Summary of Basic Science Research
As you can see by the facts detailed above, the problem of CNS response to injury is incredibly complex. No one theory or approach will overcome all of the effects of SCI, and many scientists now believe that the “cure” will not be found in a single approach, but rather in a combination of techniques. Consequently, it is important for all possible research areas to be addressed so our overall knowledge about how the system works may eventually lead to a cure for SCI.
What about the “imminent breakthroughs” you hear about regularly in the press? It must be remembered that there is a vast difference between a “scientific breakthrough” and a “clinical breakthrough”. While scientific discoveries occur quite frequently, clinical (treatment) ones do not. Public announcements of scientific progress help to keep the attention and funding focused on finding solutions to the problems caused by SCI but new scientific breakthroughs generally do not lead to immediate treatment applications.
The Search For the Cure
The 1980’s and 1990’s have been an exciting time for people interested in spinal cord injury repair and Regeneration. Both in terms of treat-ment techniques and general knowledge about nervous system function, the progress that has occurred in recent years is encouraging.
The search for a cure involves one of the most complex parts of the human body. The spinal cord is an integral part of the body’s most specialized system, the Central Nervous System (CNS). The CNS consists primarily of the brain and spinal cord.
A major role of the spinal cord is to carry mes-sages to and from all parts of the body and the brain. Some of these messages control sensation, such as knowing your finger is touching a hot stove, while others regulate movement. The spinal cord also carries mes-sages that regulate autonomic functions such as heart rate and breathing – over which we generally do not exert voluntary control.
The spinal cord carries these messages through a network of nerves which link the cells of the spinal cord to target cells in all other systems of the body. An individual nerve cell is called a Neuron, each with receptive branching fibers called dendrites. The Axon, carrying an output signal, extends from the cell body, and is covered by a protective fatty substance called a Myelin sheath which helps the impulse travel efficiently.
A Nerve Impulse from one neuron is picked up by the Dendrite of the next nerve cell in the pathway at a specialized connection called a Synapse. An electrochemical reaction causes the impulse to “jump” across the synapse and the signal stimulates the second nerve cell and the impulse then travels down its axon. The message is picked up and transmitted by a series of neurons until the connection is complete.
There are millions of nerve cells within the spinal cord itself. Some of these Lower Motor Neurons receive Motor commands from the brain and send their signals directly to the muscles. Other spinal cord neurons form relay pathways for information travelling up or down the length of the spinal cord. Still other spinal cord neurons remain intact and form intricate circuits below the level of injury. Because cells below the injury are no longer under voluntary control, they cannot be utilized as effectively and may cause unintentional movements such as spasms.
Most of the cells in the human body have the ability to repair themselves after an injury. If you cut your finger, often you have a visible laceration for a few days or weeks, followed by the formation of a scar. In time, you may not be able to tell that the cut had occurred. This indicates that skin cells regenerate, just like cells in the blood vessels, organs and many other tissues. Peripheral nerves (nerve fibers outside the brain and spinal cord), such as those located in your fingertips, also regenerate, although this process is different from that in the skin and other organs.
For years, scientists have focused on the big mystery: “Why doesn’t the central nervous system regenerate?” This question is even more perplexing because we know that central nerves in lower animal species CAN regenerate. There are no definite answers to this mystery yet, but scientists are exploring the questions in many ways.
Basic Cell Research
An important avenue of research is to look at normal cell function in the CNS of mammals. Scientists investigating this area of research are attempting to identify and describe cellular interactions in properly working systems. In addition, they are working with SCI models in an attempt to identify and explain what occurs after an injury.
Through cell research, scientists are trying to identify the following:
1. What substances are present in the CNS which “switch off” CNS nerve growth in mammals?
* It has been shown that regeneration occurs in lower animals, as well as in mammalian fetuses in the very early stages of development. At some point in development, the cells appear to lose the ability to regenerate. This loss may be related to the maturation of the nerve cells or to changes in other nervous system cells past which axons must regenerate.
2. What growth inhibiting factors, present in the CNS of mammals, prevent nerve cells from regenerating and reestablishing connections (synapses)?
* Scientists have identified some proteins in the myelin sheath surrounding spinal cord axons which inhibit nerve cell growth. Additionally, other regeneration-inhibiting proteins have been identified on the surfaces of cells that form the nervous system equivalent of a “scar”. Some scientists believe that nerve cells can be encouraged to regrow and re-establish Functional synapses by removing or altering this cellular “scar”. Antibodies generated against some of these proteins can neutralize the inhibitors and allow growth to occur. The ability of central nerves to regenerate in lower animals is thought to be due to the lack of inhibitors in their CNS.
3. Can growth stimulating substances can be introduced into the mammalian CNS to encourage nerve growth and synapse development?
