Making a case for brain gain

During the past 30 years there have been remarkable advances in organ transplants to replace damaged and diseased body parts. There has, however, until recently, been a widespread belief that brain transplants could not work in higher animals because the nervous system is fixed and immutable in adult mammals. It is true that virtually our whole complement of neurones is born in early development and stays with us throughout life. Indeed, if its structure could constantly change, the brain would not be able to undertake its task of registering and retaining a lifetime of learning and experience. One consequence of this inability to generate new neurones spontaneously is that the brain is very bad at repairing itself.

Replacement cells are not generated in response to damage or disease and the prognosis for the patient suffering such damage or disease is typically poor. But this does not mean that the brain cannot play host to cells implanted from outside. Indeed, with the limited capacity of the nervous system for self-repair and spontaneous recovery, alongside the devastating consequences of brain damage and disease, the task of developing techniques for extrinsic brain repair might be considered a particular imperative for transplant biology.

The techniques for reliable cell and tissue transplant in the brain and the nervous system were established in the 1970s by neuroscientists who were asking fundamental questions about developmental biology. If you want to understand the principles of cell survival and growth in the developing nervous system, you need an experimental design in which the source of cells - the tissue through which they grow - and their targets can be manipulated independently, and this design is solved by experiments involving the transplant of cells between different loci in the developing brain. But, once the fundamental principle that transplanted cells could survive, grow and connect in the adult brain was demonstrated, and the techniques for reliable cell transplant were resolved, a new set of prospective strategies to develop cell replacement therapies were suggested to treat previously untreatable injuries or diseases in the brain.

This scientific detective story is the subject of Bill Freed's Neural Transplantation . He tells the tale of the breaking down of previous certainties, the hopes that are offered for treating devastating disease, and the consequent social and ethical fears that are frequently raised in popular imagination - all in a manner accessible to the general reader.

Freed has been working in the field for more than 25 years. He was a member of one of the first teams to show behavioural recovery in animals with a rodent equivalent of Parkinson's disease after transplant of the missing cell - studies that have led to the first reconstructive repair of the human brain in patients with Parkinson's disease. He tells the tale of solving the technical problems to develop grafting procedures, and developing the model systems, mostly based on experimental animals, to test them. These, and many studies like them, are leading to the development of cell replacement therapies for diverse disorders of the nervous system, including Parkinson's, Huntington's and Alzheimer's diseases, multiple sclerosis, stroke, epilepsy and spinal cord injury. Different diseases are due to different causative agents, produce different types of cell damage and progress in different ways, so different models are needed and different problems have to be solved for each case. Freed, who works at the lab bench, explains the medical, technical and biological problems with an immediacy and fervency that is compelling. He also writes with a fluency and lucidity that is not common among his peers seeking to popularise their science.

The scientific advances of the past decade reveal new options for the repair of major neurological problems afflicting societies with ageing populations. The evidence is that cell transplants can work well in some neurological diseases, and the range of disorders that may be similarly treatable is vast. In which case, why is this cell-based therapy not revolutionising treatments in neurology, neurosurgery and psychiatry?

The primary reason is that these new cell therapies, while solving fundamental biological problems, raise social and ethical issues. One of the basic principles of cell transplants is that the cells that work best are those that are both of the right type (to replace what has been lost) and at an early stage of their development (when they are actively expressing their normal genetic programmes to differentiate and connect appropriately). In practical terms, this means using embryonic brain cells derived from elective abortions. The use of embryonic and foetal human tissue, whether for research or therapy, is legal in many (but not all) countries of Europe and in North America under tightly regulated conditions, but it still raises ethical opposition from pressure groups. Freed gives a sensitive account of this debate, albeit from a North American perspective. Nevertheless, the practical consequence is that for the foreseeable future suitable foetal tissues are unlikely to be available in sufficient quantity to meet even a fraction of the potential demand.

In order to overcome the limited availability of foetal donor tissues, a major focus of scientific research has been to identify alternative sources. Several have been suggested - xenotransplantation from embryos of other species such as pigs, expanding human neuronal "stem cells" in cell culture to maintain a permanent supply of cells in the laboratory, or engineering cells or cell lines, in particular from the patient, to express (or re-express) the particular genes that make these embryonic cells so suitable. All of these strategies appear feasible, but for each there are biological problems to be solved before it becomes as efficient as primary embryonic cells.

But there is another set of practical, ethical and safety issues that can render each alternative as problematic and as controversial as using human embryonic cells. It is clear that to develop an effective neurological medicine for the 21st century, the problems to be solved are as much to do with controversies relating to social, ethical and safety issues as to do with solving fundamental biological problems.

These issues require political decisions to establish and maintain a legal framework for research and an informed public debate and consensus on therapies. But these decisions need to be taken in the context of a balanced debate based on factual biology, not on misrepresentation or prejudice. To this end, Freed sets out the possibilities and limitations in a digestible form that will provide the reader with the biological background to participate in that debate, as well as providing an entertaining and informative read.

Stephen B. Dunnett is professorial research fellow, school of biosciences, University of Cardiff.