“Frontiers in Spinal Cord Research” 7th -8th September 2009 Queensland Brain Institute,The University of Queensland, Brisbane, Australia

Supported by SpinalCure Australia, SunCorp, Olympus, University of Queensland, ANZSCIN and CSL

QBI’s conference included some 26 speakers and over 100 guests eager to hear of developments in the research of and treatment of people with spinal cord injuries. They covered molecular studies, genetic and enzyme manipulations, stem cell transplantations and techniques for encouraging return of damaged nerve pathways, pain management and exercise rehabilitation.

The first speaker, Professor Charles Watson from the Prince of Wales Medical Research Unit and Curtin University discussed a new mammalian and avian spinal cord ontology based on gene expression and histochemistry. Professor Watson was stressing the importance of realising that as well as known levels of cervical, thoracic and lumbar areas within the spinal cord there were also six newly defined areas based on the gene expression in the spinal cord which helps to clarify the problem of regional variation in vertebral levels in different species.

Professor Yaobo Liu, from the Chinese Academy of Sciences in Beijing
presented a paper emphasising the importance of molecular mechanism underlying the path finding by descending axons in the developing spinal cord. His laboratory is elucidating the molecular mechanism underlying the axonal wiring of descending pathways in the developing spinal cord in order to facilitate and clarify the complexities of spinal cord connections in present and future research.

Dr Lisa Foa, from the University of Tasmania in Hobart presented a paper on how growth cone mobility is important in regeneration by influence through calcium dependent guidance clues. She described calcium as a key second messenger in axon path finding and “deciphering” the underlying homeostatic mechanism that controls calcium in the growth cone. It appears that calcium plays an important part in the signalling mechanisms that have direct implication for a wide variety of developmental and neurogenerative conditions.

Professor Alun Davies, from the School of Biosciences at Cardiff University in the United Kingdom reported on their discovery of the neurotrophin autochrine signalling mechanisms have been followed by identification of several examples of neurotrophins and other neurotrophic factors exerting effects on developing neurones by an autochrine mode of action.

Professor Brian Key, from the School of Biomedical Sciences at the University of Queensland spoke of this laboratory’s working hypothesis being that “the molecular and cellular cues, responsible for creation of this early network, are the basic building blocks used to construct neural connections throughout development”.

Dr Massimo Hilliard, from the Queensland Brain Institute, centred a paper on dendrite formation and axonal regeneration in the invivo Model involving C. elegans neurones. He emphasised the importance of correct growth guidance and maintenance of neurones and dendrites in order for satisfactory formation and function of a neuronal circuit to develop. He said how little we still know about the development of dendrites which are so much involved in the synapsing of one nerve ending to the beginning of another.

Professor Andrew Boyd, also from the Queensland Institute of Medical Research presented a paper on the receptor enzymes and the development of EPHA4 KO mice. The lack of expression of this enzyme-like substance on spinal neurones leads, in the experimental animal, to defects in the central pattern generator. An animal which is bred with this disturbance develops a characteristic kangaroo-like hopping gait (ie the KO mice). This experimentation confirms the significant role of enzyme systems within the spinal cord, which if modified have the potential to reduce or avoid the serious effects of spinal cord injury.

Professor Ann Turnley, from the University of Melbourne, also spoke about the regulation of cellular response in spinal cord injury by EPHA4 indicating that this modification by inhibition in the spinal cord offers considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for treatment of other CNS injuries.

Dr David Brown, from the Centre for Applied Medical Research in Sydney, presented an interesting paper on immune cell activity which has been recognised for some time through mediation of neuronal destruction in the central nervous system following injury as well as in autoimmune disease. His work has confirmed that these same inflammatory cell types can elaborate, alternatively, neurotrophic/neuroprotective factors and support neuronal survival. His work suggests that components of these inflammatory mechanisms seen in the spinal cord may be engineered to support injured neurones and prevent further neuronal loss and reduce injury related dysfunction. This approach also holds promise by improving the quality of life of spinal cord injured patients.

Dr Peter Crack, from the Department of Pharmacology, University of Melbourne spoke about the synergies within the spinal cord emphasising the potential neuroprotective pathways demonstrated in traumatic brain injury. Understanding the role of inflammation following damage to nerves needs to be further explored and evaluated so that we can understand the immunological cell’s response, whether good or bad, in the injured spinal cord.

Professor Alan Harvey, from the University of Western Australia presented a paper on the effects of viral vector mediated delivery of growth associated factors on survival and on the regeneration of the injured adult central nerve cells. His paper was based on the interesting concept that different growth associated factors acted on adult rat retinal ganglion cells after optic nerve injury through a viral vector.

