To Stand and Raise a Glass

JUST BEHIND THE FOREHEAD, IN the squiggly interstices of the prefrontal cortex, an intention takes form. Here the decision to, let's say, lift the right hand in a celebratory toast begins as an electrical impulse. It leaps from neuron to neuron like a nimble child hopping from stone to stone across a river. The signal reaches the shores of the motor cortex, which arcs across the top of the brain like an earmuff band, and zips down into the spinal cord, a bundle of 20 million nerve fibers crowded into the bony spinal column. The impulse reaches the first cervical vertebra, one of 33 little offramps from the spinal cord that carry the signal into motor neurons that draw breath into lungs, shrug the shoulders, flex the biceps -- or enable the muscles of the hands to grasp a champagne flute. But in 90,000 Americans, that doesn't happen. The impulses stop dead at one of the first exits. The neurons in that part of the spinal cord are crushed, or severed, or otherwise made useless by injury. There are no more stones across the river. The neck, arms, hands and everything below lie still, cut off from the source of volition. Paralyzed.

And until recently the bodies of those 90,000 quadriplegics seemed doomed to remain so forever. Patients set their sights so low that to old-timers like Barry Corbet, a paraplegic for 28 years, a medical miracle has meant ""a lighter wheelchair and a better colostomy.'' Scientists were hardly more optimistic. ""Getting spinal-cord neurons to bridge the gap caused by injury seemed like the stuff of dreams,'' says neuroscientist Jeffery Kocsis of Yale University.

But maybe not impossible dreams. The search for a cure seems a lot less quixotic than it did only a few short years ago. In part that is due to the indefatigable lobbying and infectious optimism of actor Christopher Reeve, paralyzed from the neck down in a freak riding accident 13 months ago and now campaigning hard for greater funding of spinal-cord research (page 56). In greater part it is due to the string of successes neuroscientists have scored in the 1990s. In a few weeks, according to the buzz in the spinal-cord community, the journal Science is expected to publish a groundbreaking paper from researchers at Sweden's Karolinska Institute. The scientists took adult rats whose spinal cords were completely severed, and transplanted nerves from elsewhere in the body. For the first time ever, Karolinska's Lars Olson and colleagues got nerves at the injury site in an adult mammal to regenerate and produce ""functional recovery.'' Or, as Dr. Wise Young of New York University explains it in technical terms, ""the rats walked!''

Will people? Reeve has told friends he has one goal. On his 50th birthday, he intends to stand up on his own. Then he will raise his arm to toast his family for sustaining him through his rehabilitation. Reeve is 43. ""Seven years is not an unreasonable period for us in the research community to restore enough function to Christopher for him to achieve that,'' says NYU's Young. He holds his thumb and forefinger a couple of inches apart. ""All we have to do is regenerate this much. Just this much.''

The path to a cure will be a tortuous one. ""We will not achieve a cure by throwing a single switch, as we thought 10 years ago,'' says neurosurgeon Andrew Blight of the University of North Carolina. ""Rather, it will be achieved through a series of incremental steps'' (diagram, page 54). Some of the main challenges:

When a fall, diving injury or other accident compresses the spinal cord, the tissue swells, and damaging molecules called free radicals go on a rampage. Nerve cells respond to this attack with something less than valor: they commit suicide (""programmed cell death,'' in labspeak). If the biowarfare could be stopped, more cells would survive. It turns out that massive doses of a synthetic steroid called methylprednisolone (MP), given within eight hours of injury, act like a ceasefire agreement, putting a stop to the neuronal carnage. In recent clinical trials, patients with total loss of neurological function below the injury site regained, within a few weeks, 21 percent of function after taking the steroid. Patients who received a dummy pill regained only 8 percent of lost function (spontaneous remission is rare, though not unheard-of). ""The results stunned all of us,'' says NYU's Young: it was the first time any substance had been shown to minimize damage. ""We made the leap from absolutely no hope to some hope.'' Reeve received MP within one hour of his accident. ""I believe it significantly reduced the amount of swelling in the spinal cord,'' he told NEWSWEEK. The downside is that MP is ineffective if given more than eight hours after injury. Now scientists are trying to determine the safest dose and minimize side effects.

Even neurons that have escaped being severed or complete- ly crushed may be on the cellular ver- sion of disability leave. They can't do their job of transmitting electrical impulses. The reason seems to be that spinal-cord injuries kill cells that garb the neuron's axon in a sheath called myelin. Without myelin, axons cannot conduct electricity; they short-circuit. In spinal-cord patients, UNC's Blight reasoned a few years ago, some loss of function could be due not to actual loss of axons but to electrical problems. It turns out that a substance called 4-AP increases a cell's ability to conduct electricity. ""It decreases the amount of current leaking from the neuron,'' says Blight, ""which should increase the chances that a nerve impulse will travel through the damaged region.'' Clinical trials of 4-AP proved him right. As reported in 1993 and 1994, researchers found that about one third of spinal-cord patients who retained some sensation in their paralyzed areas -- though no patients who suffered total loss of neurological function -- improved on 4-AP. One patient, disabled for 15 years, regained control of his bladder, bowel and sexual function. ""We're not talking about miracle cures,'' says Blight, ""but some patients do benefit. It could make the difference between having to be fed and feeding oneself.'' Further trials by the New York biotech firm Acorda Therapeutics, Inc., are planned for this year.

