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Introduction: Repairing the damaged nervous system
seminars in THE NEUROSCIENCES,Vol 5, 1993 : pp 383-384
Introduction: Repairing the damaged nervous system James Fawcett potentially regenerate. Axons in the peripheral nervous system regenerate when cut and reform functional connections with appropriate targetsmotor axons reconnect to muscle, sensory axons to sensory structures. CNS axons do not regenerate when cut, but essentially all have the ability to regenerate if they are given a Schwann cell environment in which to do so. M u c h effort is currently going into finding the factors which render the CNS glial environment inhibitory to axon regeneration, and it seems probable that before long it will be possible to counteract this inhibition and promote regeneration of large numbers of CNS axons at least for small distances. This, coupled with Schwann cell grafts which can promote long distance regeneration, should form the basis of the first treatments for conditions such as spinal cord injury, where the neurological deficit is primarily due to cut axons. The question which will then arise is whether the regenerating axons show any specificity in their connections. Completely random connections made by regenerating axons could be worse than no connections at all. It is likely that the behaviour of axons regenerating in the PNS and axons growing from brain grafts inserted in the adult brain is a guide to what one could expect of regenerating axons. Based on this information, one would expect regenerating axons to show great specificity in forming connections only with the correct type of neurone, but rather less specificity in determining which member of the right class of neurone. Thus, regenerating cortico-spinal axons will probably connect to motoneurones, but not be good at selecting motoneurones at the correct spinal level. Some of the techniques which are being worked out to counter the problem of lack of positional specificity in PNS regeneration may be transferable to the CNS.
NEUROLOGISTS HAVE always had a reputation for making elegant and difficult diagnoses, based on their knowledge of functional brain anatomy, and then admitting that they can offer no treatment. This reputation, whether deserved or not, is largely due to the fact that structural brain damage does not repair spontaneously and there has been no way of inducing it. In the next decade or so this will change. There are m a n y different techniques aimed at repairing structural brain damage presently under development. This issue aims to give an overview of some of these developing technologies which, when they come to fruition, should revolutionize the treatment of neurologic damage. At the most basic level, damage to the nervous system results in the death of cells, both neurones and glia, and in damage to cells, as in axotomy or demyelination. Repair of the damaged nervous system must therefore encompass replacing lost neurones and lost glial cells, and in promoting the regeneration of damaged cell processes, particularly axons. Following damage, some spontaneous repair may occur. In the peripheral nervous system, axons will regenerate, and reform functional connections with appropriate target organs, but in the CNS there is little or no functional axonal regeneration. M a n y forms of demyelination in both CNS and PNS are repaired spontaneously by either oligodendrocytes or Schwann cells. Astrocytes in the adult CNS are able to divide rapidly, and reform the boundary which separates the CNS from the PNS, the circulation and the cerebrospinal fluid. However, the crucial deficits in the CNS are the absence of axonal regeneration, the lack of replacement of lost neurones, and the failure to remyelinate some forms of lesion. The articles in this issue review recent progress in the development of techniques to correct these deficits.
Axonal regeneration This is the subject of the first three papers. The tantalizing thing about axons is that they can all
Glial
University of Cambridge, Physiological Laboratory and MR C Cambridge Centrefor Brain Repair, Downing Street, Cambridge, CB2 3EG, UK 9 1993 Academic Press Ltd
Demyelinated axons do not conduct action potentials effectively and an area of demyelination therefore has the same effect as local axotomy. While m a n y forms of demyelinating lesion remyelinate spontaneously, 383
transplantation
384 probably due to migration into the lesion of the oligodendrocyte precursor cell which is found in adult brain, and its subsequent division. Other lesions, particularly those of multiple sclerosis, do not remyelinate, the axons becoming surrounded by reactive astrocytes. It is possible to manipulate the process of remyelination and astrocytosis by means of glial transplantation, as described by R. Franklin in this issue. In developing these transplant techniques a great deal has been learned of the interactions between astrocytes, Schwann cells and oligodendrocytes.
