Many people are familiar with the story of Christopher Reeve, the actor who played Superman in the blockbuster movie of the same name. In May 1995, while riding in an equestrian competition, Reeve was thrown off his horse, severely damaging his spinal cord when he hit the ground.
In an instant, Reeve became a quadriplegic--paralyzed from the neck down. He was confined to a wheelchair and could not even breathe without a machine. Nevertheless, for nine years--until he died in October 2004--he championed the call for more research into spinal cord repair. Despite his efforts, progress was slow.
The need for advances is greater than most people realize. In the U.S., 11,000 individuals are paralyzed every year. There are now more than 200,000 Americans with spinal cord damage, a number that, ironically, has grown because of improved acute care in the hours immediately following injuries; people who once would have died from traumatic damage now survive. Some 60 percent of victims are male, 60 percent are hurt in motor vehicle accidents or athletics, and more than 40 percent are younger than 30 years. All face a lifetime with little prospect of regaining any function, and many die prematurely from complications such as organ degeneration and infection.
Finally, however, science offers glimmers of hope that nerve cells in the spinal cord and brain could someday regenerate. In several studies, rats with injured spinal cords have recovered some movement, a few even walking again. Monkeys have bounced back, too. Experts now say that even human nerves are fundamentally repairable. This news has aroused great optimism among patients and scientists, but knowledge about how regeneration happens and how those mechanisms could be turned into reliable therapies is only beginning to become clear.
Prevent the Barrier
The spinal cord, about as thick as your finger, contains millions of nerve fibers that drive a vast array of bodily functions, including muscle control and sensory processing. Injuries do not just paralyze arms and legs; victims lose control of their bladder and bowels, cease to feel skin pain and lose sexual function. For many paraplegics, being able to feel things again is almost as important as being able to walk.
It had been considered absolute truth that in the brain and spinal cord--collectively known as the central nervous system (CNS)--neurons do not regenerate. This phenomenon frustrated neuroscientists because severed nerves in other parts of the body can reestablish connections. In recent years, however, improved medical technology has shown that after a spinal cord is cut, nerve cells do begin to extend new fingers, called axons, which could carry signals across the gap. Almost immediately, however, a protein latches onto neurons trying to grow and ultimately shuts the process down. Scientists have dubbed the protein Nogo.
Nogo was found in the brain as well and more recently in some parts of the peripheral nervous system. Experts theorized that this molecular brake prevents uncontrolled nerve cell growth once the CNS is mature, as a way of stabilizing the complex network.
Researchers still had to prove Nogo's culpability. One of the leaders in this effort was Martin E. Schwab, head of neuromorphology at the Brain Research Institute at the University of Zurich. In the mid-1990s Schwab developed an antibody that would bind to Nogo so it could not latch onto the neurons and stop axon growth. Schwab partially severed the spinal cords of several rats. He then implanted a pump underneath the skin that steadily infused the antibodies into the damage site for a few weeks. Microscopic imaging showed that a thin spindle of nerve tissue was bridging the gap at the injured spot. Behavioral tests indicated that the rats moved similarly to others that did not have any spinal cord damage. They swim, balance atop poles, reach out for food and climb up ropes, Schwab says.
In 2000 independent research groups simultaneously announced that they had found the gene that prompts the production of human Nogo. By cloning this DNA, they were able to produce antibodies to it. Major pharmaceutical firms took notice; GlaxoSmithKline participated in one discovery group, and in 2001 Novartis secured the rights to Schwab's antibody formulation.
Some scientists were skeptical that the drug industry was truly interested in helping paraplegics, however. An article in Science noted that there were far too few patients--too small a market--for firms to justify the enormous expense of developing a commercial drug. The journal maintained that companies were interested in Nogo antibodies to potentially treat neurological conditions that afflict large numbers of people, such as stroke or Parkinson's disease, which involve a massive die-off of CNS neurons.
Block the Dock
Other scientists were looking for alternative solutions. Rather than trying to handcuff Nogo, neurobiologist Stephen M. Strittmatter of Yale University looked for a way to block the port, or receptor, on nerve cells where Nogo docked. In 2001 he identified the receptor and the shape of the nub on a Nogo molecule that allows it to dock there. The nub, or fragment, was a peptide molecule, which Strittmatter managed to synthesize artificially. The goal was to seal off the receptors by filling them with the synthesized peptide.
To test the approach, Strittmatter administered the peptide to spinal cord injuries in rats for four weeks, through a catheter inserted into the animals spines. A number of nerve fibers did grow back, and the rats were able to walk better than without the treatment, according to Strittmatter.
The next stage of work will be to investigate whether such compounds are safe and effective in humans. The dock stopper may possess one advantage: Strittmatter and others have recently found evidence that proteins other than Nogo dock in the Nogo receptor and thwart axon growth; crippling Nogo alone, therefore, may not leave axons free to regenerate. One suspected protein is myelin-associated glycoprotein, found in the sheath of myelin that insulates axons. Another is oligodendrocyte myelin glycoprotein. Hindering the Nogo receptor could stop all three--at least in theory.
Limiting Damage
Agents such as Nogo are not the only factors preventing a severed spinal cord from knitting back together. Regeneration is also frustrated by the body's otherwise helpful efforts to protect the wound site. Severed or crushed nerves evoke a massive inflammatory reaction. It causes fluid to fill the gap and bloat surrounding tissue, cutting off blood supply to intact neurons around the injured cells, crushing the nerve cells with pressure, and releasing various messenger molecules that prompt cell death among the neurons. The end result is that the nerve gap is enlarged. Scar tissue then begins to form to seal the wound. The scar tissue--made of dense, chainlike molecules--presents an impenetrable barrier to new axon growth.
