Five Nobel laureates working with a distinguished alliance of fellow scientists in 1993 identified ten achievable goals, one of which was "regenerate the spinal cord."  They added the proviso that reaching the goal was dependent on gathering research funds sufficient to provide the scientists, equipment and facilities necessary to pursue promising areas of research.

The time is at hand for breakthroughs in one of mankind's most heartbreaking problems, one that until now has resisted solution.

- Christopher Reeve

Reasons to believe we will find a cure for spinal cord injury

Fifteen years ago, it did not seem likely that there would be a cure for paralysis, but major recent developments have shown that there is good reason to hope. Indeed, Five Nobel laureates working with a distinguished alliance of fellow scientists identified ten achievable goals, one of which was "regenerate the spinal cord."

While a treatment may still be in the future, our understanding of how the body reacts after an injury and what we can do to help repair the damage is growing at a fantastic pace.  We now know that the natural ability of the brain and spinal cord to recover from injury, while very limited, does exist and, in some cases, can be significantly enhanced resulting in recovery of function.  Scientists have found that even rudimentary manipulations of these processes can result in improved function. There are many new technologies that will facilitate interventions in the spinal cord at the molecular and cellular levels and new, reliable and reproducible animal models now more closely approximate the human condition.

Treatments for spinal cord injury and paralysis will come through the concerted efforts of many scientists.  Scientist from different backgrounds, different fields of study, and different perspectives all working together.  The goal of the Reeve-Irvine Research Center is to become the central hub for spinal cord injury research in California and across the globe, allowing this multidisciplinary vision to give birth to treatments.

The Reeve-Irvine Research Center (RIRC) was established to study injuries to and diseases of the spinal cord, which result in paralysis or other loss of neurologic function, with the goal of finding treatments.  RIRC is devoted to studies of basic cellular and molecular mechanisms that underlie the response of the nervous system to injury.  Rich in basic science, RIRC is also connected through collaborators to clinical issues related to spinal cord injury.  All current work in the Center utilizes animal models for exploring regeneration and reinnervation of the spinal cord following injury.  The Associates of RIRC include basic scientists and physician scientists carrying out research on nervous system injury, stroke, and neurodegenerative disorders and on basic processes that underlie nervous system development, regeneration and plasticity.

Research on spinal repair and recovery from disease and injury generally falls into 3 categories: containing the damage that follows the initial injury; inducing nerve regeneration and repair; and advancing therapies that enhance remaining functioning.  Currently, research at RIRC focuses on the first two of these categories.  A research program exploring robotic technology and rehabilitation is in the works.

Containing Secondary Damage

After the initial trauma to the spinal cord, the body reacts with an immune response that leads to swelling, inflammation, and clean up of dying cells.  While this response is in some part very important, unfortunately the body can also cause itself tremendous damage.  The damage created by the body's response is called secondary damage or secondary degeneration.  The result of this is a large hole, or fluid filled cyst in the spinal cord going mm to cm above and below the initial trauma site.  To the spinal cord injured individual this can mean a tremendous difference in residual ability, for example being able to control your hands or not.  If we understand why cells continue to die after the trauma, we can look for ways to prevent cell death and keep the damaged area to a minimum, and an individual's capabilities to a maximum.  The RIRC is attacking this part of the SCI puzzle from several angles.

Dr. Oswald Steward, Director of the RIRC, uses a forward genetic approach to define the cellular processes that occur after injury that lead either to progressive degeneration on the one hand or cellular repair on the other. His work takes advantage of several differences in mice, as compared to other mammals, in their wound healing.  For example, one type of mouse has a unique wound healing response that causes a dramatic delay in the onset of secondary damage and degenerative changes in damaged neurons. This delay leads to an equally dramatic delay in the activation of macrophages and microglia, and in the development of reactive changes in astrocytes.

