Unbroken Dreams

Bruce Brady doesn’t remember slamming headfirst into the cedar rail fence. All he knows is that one minute he was skiing along the bottom of the hill toward the chalet to meet up with his son, and the next minute he was lying on the ground, bleeding from a large gash in his forehead and utterly immobile. “I couldn’t feel my feet or hands,” recalls the 48-year-old Toronto father of three. “I could only move my eyes and talk.”

Brady might have spent the rest of his life as a motor quadriplegic – paralyzed from the neck down, with minimal sensation in his legs – if not for the surgery that he underwent at Toronto Western Hospital three days after his injury. The operation relieved pressure on his spinal cord and fused five upper vertebrae together with a steel bar. Within two weeks Brady was able to stand and take a few steps; after three weeks he was walking quite well. Today, a year later, he says with some amazement, “I’m fully mobile.” Although Brady still suffers from a stiff neck and pain in his upper arms, in February he returned to his physically demanding job as an industrial sheet metal worker.

Paralyzed patients walking away from their injuries? It sounds like the stuff of science fiction. But U of T researchers say new surgical techniques, drugs, gene therapies and rehabilitation devices are helping to make significant improvements in the lives of people with spinal cord injuries. “There is real hope, and there has been real progress,” says neurosurgeon Michael Fehlings, a U of T professor in the department of surgery and the one who operated on Brady. Fehlings is also the director of the spinal program at Toronto Western’s Krembil Neuroscience Centre, the largest neuroscience centre in Canada and a world leader in spinal cord research. As he leads the way through his lab, where graduate and undergraduate students are busily examining tissue sections of a spinal cord under a microscope, characterizing types of neural stem cells, and performing delicate spinal surgery on a rodent behind closed curtains, he says, “There’s work going on all over the world, but much of the seminal work has occurred in Canada, and U of T is right in the thick of things.”

Bruce Brady’s case is an example of only one exciting strategy being used to repair the spinal cord. Brady is one of 250 people enrolled in a clinical study called STASCIS, which stands for Surgical Treatment for Acute Spinal Cord Injury Study. Fehlings, who is spearheading the multicentre study, says that in the past, patients like Brady wouldn’t have received surgery at all – let alone surgery so soon after their injury – because their necks weren’t broken but “merely” compressed. In one-third of spinal cord injuries, especially in aging but active baby boomers such as Brady, the spinal cord undergoes a combination of contusion and compression. The cord (actually a long thin bundle of nerves enclosed by the vertebrae) is jolted against bone spurs, which develop as we age, and then jammed into the tight spinal canal.

While compression sounds less serious than a fracture, the results can be just as devastating because after the trauma the nerve cells inside the spinal cord start to die, causing loss of movement, sensation, bladder and bowel control, and sexual function. “Without decompression surgery, it’s doubtful that Bruce would have improved from a complete motor quadriplegic after injury to virtually normal,” says Fehlings. The STASCIS data are just starting to emerge, but Fehlings hopes they will help determine the optimal time for surgery; so far it’s looking as though the earlier, the better. The next step: establishing guidelines about how and when to use the surgery, and spreading knowledge of the technique to certain designated hospitals across Canada. As Fehlings puts it, we’re entering a golden era of spinal cord research, reflected at U of T in a special collaboration among the fields of biology, chemistry and engineering. And Canadian research is attracting worldwide attention.

“Twenty years ago, a cure for spinal cord injury seemed impossible,” says Rick Hansen, who at that time had just finished famously wheeling through 34 countries on his Man in Motion World Tour to raise awareness and funds. “Today, it has been proven that the spinal cord can regrow, and we’re seeing an increasing number of people walking away with partial or full recovery.” He adds, “I feel proud to see Canadians leading the way in the global search for a cure.”

The whole field of spinal cord repair has changed dramatically since Hansen’s world tour in 1985, and especially since “Superman” Christopher Reeve’s equestrian accident in 1995. For millennia, spinal cord injury for most people had been a death sentence; unable to control their bladder or bowels, patients died of bladder infections. When antibiotics became available in the 1940s, mortality rates dropped. But even as recently as the 1980s, 40 per cent of patients died within a year of injury to the upper spinal cord. Today’s rate: only about five per cent.

A modern turning point occurred when Fehlings – who has an MD and a PhD – was a graduate student working under Dr. Charles Tator, then chairman of Uof T’s division of neurosurgery (and currently a Uof T professor of surgery and a recipient of the Order of Canada). Together Tator and Fehlings played a major role in a discovery that shook up the global scientific community when they published their work in 1991. The hypothesis – controversial at the time but now widely accepted as fact – was that spinal cord injury is a twostep process. First there’s the initial mechanical trauma. But following that, there’s a secondary injury: the spinal cord undergoes a kind of stroke. The blood vessels, disrupted by the initial injury, interrupt blood flow to the nerve cells, which die, greatly amplifying the original damage. These secondary injuries occur anywhere from minutes to months afterward. Fehlings says, “So while we couldn’t undo the initial injury, we thought, You know what? We might be able to intervene to prevent the secondary injury from happening.” It’s now a standard of care for patients to receive medicines immediately following injury to bump up their blood pressure and improve blood flow to prevent secondary damage.