Professor Masaya Nakamura, from the Department of Orthopaedic Surgery, Keio University in Tokyo, Japan discussed the substance, hepatocite growth factor, which may be one of the deficient factors resulting from damage to the central nervous system, in brain and spinal cord. His paper emphasised the importance of blood vessel development as well as axonal regrowth with functional recovery after spinal cord injury. He reported that with the injection in the common marmoset animal into the fluid space around the spinal cord of recombinant human hepatocite growth factor protein, reduced the damaged area and promoted functional recovery after spinal cord injury.

Dr Yona Goldsmit, from the Australian Regenerative Medicine Institute at Monash University in Victoria presented a paper on the role of EPHA4 in mediating astrocytic gliosis after brain and spinal cord injury. This laboratory has already shown that using mice which have been prevented from expressing EPHA4, there is decreased astrocytic gliosis (scarring) concurrent with excessive axonal regeneration and recovery of function in these animals.

Professor John Kessler, from the North Western University School of Medicine, Chicago, USA presented a further paper on regulation of gliosis after spinal cord injury. The formation of glial scar after spinal cord injury is a major impediment to potential regeneration of axones that have to try and grow through this barrier. Understanding the mechanisms underlying gliosis will therefore be essential for devising new therapeutic approaches.

He emphasised that, since all the elements of both signalling systems are present in progenitor cells (early cells) in the spinal cord and brain, interactions between these two important systems will regulate the generation of astrocytes during the development as well as after injury.

Professor Alan Mackay-Sim, from the National Centre for Adult Stem Cell Research, Griffith University, Brisbane summarised the strategies for spinal cord repair. He has been part of the research team that recently reported on the six patients who were treated with their own olfactory and sheathing cells (three were controls). His paper emphasised the potential of spinal cord nerves to be “plastic” and ready to try and attempt to regrow and rejoin for function after injury. Professor Mackay-Sim emphasised the importance that research should not be undertaken without assessing the degree of acceptable risk in the experimentation and that there should be no increase in damage to the spinal cord on to the patient’s spared function.

His paper also emphasised that recent animal studies show that it is possible to greatly reduce secondary degeneration (late) by applying growth factors to the injury site in the week following injury. Further delayed transplantation of olfactory and sheathing cells also appears therapeutic. One can envisage, therefore, future human treatments will include a mixture of early and late therapies.

Dr Marc J Ruitenberg, presented a paper from the University of Queensland, School of Biomedical Sciences in Brisbane, on the “Revisiting the parameters for regeneration”. This paper emphasised that despite significant global research, reconstruction of the central pathways in the nervous system has proved difficult due to the limited intrinsic regeneration potential of the central nervous system neurones, scar formation and the development of cyst-like cavitations. Dr Ruitenberg emphasised the importance of the recent research here in Australia where there was successful regeneration in primary olfactory pathways and then comparing these encouraging results with those previously reported on experimentation using the optic nerve which is also an essential part of the central nervous system.

Dr Paul Wrigley, from the Pain Management Research Institute at Royal North Shore Hospital, University of Sydney, confirmed that people with spinal cord injury consistently rate pain as one of the most difficult problems to manage despite the fact that there is a significant loss of normal pain sensation below the level of the spinal lesion. He described neuropathic pain as occurring in almost 50 percent of people with spinal cord injury and yet remains very difficult to treat. There is the danger that stem cell grafting could result in complications which would include neuropathic pain.

Professor Janet Keast, from the same institution, spoke on the “plasticity” of spinal nociceptive circuits after spinal cord injury. Professor Kaest has used the experimental animal in studying various types of neuropathic pain triggered by different types of spinal injury.

Professor David Adams, from the Health Innovations Research Institute in Victoria, presented a fascinating paper on the venom of the marine Conus snails. The peptides from this venom are being currently developed as a treatment for neuropathic pain.

Professor John Steeves, from the ICORD Organisation (International Collaboration on Repair Discoveries) in Vancouver, summarised a number of recent scientific discoveries and technological developments which promised superior treatment strategies to enhance functional recovery and improve the quality of life after spinal cord injury. He presented the framework within which optimal translation process and challenges to conducting spinal cord injury clinical trials must be in place and observed in order for an appropriate assessment of these trials to be made and not lead to misleading conclusions and optimism. His paper summarised at least twelve different clinical research projects using various substances including methylprednisolone, embryonic stem cells and stem cell implants using bone marrow as well as the use of Schwann cells which are found in peripheral nerves. As yet none of these experimental therapies have yet been proven using accepted scientific method in humans.