Elizabeth Bradbury of King's College London may have found a way to clear this thicket with a molecular machete called chondroitinase ABC. This bacterial enzyme removes the sugars from proteoglycans, dissolving them. Bradbury partially severed the spinal cords of rats and then immediately treated the injured areas with chondroitinase ABC. The substance did its job. Through a microscope, she could see that nerve cells at the injury site were making new connections. Two weeks later the treated rats were walking almost as well as the uninjured control group. The untreated rats failed miserably.
To improve delivery of such agents, Dennis J. Stelzner of the State University of New York Upstate Medical University has packaged the enzyme in biodegradable nanospheres and injected them into the injury site. As he explained at the Society for Neuroscience's annual meeting in October 2004, the nanospheres degraded over time, gradually releasing their contents. This means that only a single injection might be needed to treat a wound, rather than multiple injections, each one bearing a danger of further injury and infection.
Piercing the Scar
Scar tissue problems could perhaps be overcome in another way as well. Back in 1985, Geoffrey Raisman, now at University College London, discovered a unique trait of the olfactory system (sense of smell). Unlike other nerve cells, most olfactory neurons can regenerate spontaneously when damaged--such as when we have a cold or sniff a strong solvent. Raisman found that newly sprouting nerve fibers are surrounded by olfactory ensheathing cells (OECs), specialized cells found nowhere else in the body. In time, Raisman's team managed to cultivate OECs from rats and transplant them at the injury site in rats whose spinal cords had been partially severed.
Through a microscope, Raisman could see that the OECs lined up tightly, creating a bridge between the two ends of cut spinal nerves. New axons began to grow along this scaffolding until they had traversed the gap. Insulating myelin sheath also began to form along the fresh nerves. As a result, the rodents were once again able to use their forefeet to grasp food and undertake complex motor activities such as climbing. In follow-up experiments, Raisman showed that the therapy could be successful even when applied two or three months after an injury. Several labs are now working with olfactory ensheathing cells.
Other kinds of repair could help restore certain bodily functions, such as control over the bladder and bowels. More than half of spinal cord injuries are partial; many nerve fibers remain more or less intact, but because of injury trauma and inflammation they have lost their myelin sheaths. Without the insulating layer the nerves no longer conduct electrical signals properly.
Cells called oligodendrocytes are responsible for producing myelin in the CNS. Neurobiologist Hans Keirstead of the University of California at Irvine is now trying to coax them to restore the insulation in damage sites. One controversial tool is the embryonic stem cell, which can develop into virtually any type of cell in the human body. Keirstead is using special culturing techniques to turn them into the precursors of oligodendrocytes, known as oligodendrocyte progenitor cells. In early tests, injecting these cells into the spinal cords of rats seven days after damage led to partially restored motor function eight weeks later. The rodents were not playing soccer, Keirstead noted at the October 2004 neuroscience meeting, but they were doing extremely well.
False Hopes
Another group of rats that did not receive the progenitor cells until 10 months after their injuries experienced no recovery. Keirstead theorizes that scar tissue prevented remyelinization. It is possible that a combination therapy employing olfactory ensheathing cells in addition to progenitor cells might work.
When such ideas are mentioned, however, Schwab of Zurich notes that other investigators who have tried to combine different healing schemes have had discouraging results. Even in animal tests, combination therapies proved to be extremely complex, he says.
This bare fact highlights a disturbing facet of spinal cord research: much of it is being conducted under a spotlight of publicity, which may influence scientists to prematurely try unproved therapies on humans. For the past 30 years there have been questionable experiments on paraplegics, Schwab maintains. In most cases, he adds, the scientific foundations were rudimentary. Trying a treatment too soon not only raises false hopes, it can cause phantom pain from new nerve pathways that make improper connections.
Schwab insists that investigators follow the tried-and-true routine for medical experimentation: first test in lab cell cultures, next in rodents, then in primates and only then--with knowledge of benefits and side effects--in humans. Others add the warning that success in rodents may not lead to success in people; the species differ dramatically in everything from the size of their spinal cords to the way in which they walk. Testing on primates such as apes, which are much more similar to Homo sapiens than rats are, is controversial, however. For example, cuts into primate spinal cords must be made that may leave the animals paralyzed should trial treatments fail.
Yet no leap to humans can be made without this kind of intermediate step. Schwab's latest research may serve as a model. Following his promising tests of Nogo antibodies in rats, he moved on to rhesus monkeys. Deep cuts into their backbones caused the animals to be paralyzed on one side, and they could scarcely use one hand. Within seven weeks of treatment, they had regained a significant amount of dexterity. They opened drawers, they grabbed food--almost like healthy monkeys, Schwab notes.
Because the monkeys showed no side effects, Schwab will now test Nogo antibodies on numerous paraplegic people in scattered research centers, in part so other scientists can oversee the results. Schwab does not expect miracles, and he would be overjoyed even to restore key functions such as bladder control and sexual function, for which only a small number of reconnected nerve pathways are needed.
Such simple progress is all that paralyzed people anticipate, as evidenced in letters and e-mails they send to Schwab's office. He does not see much disappointment in them when he explains the hard truth about modest, if any, possibilities for improvement in a given experiment. He says the patients are not expecting wonders, because they are aware that the situation is complex. But after so many years of silence, most of them are glad to know that today there is serious work on therapies. As for concrete results, they tend to think of the next generation.
(The Author)
ULRICH KRAFT is an editor at Gehirn & Geist.
