drawing more resources to the field, say researchers. This may speed up the pace of development--as will relentless pressure from Reeve, the most tireless campaigner on behalf of spinal chord research. ''There is no reason this problem can't be overcome,'' he exhorted the meeting of neuroscientists. ''I might be able to wait three or five years, but I couldn't wait another 20.''

By Catherine Arnst in New Orleans

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