Professor Hideyuki Okano, from the Department of Physiology, Keio University in Japan, presented a paper which summarised the regeneration of the damaged central nervous system using embryonic cells and induced pluripotent stem cells in experimental animals such as the rat and the marmoset. His work has given some important clues to help in understanding the establishment of regenerative processes for damaged central nervous system neurones but requires further research in the near future.

Associate Professor James Middleton, Director of the NSW Statewide Spinal Cord Injury Service, summarised the strategic perspective which has been developed by this service in providing appropriate treatment and rehabilitation for patients suffering from spinal cord injury in New South Wales. His paper confirmed the recent estimate of a total annual cost of spinal cord injury in Australia to be around $2 billion with a life time cost per incident case estimated to be $5 million for paraplegia and $9.5 million for tetraplegia.

Professor Middleton identifies over 190 registered trials in recent clinical research in spinal cord injury predominantly only in phase one or phase two confirming the considerable challenge which still remains in achieving confirmed promising treatments aimed at producing a cure.

Dr Tim Geraghty, from the Spinal Injuries Unit, Princess Alexandra Hospital in Queensland, presented a paper on the use of “autologous olfactory and ensheathing cell transplantation in human paraplegia - a three year clinical trial”. Following the encouraging results in animal models, olfactory ensheathing cells were used in this trial involving six patients with complete traumatic thoracic paraplegia (six months to three years post injury). Three participants in the group were “controls” who did not receive surgery and the three were treated with the olfactory ensheathing cell implants. After the three years of follow up, MRI studies showed no change from the pre-operative scans with no evidence of tumour formation or post traumatic syrinx findings. There was no onset of significant neuropathic pain in these patients but no functional changes were observed. One transplant recipient was reported as having an improvement over three spinal segments for light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. This research, which involved only a small number of patients, has been encouraging in that no serious side effects were identified with the use of these cells. Further research is necessary for final conclusions to be drawn.

Professor Sarah Dunlop, from The University of Western Australia, spoke of the influence of physical activity on nerve cells emphasising the importance of exercise which will stimulate nerves, either partially or seriously damaged, attempt to possibly re-synapse and re-function after injury. Professor Dunlop emphasised the importance of continuing a disciplined physical therapy program using various inputs to encourage nerve re-function, for example total body movement, vision and emphasis on sensory input as well as motor output.

Associate Professor Glen Davis, from the Clinical Exercise and Rehabilitation Unit, Faculty of Health Sciences, The University of Sydney, presented a paper which summarised the available literature on the effects of functional electrical stimulation/evoked exercise since the earliest date until 2009. His paper dealt with the effects on paralysed muscle using the FES to induce exercise. In the lower limbs, muscle mass increases with this technique, venous return increases, circulation to the skin and muscle increases and the bodily metabolic processes increase. With regard to aerobic fitness and metabolism in patients with spinal cord injury, there has been no convincing evidence in Professor Davis’ work of arm cranking as causing or reducing functional improvement nor any definite evidence that aerobic exercise routines increase patient’s “fitness”. There is increased exercise efficiency which after leg exercising in those patients with significant spinal cord injury and FES cycling improves aerobic fitness.

Professor Mary Galea, from the Rehabilitation Sciences Research Centre, The University of Melbourne, emphasised that in patients with clinically complete injuries, physical therapy has been primarily directed to activities to improve independence, for example, teaching new strategies to move in bed and to transfer in and out of wheelchair and provision of assisting devices rather than exercising the paralysed limbs. Professor Galea challenged this paradigm of rehabilitation stating that inactivity following spinal cord injury may further exacerbate the neurologic impairment caused by paralysis due to a decline of neural circuits with non use. Lack of physical activity has been shown to increase the complication of osteoporosis and obviously diminish muscle mass and even diminish diameters in the femoral artery as an essential supplier of blood to the lower limbs. Muscle receptors diminish bodily active and passive movements. FES should continue to be used as an important adjunct to enhancing the recovery of neuronal function and maintaining neuromuscular facilitation.

She described the challenge of continuing physical therapy in the community following discharge from hospital. There is now a plan in Victoria to educate community exercise instructors to visit patients in their own home in order to ensure the continuation of an efficient exercise routine.

In summary, this conference has brought together a remarkable group of scientists and clinicians to summarise the present situation with regard to enhancing recovery in the injured central nervous system, particularly the spinal cord.

Prof John Yeo, November 2009