* Investigators are attempting to alter the Environment around the injury site to encourage nerve cell growth and repair. As described above, our peripheral nerves can regenerate. This is due to the presence of cell proteins that stimulate rather than inhibit nerve growth. When these cells or the factors they produce such as “growth factors that nourish nerve cells are introduced into the CNS, central nerve regrowth can occur. Finding ways to effectively introduce these cells or substances to achieve functional recovery is a major goal of “cure” research today.
Development of New Therapeutic Approaches
Ongoing research using animal models to test possible new therapies is progressing more rapidly than ever before. This type of research takes several forms that can best be explained as they apply to solving certain types of damage that result from SCI. There are three major classes of damage to neural tissues that have been identified, each requiring a different therapeutic approach:
1. Death of nerve cells within the spinal cord. Because nerve cells lose the ability to undergo cell division as they mature into the highly specialized forms that make up our nervous systems, the death of nerve cells due to injury presents a difficult problem. No functional connections can be established if the nerves no longer exist. Therefore, replacement of nerve cells may be required.
2. Disruption of nerve pathways. When the long axons carrying signals up and down the spinal cord are cut or damaged to the point where they break down after an injury, the parents nerve cells and axons often survive up to the point where the injury occurred. In this case, regeneration of damaged axons is a real possibility to re-establish connections of nerve circuits.
3. Demyelination, or the loss of the insulation around axons. Animal studies and recent studies of human specimens have established that in some types of SCI, the nerve cells and axons may not be lost or interrupted, but that the loss of function may be due to a loss of myelin sheaths. As described above, myelin sheaths provide insulation so that electrochemical signals are carried efficiently down the long, thin axons. This type of damage may be the most amenable to treatment because rewiring of complex circuits may not be needed and remyelination of axons is known to be possible.
Although specific human injuries may involve any or all types of damage just described, therapies developed to combat any one of them might restore important functions. The “cure” for spinal cord injury may take the form of multiple strategies, each in turn restoring functions that make important improvements in the quality of life for a spinal cord injured individual.
The approach to “cure” research then, is to concentrate on techniques that hold the promise of repairing specific types of spinal cord damage. With the explosion of efforts and progress in the fields of Neuroscience and Molecular Biology (sometimes called genetic engineering), the scope of possible new therapies is wider than ever before.
Replacement of Nerve Cells
Mature nerve cells cannot divide to heal a wound as skin cells can. Replacement of nerve cells requires transplantation of new nerve cells into the site of the injury with the hope that they will mature and integrate themselves into the host nervous system. One approach is to transplant healthy CNS cells from the same animal species. Researchers have been unanimous in their agreement that transplantation of adult nerve tissues does not work, while embryonic or fetal transplantation can be quite successful. The embryonic tissues do grow and develop, and scientists hope that they will form circuits that will return important functions to areas below the injury. Research to date has not supported the hope that host axons would use these grafts as “bridges” across the injury site. An important consideration is that if fetal tissue transplants prove successful in animal models, transferring this approach to human beings will involve important ethical considerations regarding donor tissues and other important questions about immune rejection of cells transplanted from one individual to another.
Another approach that may avoid some of those problems is the use of genetic engineering to manufacture “cell lines” that would work as nerve cells after grafting. This approach involves inserting segments of DNA (genes) into fetal nerve cells that allow the cells to divide indefinitely, creating an ongoing supply of donor tissue. The use of purely neuronal cell lines diminishes the chances of immunological rejection of the grafts. Recently, rodent cell lines have been developed that stop dividing after transplantation (so there is no risk of tumor formation), and that mature into very specialized nerve cells. Research has not yet shown that these cells can restore function after spinal cord injury.
Very recently, scientists have learned that some cells of the adult CNS can be stimulated to divide and develop into new nerve cells. This exciting finding has opened up new possibilities for cell line development without a need for fetal tissue donors.
Regeneration of Damaged Axons
Nerve cells in both the central and peripheral nervous systems are associated with helper cells called neuroglial cells. After injury, the CNS helper cells largely inhibit regeneration, while those of the peripheral nerves, the Schwann Cells, stimulate regeneration, even in humans. Scientists are attempting to isolate these cells from peripheral nerves and transplant them into the spinal cord to induce regeneration by providing an altered, supportive environment. In this strategy, a SCI individual could act as their own donor, since Schwann cells can be obtained from biopsies of peripheral nerves in adults.
Schwann cells, nerve cells and some other cells make proteins known to nourish nerve cells called “growth factors”. By introducing these factors into injury sites alone or in combination with grafts, researchers hope to stimulate additional nerve regeneration and promote the health of nerve cells. This approach has been shown to stimulate CNS regeneration, including growth of axons from nerve cells within the spinal cord and those from the brain that send their long axons down the spinal cord. Significant restoration of function has not yet been achieved.
Another technique is to genetically alter cells so that they produce large amounts of growth factors and to introduce these into the injury site. While nerve fibers have been stimulated to grow by such grafts, this type of research is in its very early stages. Cells making many types of factors will have to be tested and functional recovery carefully demonstrated.