Promising Directions in SCI/D Research
by Bob Yant
Nerve cells operate by communicating via long extensions called axons, which carry nerve impulses in the same way that a telephone wire carries signals. The nerve cell body converts signals from other sources and the axon carries the signal to other nerve cells. A simple comparison for a nerve cell and its axon is to imagine a tennis ball with a long string attached to it. The tennis ball is the nerve cell body, which converts signals from other sources in the same way that the mouthpiece of a phone converts sound to electrical signals. The string is comparable to the axon, which carries the signal to other nerve cells.
Two of the most important aspects of spinal cord injury (SCI) repair include:
- Axon damage, which interrupts the exchange between brain and spinal cord. Damaged axons wither, die off and are carried away.
- The nerve cell bodies survive SCI and, at least in theory, can be made to regrow (regenerate) their axons. Finding a way to stimulate productive regeneration is the most sought-after achievement in spinal cord injury research.
When an able-bodied person wants to cause muscle movement, a signal from the brain travels down the spinal cord and out to peripheral nerves connected to the muscle. Sensation travels in the opposite direction in the spinal cord, with a signal for feeling originating in the skin and then traveling from peripheral nerves up through the spinal cord to the brain. Therefore, SCI repair strategies must cause the neurons in the brain that control movement to regenerate their axons back down to the lower spinal cord. Likewise, the nerve cells below the injury site that relay sensation to the brain must be made to regrow their axons up through the injury site.
Tipping the Balance Toward Growth
Over the last twenty years, the prevailing theory regarding the inability of axons to regrow after injury has been that the environment in an adult spinal cord is not conducive to growth. An emerging concept is that there is an equilibrium in the spinal cord between inhibition and growth. When we are young and our nervous system is developing, the equilibrium is tilted more toward growth. During this period, there is an abundance of nerve growth molecules in the spinal cord. As an adult, when growth is no longer needed, an active inhibition in the spinal cord helps to maintain the growth/inhibition equilibrium. Scientists can tip this equilibrium toward axon regeneration by either reducing the inhibition in the spinal cord or increasing the known growth promoters in the spinal cord.
Researchers have discovered naturally occurring nerve growth molecules (growth factors) that are specific to different nerve cell types. Motor neurons, which control movement, regrow in the presence of a growth factor named neurotrophin 3 (NT-3). Sensory neurons regenerate their axons in the presence of a molecule called “brain derived neurotrophic factor” (BDNF).
Scientists working on inhibition have made substantial progress. A number of different inhibitory molecules have been identified and methods to block or disable the inhibitors have been developed. Three different inhibitory molecules have been found in myelin, the white matter that wraps around axons (similar to the way insulation wraps around electrical wire). Recent studies have identified three different “receptors” for these inhibitory molecules. The inhibitory molecules are “keys”, the receptors are the “locks”, and a number of strategies are being developed to either soak up the inhibitory molecules with decoys to block the interaction between key and lock. Other inhibitory molecules have been found in the scar that forms at the site of injury in the spinal cord; the receptors for these have yet to be identified and represent an important target for research.
Stem Cell and Combination Treatments
There is much excitement about the potential of embryonic stem cells’ to replace nerve cells that have been damaged by injury or disease. In the case of spinal cord injuries, the most developed approach uses embryonic stem cells to replace myelin-forming cells (oligodendrocytes), which die as a result of a spinal cord injury, and thus regenerate the myelin sheath on surviving axons. This may lead to improved function after spinal cord injury, but the main problem in SCI repair remains growing axons. So far, embryonic stem cells have not been able to regenerate axons.
For successful repair of the injured spinal cord, several steps must occur. Strategies incorporating the multiple steps are called combination treatments. A spinal cord injury creates a cavity at the injury site. A successful spinal cord repair strategy would provide a supportive surface or substrate through which nerves could grow. Additionally, surviving nerve cell bodies, both above and below the injury must be stimulated to regrow their axons. Scientists are attempting to create a bridge at the injury site for regenerating axons to cross. A number of artificial substances, such as small plastic tubes, have been developed. Additionally, a variety of cells have been used as a graft into the injury site. One promising approach involves taking cells from the patients themselves, so the implanted cells would not be subject to immune rejection. Candidate cell types include “olfactory ensheathing cells” taken from the nose, and stem cells extracted from bone marrow. Experiments in animals indicate that both these cell types may have some ability to form a permissive bridge and facilitate spinal cord damage repair.
Scientists have made important progress getting axons to grow into a graft that bridges across an injury site, and recently, researchers have managed to coax axons to grow back out of the graft and continue growing on the opposite side.
Regenerating axons the entire length of the spinal cord is a daunting, but not impossible, task; however, it might not be necessary to regenerate axons the entire length of the spinal cord. Animal and human spinal cords are segmental. It might be sufficient to get growth into a top segment and then the existing spinal cord architecture would transmit a signal from segment to segment down the spinal cord. Also, even short distance growth could be of immense importance for people with injuries at the cervical level. Growth over a single segment could restore hand movement and thus the ability to eat independently, to push up, (and therefore the ability to transfer from a chair to a bed), or to use a joystick to guide a motorized wheelchair.
It is difficult for people living with SCI to discern the truth about claims of spinal cord injury research advances. Scientists have been making claims of recovery in animals and humans for more than 20 years. Most of these claims have turned out not to be true.
We live in a time of rapid scientific and technological advances. New methods and tools hold great promise in the quest to make basic science discoveries. Top-notch SCI researchers whose work has been replicated by other scientists are now talking about bringing various promising therapies to clinical trials. This represents an important and historical change in the direction of SCI research.