But Fehlings believes there’s much more we can do to protect those vulnerable nerve cells. In work that won the Gold Medal Award in Surgery from the Royal College of Physicians and Surgeons of Canada, his own lab determined that spinal cord injury causes a dangerous shift in the critical balance of the natural salts in the injured cells. Within hours of the injury, sodium enters the cells, followed by water, which causes swelling. This then attracts calcium into the cells, triggering damage far beyond the initial injury. Fehlings is looking for a way to prevent this from happening

One possibility may be a drug called riluzole. Originally developed as an anti-epileptic, it also seems to slow the rate of nerve cell degeneration in people with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. Could riluzole also have neuroprotective effects in people with spinal cord injury? Fehlings is attempting to find out, and later this year will launch a clinical trial with riluzole. Much of the funding for the study will come from the Christopher and Dana Reeve Foundation, which has designated nine centres of excellence in North America to take promising therapies and move them into clinical use. Of the nine centres chosen, the Krembil Neuroscience Centre is the only one in Canada.

If riluzole works, it could have important implications all over the world – including among soldiers in Iraq and Afghanistan. “With their body armour, soldiers aren’t dying of torso injuries like they did in Vietnam,” Fehlings explains. “But with these crazy bombs, the vehicle implodes and the soldier’s spine gets crushed. We received a $3-million grant from the U.S. Department of Defense to do clinical trials on spinal cord injury, and they like riluzole because it can be given as a pill by a medic in the field.” Riluzole, now off patent and very cheap, would be particularly welcome in developing countries, where spinal cord injuries are prevalent due to the lack of safe roads, safe vehicles, seatbelts and workplace regulations.

But protecting nerve cells from degeneration is only half the story. The other half involves regenerating nerves that have already been damaged. It’s been known for a long time that if you sever a nerve in your arm or leg, it will eventually regenerate on its own. That doesn’t happen in the spinal cord. Why not? In another important Canadian discovery, a group of Montreal researchers found that the culprit was myelin, the insulating layer around the nerve fibres. The myelin in the spinal cord, which transmits signals from the brain, contains inhibitors that block regeneration.

There are intensive efforts now to find the best way to stop that process and encourage regeneration. One option is Cethrin, a protein drug that can be applied directly onto the spinal cord during surgery. Developed by Montreal neuroscientist Lisa McKerracher, Cethrin recently underwent the first phase of clinical trials in eight centres, one of which is the Krembil. Of the 37 patients, all of whom had no muscle function or feeling below the site of their injury, about one-third showed some recovery, and 15 per cent showed major recovery, such as regaining hand function or leg movement.

One study participant is a 64-year-old Toronto shopkeeper who broke his neck when he fell face first against the door of his shop. Because he immediately went into cardiac arrest, surgeons couldn’t operate on him until he stabilized, five days later. Fehlings met him in the intensive care unit. “He was a quadriplegic, with no movement in his shoulders or hands and no control of his bowel or bladder,” Fehlings says. Following the surgery and treatment with Cethrin, the man recovered partial use of his hands and can now feed himself. He also regained control of his bowel and bladder, and with assistance he can stand and take a few steps. “I was shocked,” says Fehlings. “Shocked! I had never seen that in my career.” While spontaneous recovery occurs in seven per cent of cases of spinal cord injury, he says, “The chances that somebody with a complete spinal cord injury at five days would spontaneously recover like that are close to zero.” The U.S. Food and Drug Administration has given the green light to move forward with a large randomized Cethrin trial later this year.

Another exciting avenue of research involves replacing damaged nerve cells with neural stem cells. Collaborating with U of T stem cell researchers Cindi Morshead and Derek van der Kooy, Fehlings’ lab performed tests on rodents whose spines were crushed. The neural stem cells served to regenerate the original damaged cells, and some of the animals recovered the ability to walk. This strategy is close to clinical trials, and may one day also have major implications for people with multiple sclerosis and for children born without myelin.

While developing the right drug or combination of molecules is crucial, it’s equally important to have a way of getting the medicine to where it needs to go. Many of the drugs can’t be taken orally or intravenously because of severe side-effects, and if they’re injected into the spinal cord they’ll simply be washed away along the river of spinal fluid. How to get the drugs to stay put and do their job? Molly Shoichet, Canada Research Chair in Tissue Engineering and a U of T professor in the Department of Chemical Engineering and Applied Chemistry, leads a team that has developed a unique water-based gel made of naturally derived hyaluronan and methylcellulose, both carbohydrates.