Mice also do not form the hole or cavity after injury in the spinal cord that is seen in all other mammals.  Instead the injury site is filled with a tissue matrix that draws the damaged ends of the spinal cord closer together.  The cavity that is formed in other mammals is a big problem for regenerating nerve cells.  Axons, the long projections from a nerve cell that make contact with and transmit messages to other nerves cells, can not grow across a fluid filled space, they need a bridge or scaffold to grow across.  Mice naturally develop a bridge. Using a genetic approach,  Dr. Steward is figuring out how mice form this tissue matrix.  One we understand how mice do this, Dr. Steward will then be able to take that information into other mammalian systems.

These studies are providing clues on how to manipulate early responses to injury and so prevent progressive necrosis (cell death) and cavitation (the creation of a cyst or hole in the spinal cord).  Looking forward, it may be possible to develop treatment strategies that mimic the effects of certain genes that delay onset of degenerative processes so as to enhance repair.

Another approach to preventing secondary degeneration comes from Dr. Aileen Anderson.  She is the newest faculty at RIRC and works on the immune system.  She has found that by blocking part of the pathway that brings certain immune system cells into the injury site, she can improve functional recovery.  Animals who have had this treatment walk better than those that did not.  We know very little about how the immune system functions in the injured spinal cord.  Dr. Anderson's work  is critical to our understanding of this, without which treatments will be inadequate.

The RIRC has yet another project underway that has tremendous potential for reducing secondary damage.  Dr. Hans Keirstead is working on a different part of the immune system.  He has found that if you block killer T-cells from coming into the injury site with an immune system modulator, there is tremendous tissue sparing after an injury.  Rather than forming a big hole, animals who receive the immune system modulator immediately after injury have almost normal amounts of tissue at the injury site.  This translates into much better recovery of function.  Animals who received treatment immediately after injury walked much better.  Dr. Keirstead thinks that for humans it might be the difference between walking with a limp or being in a wheel chair.  Dr. Keirstead has the human version of the immune system modulator and is hoping to go to human clinical trial in 2003.

Enhancing the growth and regeneration of damaged nerve cells

RIRC has may different projects dedicated to this area.  We are using mouse models to study reinnervation and regeneration, human embryonic stem cells, olfactory ensheathing glia, and demylinating techniques in combination with tissue transplants.

Using mouse models, Dr. Oswald Steward is examining reinnervation and regeneration after injury.  The mouse model is not the most common model, rats are used far more often, but has several advantages.  We know quite a bit about the mouse's genetics and can use that information to add in genes that make proteins for growth factors and other molecules that are thought to enhance axon growth.  Dr. Steward is working with this model because if there is any regeneration or reinnervation, we are more likely to see it and then can manipulate this to make it better.  His idea is that if we start in a system where the bar is set low, we may be able to find things that we wouldn't see in a more complex system.  This information can then be taken into other animal models, and hopefully eventually into humans.

Dr. Keirstead is using a different approach.  His work generally uses rats, which look a lot more like humans after SCI.  There is now evidence that the environment around the injury site plays a role in stopping axonal regeneration.  Indeed, it has been found that myelin creates a cellular environment that inhibits regeneration. However, myelin is the insulation around an axon that allows electrical messages to be sent. Without myelin, neurons cannot communicate and signals from the brain will not reach their destinations.

Dr. Hans Keirstead has developed a novel immunological technique for temporarily removing myelin from discrete areas of the spinal cord. He has used his innovative technology, on which he holds a patent, to show that it is possible to promote axon regeneration in the spinal cord of experimental animals by temporarily removing myelin.  Once the axon has grown through the injury to its pre-trauma site, the myelin can be regenerated allowing restoration of function.  However, you still have the problem of the fluid filled hole that the axons must cross.  To deal with this, Dr. Keirstead transplants Schwann cells, myelin makers of the periphery, into the cavity to act as a bridge.  of the transplant studies underway, this is the most likely to go to clinical trial first.