Neuronal transplantation There are no neuronal precursors in the adult mammalian brain and the only way to replace dead neurones, therefore, is by transplantation. Neurones will survive transplantation, but only if they are taken from embryos just after they have undergone their final cell division. Such embryonic transplants then have the ability to grow processes into the host brain and receive them from host neurones, with functional synaptic connections being made between appropriate neuronal types. The axons growing from the transplants cannot usually grow for long distances through the host brain, unless they are growing through an area rich in target neurones, in which case they can skip the small distances from neurone to neurone and thus grow for many millimetres. This is a major restriction in the possible therapeutic use of neuronal grafts, since it means that transplants must be put in a target area, rather than in the position of the cells whose function they are replacing. It is, therefore, seldom possible to recreate a whole
Introduction
neuronal circuit. Nevertheless, this is not a problem in some conditions, development of successful transplantation strategies for which are described in the articles by P. Brundin and K. Wictorin, and by M.J. Gibson and A.-J. Silverman. A second major problem in neural transplantation is the poor survival of many transplanted neurones. This, combined with the many problems involved in obtaining suitable human embryonic tissue, makes it very difficult to use neural transplantation as a routine clinical procedure. Embryonic neurones are dependent for their survival on trophic molecules and the use of such molecules for improving neuronal grafts is discussed by R. Barker et al. Another alternative is to use modern molecular biological techniques to modify cells before they are transplanted, either by making them into immortal cell lines, or by adding genes. There is also the possibility that the whole transplantation procedure can be replaced by hijacking normal brain cells, and altering their function so as to replace functions which have been lost. This can be done by using viruses to put new genes into brain neurones and glia. These molecular biological techniques are described in the paper by P. Horellou and colleagues. O f the procedures described in this issue, only the transplantation of neuronal cells for the treatment of Parkinson's disease and repair of peripheral nerves has so far reached clinical practice. Progress in working out the basic science of nervous system repair has recently been so rapid that one can confidently expect many other techniques which are presently being developed in the laboratory to become part of routine medical treatment within the next decade or so.
Introduction: Repairing the damaged nervous system James Fawcett potentially regenerate. Axons in the peripheral nervous system regenerate when cut and reform functional connections with appropriate targetsmotor axons reconnect to muscle, sensory axons to sensory structures. CNS axons do not regenerate when cut, but essentially all have the ability to regenerate if they are given a Schwann cell environment in which to do so. M u c h effort is currently going into finding the factors which render the CNS glial environment inhibitory to axon regeneration, and it seems probable that before long it will be possible to counteract this inhibition and promote regeneration of large numbers of CNS axons at least for small distances. This, coupled with Schwann cell grafts which can promote long distance regeneration, should form the basis of the first treatments for conditions such as spinal cord injury, where the neurological deficit is primarily due to cut axons. The question which will then arise is whether the regenerating axons show any specificity in their connections. Completely random connections made by regenerating axons could be worse than no connections at all. It is likely that the behaviour of axons regenerating in the PNS and axons growing from brain grafts inserted in the adult brain is a guide to what one could expect of regenerating axons. Based on this information, one would expect regenerating axons to show great specificity in forming connections only with the correct type of neurone, but rather less specificity in determining which member of the right class of neurone. Thus, regenerating cortico-spinal axons will probably connect to motoneurones, but not be good at selecting motoneurones at the correct spinal level. Some of the techniques which are being worked out to counter the problem of lack of positional specificity in PNS regeneration may be transferable to the CNS.