Shoichet, happy to demonstrate the remarkable properties of this gel, grabs a syringe from her lab in U of T’s Terrence Donnelly Centre for Cellular and Biomolecular Research. “Just push lightly,” says Shoichet as she hands over the syringe with its very fine 30-gauge needle. “See the gel coming out? When you apply pressure it thins and flows through the needle, but when it comes out it gels immediately.” In animal testing, not only did the gel succeed in delivering the drug on top of the spinal cord in a minimally invasive procedure, but it sealed up the hole made by the needle and minimized inflammation after the injury. “It’s very cool and there’s nobody else who has done anything quite like this, so we’re very excited,” Shoichet says. The gel keeps the drug in place for a few days, but the goal now is to extend that time to 30 days of drug therapy with a single injection.

Shoichet’s team, in collaboration with Charles Tator’s lab, has also developed a tiny tube designed to bridge the gap in a severed spinal cord and encourage nerves to regenerate. Only five millimetres long and made of a degradable sugarbased polymer, the tube looks like a soft, transparent, miniature drinking straw with the consistency of Jell-O. Incorporated into the tube are stem cells and microbeads that can be filled with proteins that stimulate cell growth. When the tube is inserted into the spinal cords of animal models, it acts as a temporary scaffolding to which cells can adhere. “We get tissue regeneration,” Shoichet says, although that hasn’t yet translated to a significant improvement in the animals’ mobility. “Stem cells have a tremendous amount of potential, and we’re still learning how to harness that.” Another bioengineering strategy to promote nerve cell regeneration involves gene therapy. There’s particular interest in a gene called VEGF, or vascular endothelial growth factor. It’s an important gene that makes blood vessels. In animal studies, rodents with a spinal cord injury who received a gene therapy technique to cause cells to express VEGF showed dramatically improved recovery. More work is needed before this therapy can progress to human trials.

Much of the focus of the clinical trials is on acute injury – the one that’s just happened. So what about the person living with a chronic spinal cord injury? Not only is some of the U of T research targeting chronic patients, but there are promising therapies already under study. It’s been known for 20 years that the main control mechanism for walking is not in the brain but in the spinal cord; the brain merely finetunes it. Therefore, if a person with a spinal cord injury is suspended over a treadmill while physiotherapists manually move his legs rigorously and persistently, his central nervous system can be retrained to contract the muscles in the right order, enabling him to walk. “It really works,” says electrical engineer Milos Popovic, associate professor in U of T’s Institute of Biomaterials and Biomedical Engineering. “But the problem is it’s very time-consuming and labour-intensive. You need three physiotherapists to do this.”

Popovic, who used to design airplane systems, has devised a better way to stimulate the muscles. He invented a portable, programmable, wallet-sized device that delivers electrical stimulation through electrodes, forcing the muscles to contract. The device has been tested on more than four dozen people, some of them who had been living with spinal cord injuries for years. They underwent hour-long sessions either three times a week over 12 to 18 weeks for locomotion, or daily over eight weeks for hand grasping, then were tested on how well they could carry out the movements on their own, without the device. “We got dramatic improvements,” Popovic says. All improved their locomotion, with a resulting reduction in the need for assistive devices. One man, barely able to stand since his spinal cord injury 20 years ago, can now walk. Another went from a wheelchair to two canes. A third, who could walk only slowly, doubled his speed. Popovic, who is also the Toronto Rehabilitation Chair in Spinal Cord Injury Research, is now in the middle of larger-scale trials.

The reality is that some of these surgical, drug and rehab methods will prove to work better than others, and it takes time to figure out which ones are the best and the safest. Meanwhile, some Canadians, impatient for a cure, may be tempted to travel to China, Brazil or Portugal to undergo procedures such as cell transplants that are available there for a price. But researchers here warn that these therapies are unproven and unregulated, and there are risks of serious infection such as meningitis. Worse, the surgery could cause scar tissue that would prevent patients from taking advantage of a better procedure in future. “I can totally understand why a family would want to try this, but the concern is they may burn their bridges,” says Fehlings. “In the past, people would have nothing to lose, but it’s a different story now. The potential for evidence-based therapies that really work is looking very feasible.”

So feasible, in fact, that Fehlings believes we’ll see some important results in the next three to five years. “It’s not just that we’re doing some nice science here,” he stresses. “This is really going to have an impact on people’s health.”

Marcia Kaye (marciakaye.com) of Aurora, Ontario, is a magazine journalist and best-selling author specializing in health issues.