Edited by William J. Freed, The MIT Press, Cambridge, MA, 2000.
Neural transplantation and the surgical contributions to regeneration in the nervous system hold enormous promise for the treatment of human disease. Most neurosurgeons are familiar with the limited number of papers written about transplantation, but few understand the vast amount of research that is the background for the rudimentary human reports today. William J. Freed is Director of the Cellular Neurobiology Branch in the Division of Intramural Research at the National Institute of Drug Abuse, Addiction, Research Center. He is editor of the Cellular and Molecular Neuroscience section of Experimental Neurology and a past president of the American Society for Neural Transplantation and Plasticity. Neural Transplantation is a remarkable summary of the background that underlies our current efforts in transplantation. This book will undoubtedly serve as one of the fundamental references in the field for many years to come.
Dr. Freed begins by emphasizing the chronic nature of neurologic disease and the great costs that are associated with it, thus emphasizing the need for transplantation and regeneration research. The review of brain structure and development is rudimentary for a neural scientist, but is an excellent background for the book.
The concept of neural transplantation is old, but in practical terms the field is barely 20 years old. The remainder of the history is detailed and interesting. The author reemphasizes the fundamental contributions of Cajal. He reminds us that distinguished neuroscientists have been interested in this since the early part of the century, and significant contributions were made beginning in 1950, even though real emphasis on the field began in 1979. There is a practical chapter on reasons why transplants might be used. These reasons are to produce new neuronal inputs or facilitate growth of axons from existing inputs, to produce growth factors and related substances, to direct axonal growth, to provide interconnecting neurons, to re-myelinate injured axons, and to form new connections within injured brain. The details of what is required to obtain viable tissue for transplantation are summarized. The emphases upon current guidelines that must be met if fetal transplantation is envisioned are important in view of the many moral and ethical questions surrounding the much simpler field of genetic modulation. He also discusses the issue of personality change following brain transplantation, both deliberate and incidental. The moral and ethical issues are discussed first, which is a unique and important contribution to the whole concept of modulation of brain function, especially when there are important social implications.
The author then discusses specific diseases in great detail. The treatment of Parkinson's Disease begins this discussion probably because so much has been done regarding the treatment of this disease. The details are very well described and the chapters should be read by anyone either involved or interested in the treatment of Parkinson's Disease. Both fetal and adrenal medullary transplantation are described with a review of every paper written on humans who had these procedures, and there is an excellent chapter on studies in subhuman primates. The chapter on clinical studies is the best review in this highly controversial field. The review of the clinical studies is extremely well done. The author concludes that a significant number of human patients have been subjected to experimental procedures that had little chance of success because of poor planning or insufficient basis in animal experimentation. However, he concludes that state-of the-art technology is benefiting patients receiving transplants. Because his conclusion that the procedure is still investigational and that it is too early to draw definitive conclusions from the assessment of the clinical research at this point is in keeping with my own view, I think his conclusion is correct.
The next topic he discusses is use of transplants to influence localized brain function more generally. The majority of this work has been done in the field of chronic pain. A few patients have been demonstrated to benefit from this. The results of transplantation of cells into the spinal cord in semipermeable capsules are particularly intriguing and promising.
Harvey Cushing attempted to transplant the pituitary into the medial temporal lobe in 1912. Some of the most promising modern work has been in transplantation of the pituitary. The review of hypothalamus and pituitary transplantation and the potential uses is germane. Of course, the greatest value for the largest number of patients is likely to be in transplantation that can restore function in an injured cerebral cortex. The majority of these patients would be stroke victims. At present there is no practical experiment, but the investigations are certainly ongoing. Treatment of more specific chronic neurologic diseases such as Huntington's disease, trauma to the spinal cord, and trauma to the visual system are all important. After stroke, spinal cord trauma is the area of transplantation with the greatest potential public health benefit because of the numbers of patients involved and their severe disability. Dr. Freed thinks that actual reconstructive treatment of spinal cord injury will become possible in the foreseeable future and I concur.
The relationship of genetic engineering and tissue transplantation is an important one. One of the important issues in transplantation is customizing the cells, and the best way to do this will be through genetic engineering. This may be through harvesting tissue directly from other sources such as fetal cells, but a much more promising technique is the creation of an industry producing stem and progenitor cells which will avoid the controversy that always surrounds fetal tissue utilization. There is much talk about stem cells, but it is not certain that all understand exactly what they are. Stem cells are not terminally differentiated and they are immortal or at least immortal relative to the life of the host and each daughter cell may remain a stem cell but differentiation can occur under some circumstances. In addition, embryonic stem cells are totipotent but further along the line of differentiation it may be possible to produce progenitor cells already destined to become specific cells of the central nervous system. There are two fundamental theories in stem cell use currently. One is that the totipotent cell can be employed and directed to differentiate as desired by various growth factors. The second is that a cell already destined for differentiation can be used when it is still with the capacities of the stem cell. We already have available to us human neural stem cells and the use of stem cell biology, and technology is likely to play a very important role in transplantation. One of the most important ways that this can happen is through producing modified cells that will create appropriate neurotrophic factors and neurotransmitters. Another possibility that the author discusses is direct gene transfer to modify existing cells. After producing such a masterful review, Dr. Freed then provides us with a cautionary conclusion. He points out that we are not likely to be able to implant brains, to exchange personalities, or to do other related things so dear to the heart of the science fiction movie makers. He believes our current approachable goal is to repair localized damage of the brain and spinal cord induced either by trauma or disease accurately and reliably. It is his opinion that for the foreseeable future we will be able to modify specific circuits with specific functions and the vast interconnected nature of the brain will prevent larger goals from being attained.
This is a superb book, and it is the best review currently available in this extremely important field. It is a must for the library shelf of everyone involved in this research. It is also readable and general enough in its nature to be important for anyone who has an interest in this fascinating and very important field.