The ultimate challenge is inducing damaged nerves to hook up again, forming networks that carry sensations of pain and pleasure, that lift a finger and propel a leg. Nerves outside the brain and spinal cord -- in the hand, say -- grow back after injury. But cells of the central nervous system balk. In 1987 Dr. Martin Schwab of the University of Zurich discovered why: a protein somehow prevents neurons from regenerating. By 1991 Schwab had found a way to neutralize the protein: sic an antibody on it. Giving the antibody to rats whose spinal cords had been partially severed allowed nerves to regrow. ""For 100 years the dogma was that the adult nervous system does not regenerate,'' says neuroscientist Fred (Rusty) Gage of the Salk Institute. ""But now we know that is not true.''

In another approach, researchers are grafting fetal nerve cells into the injury site. An injured spinal cord develops a cavity as nerve tissue deteriorates, producing an effect akin to Swiss cheese. At the University of Florida, Gainesville, researchers led by Drs. Paul Reier and Doug Anderson transplant rat fetal tissue into these cavities in adult rats. When the graft was performed soon after injury, six of eight animals ""showed measurably improved function,'' says Reier. But if treatment began weeks after the injury -- in human terms, years later -- there was little to no improvement. Whatever the scientific promise of fetal transplants, however, they may never be politically feasible in humans, given the incendiary nature of abortion politics. And as with any other transplant, there would be a risk of rejection.

A better bet may be to genetically engineer cells to churn out the neuronal version of Miracle-Gro. Salk's Rusty Gage takes skin cells from a rat, splices in genes that order up the manufacture of ""nerve growth factor'' and injects them into the rat's injured spinal cord. Some neurons regrow, and his rats, which before dragged their hind legs, walked a little better.

Restoring movement and sensation to a quadriplegic (who has little or no neurological function from the neck down) may be no harder than curing a paraplegic (neurological function in the upper half of the body but little or none below). Although the site of damage differs, the extent of damage -- the amount of nerve fibers that must regenerate and reconnect -- may not. Nor must all of the original nerves be restored to working order, neuroscientists realized only recently. The human nervous system has so much built-in redundancy that if a mere 10 percent of spinal neurons work, the body might be able to move, though not as well as before. That means that researchers might not have to regenerate all of the crushed or severed axons -- just 10 percent of them.

The crucial distinction seems to be between total loss of neurological function (usually because the spinal cord was severed) and partial loss (the neurons were only crushed and compressed). Christopher Reeve's accident, according to two key pieces of evidence, did not sever his spinal cord. Nerves running to the muscle just behind the top of his right shoulder are working fairly well. He has some sensation, albeit impaired, from his right elbow to his fingertips, in his upper spine, by his left ribs and in his left leg. And he can breathe without his respirator for an hour or more.

Before and until there is a cure, there is rehabilitation, which doesn't mean just wheelchair basketball anymore. At Craig Hospital in Denver, 15,000 patients including George Wallace and Detroit Lions right guard Mike Utley have learned to ride horses, wheelchair-ski and shoot photographs -- and game -- with specially designed camera and hunting equipment. Utley learned to sky-dive. At Craig and elsewhere, quads and paras can tap a whole Smithsonian of inventions. Velcro-equipped cutlery lets them eat on their own even if they cannot grasp a fork. Voice-acti- vated computers let them e-mail friends and surf the Net. Special wheelchairs are close to magic carpets. Reeve uses one that responds to puffs of breath: a hard puff turns his chair right, a soft one turns it left.

More than rehab but less than cure is ""functional electrical stimulation.'' FES systems are basically bionic men in a box: since motor neurons no longer receive the electrical impulses from the spinal cord needed to make muscles move, FES supplies them. At Case Western Reserve, for instance, researchers led by biomechanical engineer Hunter Peckham implanted electrodes into 39 quadriplegics, all of whom could move their shoulders but nothing lower. Various shoulder motions send specific commands to a microchip, usually in a wheelchair. The chip decodes the signals and issues a sequence of electrical commands to electrodes in the hand, moving muscles to grasp a cup, use a fork, comb hair. At the Miami Project to Cure Paralysis, founded by former football player Nick Buoniconti after his son Marc was paralyzed from the neck down in a college football game, FES devices enable ""paralyzed'' patients to walk a full mile. Unfortunately, the devices can cost $10,000. The electrodes are implanted in the pelvic region; they can restore bladder and bowel function. In the chest, they can restore breathing, freeing the patient from a respirator.

Each year as many as 12,000 Americans join the more than 200,000 who already live with paralyzing spinal-cord injuries. Most are young; most are men. Most (44 percent) are injured in car crashes; 22 percent get hurt in falls, and 18 percent are injured playing sports, usually diving. Just two generations ago many of these patients died from the injury. But now 90 percent survive, living an average of 40 years in bodies that have become inescapable prisons, prisons whose keys science was not even close to finding. These people will not all rise up from their wheelchairs tomorrow. But where once there was only a field of despair, hope is finally sprouting. Remember: the rats walked.

Antibodies: Naturally occurring proteins in the spinal cord prevent neurons from regenerating. When lab rats are injected with antibodies that tie up these inhibitory proteins, the neurons grow again.

Genetic engineering: Researchers take animal skin cells and splice in a gene that makes growth-promoting substances. The cells are then transplanted back into the animal and induce neurons to partially regrow.

Fetal tissue: Scientists graft nerve cells from rat fetuses into the cavity left by a spinalcord injury in an adult rat. Although the experiments seem promising, the politics of abortion may make human fetal grafts a nonstarter.

SOURCE: DR. WISE YOUNG, NEW YORK, NEW YORK UNIV. RESEARCH BY BRAD STONE, ILLUSTRATIONS BY CHRISTOPH BLUMRICH, STANFORD KAY--NEWSWEEK

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