A second tissue transplant approach by Dr.Keirstead is with human embryonic stem cells.  Dr. Keirstead recently renewed an agreement with Geron and will continue working with human stem cells.  He has been able to culture the cells and keep them happily multiplying, push them to become nervous system tissue, particularly CNS myelin makers, and is now transplanting these cells into rodents with spinal cord injuries.  The preliminary results are very encouraging, however much additional research is needed before this treatment will be available for humans.  The good news is that what he's seen so far is very promising and stem cells may indeed be an important part of a treatment for spinal cord injury.

A third tissue transplant approach by Dr. Keirstead uses olfactory ensheathing glia, or OEGs.  OEG's normally support the regeneration of olfactory neurons (smell neuron), which are the only central nervous system neurons in adult humans to regularly regenerate.  Dr. Keirstead has transplanted rat OEG's into rats and is now using human OEG's transplanted into rats as the next step toward treatments for humans.  The National Institutes of Health had been waiting for over 5 years to give a store of pure human OEG's to a scientist with a far reaching and forward thinking research program.  Dr. Keirstead, it turns out, is the scientist they were waiting for.  He has successfully grown the human OEG's in culture, no mean feat in itself, and is now transplanting these cells into rats with spinal cord injury.  Preliminary results indicate that animals with these transplants recover function much better and there is a suggestion that OEGs may play a role in bring bladder function back faster.

Rehabilitation

The RIRC will be entering into this area in the coming years.  Center Associate Dr. David Reinkensmeyer is heading the creation of a robotics rehabilitation facility here at UCI.  He is specifically interested in the area of biomechatronics, or the use of intelligent electromechanical systems to diagnose, treat and support affected functions of the human body.

Researchers at UCLA have found that the spinal cord below an injury can remember how to walk or stand, but it must be retrained to do so.  Animals with spinal cord injuries can learn to walk on a treadmill, and humans can also.  While injured individuals can not walk on their own, with body support and therapists or, even better, robots moving their legs, they can begin to retrain their muscles and nerves to produce walking movements.  This may be very important for keeping an injured individuals body ready for when treatments become available and further data suggests can help improve what function is left after injury.  Christopher Reeve's improvements may well be because of the physical therapy, including treadmill walking.

The field is currently on the threshold of major discoveries that will lead to new treatments for neurological dysfunction brought about by injury, stroke, degenerative diseases, and developmental and genetic disorders. Scientific discoveries that lead to new treatments will lead to fundamental improvements in quality of life for disabled individuals. 

The Reeve-Irvine Center is housed in the William J. Gillespie Neuroscience Research Facility in the UC Irvine Biomedical Research Center. The 78,300-square-foot, four-story facility is home to a core group of prominent scientists who integrate basic and clinical neuroscience to find causes of and cures for devastating neurological diseases, including schizophrenia, epilepsy, and Alzheimer's. In addition to the Reeve-Irvine Research Center, the Gillespie Neuroscience Research Facility also houses the Center for Brain Aging and Dementia, and the research laboratories of faculty in the departments of Neurology, Psychiatry, and Pharmacology.

The architecture of the building is specifically designed to maximize interactions.  Each floor is made up of two major suites of laboratories that are interconnected; there are no walls separating the various laboratory groups.  Shared equipment is located in a central area that includes large open hallways that interconnect the two suites.  The offices are arrayed around a central atrium open to all floors, and each floor contains "social areas" where personnel from the different laboratories gather. 

The group of researchers housed in the Gillespie Neuroscience Research Facility represents a part of the broader neuroscience community at UCI. Faculty with research programs related to nervous system development are located in the department of Developmental and Cell Biology and the department of Neurobiology and Behavior, both of which are located on Arts and Sciences campus. Faculty in these departments are Associates of the Reeve-Irvine Research Center. Interactions among the personnel of the participating labs occur on a daily basis, due to the existence of numerous collaborative projects, cooperatively taught courses, and topical seminars.