NEUROLOGISTS HAVE always had a reputation for making elegant and difficult diagnoses, based on their knowledge of functional brain anatomy, and then admitting that they can offer no treatment. This reputation, whether deserved or not, is largely due to the fact that structural brain damage does not repair spontaneously and there has been no way of inducing it. In the next decade or so this will change. There are m a n y different techniques aimed at repairing structural brain damage presently under development. This issue aims to give an overview of some of these developing technologies which, when they come to fruition, should revolutionize the treatment of neurologic damage. At the most basic level, damage to the nervous system results in the death of cells, both neurones and glia, and in damage to cells, as in axotomy or demyelination. Repair of the damaged nervous system must therefore encompass replacing lost neurones and lost glial cells, and in promoting the regeneration of damaged cell processes, particularly axons. Following damage, some spontaneous repair may occur. In the peripheral nervous system, axons will regenerate, and reform functional connections with appropriate target organs, but in the CNS there is little or no functional axonal regeneration. M a n y forms of demyelination in both CNS and PNS are repaired spontaneously by either oligodendrocytes or Schwann cells. Astrocytes in the adult CNS are able to divide rapidly, and reform the boundary which separates the CNS from the PNS, the circulation and the cerebrospinal fluid. However, the crucial deficits in the CNS are the absence of axonal regeneration, the lack of replacement of lost neurones, and the failure to remyelinate some forms of lesion. The articles in this issue review recent progress in the development of techniques to correct these deficits.
Axonal regeneration This is the subject of the first three papers. The tantalizing thing about axons is that they can all
Glial
University of Cambridge, Physiological Laboratory and MR C Cambridge Centrefor Brain Repair, Downing Street, Cambridge, CB2 3EG, UK 9 1993 Academic Press Ltd
Demyelinated axons do not conduct action potentials effectively and an area of demyelination therefore has the same effect as local axotomy. While m a n y forms of demyelinating lesion remyelinate spontaneously, 383
transplantation
384 probably due to migration into the lesion of the oligodendrocyte precursor cell which is found in adult brain, and its subsequent division. Other lesions, particularly those of multiple sclerosis, do not remyelinate, the axons becoming surrounded by reactive astrocytes. It is possible to manipulate the process of remyelination and astrocytosis by means of glial transplantation, as described by R. Franklin in this issue. In developing these transplant techniques a great deal has been learned of the interactions between astrocytes, Schwann cells and oligodendrocytes.
Neuronal transplantation There are no neuronal precursors in the adult mammalian brain and the only way to replace dead neurones, therefore, is by transplantation. Neurones will survive transplantation, but only if they are taken from embryos just after they have undergone their final cell division. Such embryonic transplants then have the ability to grow processes into the host brain and receive them from host neurones, with functional synaptic connections being made between appropriate neuronal types. The axons growing from the transplants cannot usually grow for long distances through the host brain, unless they are growing through an area rich in target neurones, in which case they can skip the small distances from neurone to neurone and thus grow for many millimetres. This is a major restriction in the possible therapeutic use of neuronal grafts, since it means that transplants must be put in a target area, rather than in the position of the cells whose function they are replacing. It is, therefore, seldom possible to recreate a whole
Introduction
neuronal circuit. Nevertheless, this is not a problem in some conditions, development of successful transplantation strategies for which are described in the articles by P. Brundin and K. Wictorin, and by M.J. Gibson and A.-J. Silverman. A second major problem in neural transplantation is the poor survival of many transplanted neurones. This, combined with the many problems involved in obtaining suitable human embryonic tissue, makes it very difficult to use neural transplantation as a routine clinical procedure. Embryonic neurones are dependent for their survival on trophic molecules and the use of such molecules for improving neuronal grafts is discussed by R. Barker et al. Another alternative is to use modern molecular biological techniques to modify cells before they are transplanted, either by making them into immortal cell lines, or by adding genes. There is also the possibility that the whole transplantation procedure can be replaced by hijacking normal brain cells, and altering their function so as to replace functions which have been lost. This can be done by using viruses to put new genes into brain neurones and glia. These molecular biological techniques are described in the paper by P. Horellou and colleagues. O f the procedures described in this issue, only the transplantation of neuronal cells for the treatment of Parkinson's disease and repair of peripheral nerves has so far reached clinical practice. Progress in working out the basic science of nervous system repair has recently been so rapid that one can confidently expect many other techniques which are presently being developed in the laboratory to become part of routine medical treatment within the next decade or so.