A hot summer afternoon in July 1994. Andy heads down the woodlands on his mountain bike, eager to get home and beat the heat with a few beers. A rainy day in March 1998, Stephanie stretches her legs in her Ford Explorer waiting to reach home after shopping for school clothes for her children. A bright morning in June 1999. Terry sets off to explore the skies in his paraglider. A sunny day in March 2003. Paul revs up his bike’s engine hoping to join his fiancée and kids for the weekend. Disparate images from the lives of different people. What unites them today, however, is the image of a determined individual pushing the wheelchair.
For all of these people and the scores of others whose life took a turn after their spinal injury, every single step towards a “walk again” drug is a glimmer in the darkness that they are unrelentingly fighting, day in and day out. Research in the field of spinal cord injury is a hotbed of discovery with new and promising results sprouting at an exciting frequency. However, no one method described to date holds the promise of the magic bullet. That said, a combination of different approaches that were demonstrably effective in helping injured rats, dogs and monkeys regain movement, is likely to constitute the multipronged approach to return the gift of the gait. What is the state of the art in the realm of therapy? How close are we to an efficacious combinatorial strategy to combat spinal cord damage?
36,000 is the number of people who live with an injured spinal cord in Canada.1050 is the number of new cases every year. 55 percent of these injuries result from motor vehicle accidents while 18 percent is attributed to falls. Loss of sensation and motor functions transforms a healthy, spry individual into a hapless wreck. A disruption of the neuronal circuit that relays sensory input from the body to the brain makes the patient lose control of movement, breathing, bladder, bowels and sexual function. So what befalls those nerves that should be firing cues and transmitting signals? A quick look at what happens at the cellular level in paralyzed patients unveils why the task of combating spinal cord damage is so herculean.
When the spinal cord is damaged by injury, the bundle of nerves that constitute it gets severed. Damaged spinal nerves are prevented from sprouting new, refreshed connections by a battery of inhibitory proteins and other chemical signals. Ironically, these molecules are released upon injury and the ruptured nerves remain trapped in this cul de sac. One such protein which has been the topic of fierce scientific debate over the last decade is dubbed Nogo, understandably, for its role in preventing nerve regeneration. Sitting on the membrane of the damaged neurons, the notorious Nogo signals to the nerve cell and stymies the neuron’s efforts at regeneration, quite like a sentinel jealously guarding the gateway to regrowth. These neurons rarely ever make it. The discovery of Nogo and its receptor by three independent research groups on either side of the Atlantic came as a watershed in the field of spinal injury research. Efforts to suppress Nogo and its receptor hold great promise for therapy.
Nipping the no-go
Scientists at the University of Zurich in Switzerland, headed by Martin Schwab are already testing antibodies to Nogo in humans. When injected into the spinal cord of injured rats, these antibodies have been shown to induce the sprouting of axons, the spidery branches of nerve cells that burgeon and make contact. Using an ingenious technique in which a minipump that delivers the antibody directly to the lesion site is implanted under the skin of the injured rats, the Swiss team showed that the antibodies indeed have a therapeutic effect. “It is interesting that these antibodies also have a treatment effect on the rats besides the improved axon regeneration. The antibodies must have an effect on the neuronal metabolism and the existing plasticity of the neurons”, says Phillip Popovich, neurobiologist at Ohio State University. The treated rats were able to swim, traverse a narrow beam and cross the rungs of a ladder without slipping. But will the human volunteers who received the antibodies in the recently conducted clinical trials show such dramatic improvements? Or are we so complex a species that leaps and bounds for rats equal mere twitches for humans? Scientists and doctors alike are agog with curiosity while the initial results of the trials are pending.
Although blocking the inhibitor Nogo might open the floodgates to burgeoning nerve cells, targeting the receptor of the inhibitor is likely to expatiate the therapy, argues Steven Strittmater, who co-discovered Nogo at Yale University. The Nogo-receptor mediates the inhibition of nerve regrowth not only by transmitting the Nogo signal but also by responding to other inhibitory molecules that seep out of the injured nerves. In this way, it acts as a common conduit for several treacherous regeneration-blockers. Nipping it might just tuck the block away! This is precisely what his team is trying to do at Yale. But will this yield the “broader effects” he claims to see? Or is the conundrum much more convoluted? Sadly, the answer to the latter is in the affirmative.
“Blocking the inhibitors might not be sufficient to envisage a complete recovery in humans”, warns Lisa Schnell, senior scientist in the laboratory of Martin Schwab in Zurich. What is required, in addition, is a boost- a buttress for the body’s own repair mechanism. This underpinning comes from a not-so-unlikely quarter- the body’s immune system. Macrophages are little white blood cells that act like armed soldiers who defend the body against invading pathogens, carry out tissue repair and secrete growth factors that promote healing. They are almost ubiquitous in the body. In the brain and the spinal cord however, they are prevented from executing their repair function. This curious phenomenon is called ‘immune privilege’ and it is to this ‘privilege’, among other factors, that the inability to regenerate damaged nerves is imputed. Researchers at US based Proneuron Biotechnologies in collaboration with scientists in Israel found a way around. They came up with ProCord®, specially treated macrophages that promote the natural activity of the immune system and foster regeneration of severed nerves. These macrophages are incubated with skin and cultured in dishes – a process which helps them adopt properties propitious to nerve regeneration. Clinical trials are underway and many fingers are crossed.
Countervailing the inhibitory environment inimical to nerve regrowth calls for stimulants. Growth factors that promote nerve regeneration are key in building the bridge between the lesion and the rest of the spinal cord. Olfactory tissue taken from the nasal passages harbours a plethora of cell-types that might just be the answer. Renewable neurons, progenitor stem cells and olfactory ensheathing cells, all of which are housed at the back of the nose, are capable of providing the growth cues and support needed for the damaged axons to stay functional and keep ramifying. Although initial clinical trials in Portugal and Australia yielded only modest improvements in sensation, researchers headed by Geoffrey Raisman at University College in London are now trying to transplant olfactory ensheathing cells onto the damaged spinal cord of patients. They claim that they have been able to successfully obtain enough of these cells from adult humans and have found the safest and least traumatic route to transplanting these cells onto the spinal cord of a subset of spinal injury patients. The concern in this method, as in many others which try to stimulate nerve regrowth, is of uncontrolled rewiring. A neuronal network gone haywire might have consequences more catastrophic than the injury itself. This manifests in a condition called hyperalgesia wherein a simple touch is sensed as pain by the patient. Fortunately, reviving the growth of damaged neurons is not the only way to go. Scientists have also shown that rupture and permanent damage of nerve cells can be prevented with timely intervention- within 72 hours of serious spinal injury.
Wired to Walk
In 2004, researchers at Purdue University headed by Biophysicist Richard Borgens reported that injecting a chemical substance called polyethylene glycol (PEG) into the spinal cord of dogs, within 3 days of spinal injury prevented permanent nerve damage. The hypothesis is that PEG prevents the inhibitory molecules from leaving the ruptured nerves and therefore from entering the jousting field. The nerve cells thus get the happy chance of repairing themselves and continue to transmit nerve impulses. Nearly 75 percent of the treated dogs showed complete recovery and more than half of them were walking again. However, the human scenario is likely to be more complicated as motor activities in humans, unlike the situation in dogs, are not purely under the control of the spinal cord. The Purdue team has also attempted to induce nerve regeneration using small gadgets called oscillating field stimulators, tiny devices implanted in the injury site. The gizmos produce weak electrical fields across the injury site and impel nerve regrowth. The treatment produced astonishing results in a statistically significant number of volunteers. Unfortunately, the approach does not work with long-suffering patients and cannot be considered a comprehensive cure. “There is only one compelling vision for the future – and that is a program of different types of therapy beginning within hours of the injury and extending to long term, neurologically stable, chronic patients”, agrees Richard Borgens.
As we rush from one ordeal to the next, being alive is the last thing on our minds. Rarely do we take a moment to celebrate the gift of life. Why? Perhaps because we’re too busy living it. But the thousands of individuals who are living their watered-down version of life, a mere vegetable existence, think about it everyday. Even as they push their wheelchairs forward, they hope to live again- in the truest sense of the word. While a solution may not be at hand it is certainly not a far cry.
1. Website of ‘The Canadian Paraplegic Association’.
2. Hollicky, R. SCI Recovery: The Global Search. New Mobility Online Magazine.
3. Home Page of the Spinal Repair Unit, The Institute of Neurology, University College London.
4. Nair, P. “Walk again drugs to be tested on people” New Scientist.11 Feb. 2006 p11.
5. Liebscher et al., “Nogo-A Antibody Improves Regeneration and Locomotion of Spinal Cord-Injured Rats”. Annals of Neurology. November 2005. p706-719.