Book Review

Scientific American Molecular Neurology

N Engl J Med 1998; 339:932-933September 24, 1998

Article

Scientific American Molecular Neurology
(Scientific American Introduction to Molecular Medicine.) Edited by Joseph B. Martin. 321 pp., illustrated. New York, Scientific American Library, 1998. $69. ISBN: 0-89454-030-0

Molecular biology began as a scientific discipline with the discovery of the double helical structure of DNA by Watson and Crick in 1953 and the establishment of the complete genetic code by Nirenberg in 1966. In rapid succession came the discoveries of the first sequence-specific restriction endonucleases, recombinant DNA molecules, plasmid vectors for cloning, identification of specific DNA sequences by the Southern blot technique, DNA-sequencing methods, genetic-linkage analysis, positional cloning, and the polymerase chain reaction. These molecular methods have entered the clinical arena with great success and have provided molecular insights into the mechanisms of disease that were undreamed of just 35 years ago.

Molecular neurology as a discipline owes its birth and existence to these molecular approaches. Francis Collins, the director of the Human Genome Project at the National Institutes of Health, estimates that 3 to 4 percent of the 3 billion nucleotides in the human genome have been sequenced. Thus, we have detailed information on a limited number of the 70,000 to 80,000 genes expressed in a human cell, including the neurons and glia of the brain. Despite the relatively small amount of genetic information at our disposal, enormous progress has been made in deciphering several major neurologic diseases with the use of these methods.

Great credit must be given to Joseph B. Martin among a small group of neurologist-neuroscientists who recognized in the late 1970s and early 1980s the importance of molecular biology for elucidating the mechanisms of neurologic disease. His enormous influence in bringing the field of molecular neurology into being in a rather short period is evidenced in his organizing and editing of Molecular Neurology. Every area of molecular analysis of neurologic disease included in this well-written and beautifully illustrated book provides evidence of his positive and catalytic efforts at Harvard and the University of California at San Francisco.

The book contains 15 chapters by 21 authors, 15 of whom are faculty members at Harvard or the University of California at San Francisco and have worked closely with Martin for many years. The clarity and immediacy of the exposition of theory and data throughout the book are testimony, in my view, of Martin's excellent editing and personal knowledge of the authors' fields and qualities.

The editor enhances the book by including a foreword and an epilogue, which outline his orientation and rationale for the book and ideas for future research. These features unite the central theme and give the book added cohesion. James Gusella and Joseph Martin begin the book with a clearly worded chapter on the principles of neurogenetics that provides the definitions and explanations of technical advances needed by the reader. The chapters “Huntington's Disease and Other Trinucleotide Repeat Disorders” by Anne Young, “The Molecular Genetics of Alzheimer's Disease” by Rudolph E. Tanzi, “Genetics of Epilepsy” by James McNamara, “Molecular Genetics of Brain Tumors” by Mark Israel, “Molecular Neurology of Prion Diseases” by Stanley Prusiner, “The Molecular Pathogenesis of Multiple Sclerosis” by Jorge Oksenberg and Stephen Hauser, “Amyotrophic Lateral Sclerosis and Inherited Motor Neuron Diseases” by Robert Brown, and “Molecular Genetics of Peripheral Neuropathies” by James Lupski stand out as brilliant expositions in which the molecular data are clearly and succinctly expressed and future directions of investigation become real and understandable.

The descriptions of potential pathologic mechanisms as suggested by the molecular data are important features, because they make clear to the reader the way in which the author conceives the molecular pathogenesis of disease, giving an unexpected but very welcome insight. I found Anne Young's discussions of protein–protein interactions very compelling explanations of the way in which the CAG-encoded polyglutamine repeats found in Huntington's disease, autosomal dominant spinocerebellar ataxias type 1 and type 2, Machado–Joseph disease, and DRPLA (dentato-rubro-pallido-luisian atrophy) among others may theoretically result in their characteristic neuropathologic effects. Similarly, Rudolph Tanzi's presentation of the complex molecular genetics of Alzheimer's disease makes explanations of the way in which mutations of the β-amyloid precursor protein gene and the presenilin genes may lead to the neuropathological characteristics of this disease approachable and easily digestible. Careful, thoughtful molecular–neuropathological correlations abound throughout the book, and they heighten one's understanding of exactly how DNA mutations, deletions, duplications, and repeats and altered regulatory mechanisms translate into disease. It is the uniform ability of the authors to translate molecular data into relevant mechanisms of disease that makes this book immediately relevant and so valuable.

The book ends with an epilogue in which the editor offers a critique of the current state of our knowledge beyond that expressed by the authors and suggests where research must go from here. For example, he asks how we should evaluate the recent observation that endoplasmic-reticulum–associated binding protein moves to the inner plasma membrane when it comes into contact with A-β. His message is that the study of isolated molecular events involving β-amyloid precursor protein, apolipoprotein E-ε4, the presenilins, endoplasmic-reticulum–associated binding protein, and others will not be adequate. Only by the study of a cascade of events in which molecular interactions are clarified will effective therapy be found for Alzheimer's disease. Martin also asks several questions. How do the polyglutamines that migrate to the nucleus in Huntington's disease, autosomal dominant spinocerebellar ataxia type 1, and Machado–Joseph disease lead to neuronal degeneration? Are β-pleated sheets of polyglutamine aggregates an important theoretical consideration? How does the overexpression of bcl-2 in a transgenic mouse with extra copies of the human gene encoding the cytosolic form of copper–zinc superoxide dismutase, which is a model of motor neuron disease, provide protection? What is the role of protein X in the causation of spongiform encephalopathy? Martin has provided more than editing here. The epilogue provokes increased reasoning and scrutiny of the molecular facts provided and keeps the reader thinking about future experiments right to the end.

This book is a remarkable contribution to the neurologic literature because it provides a succinct, lucid, and exciting portrayal of our knowledge of the molecular basis of neurologic disease at the end of the 20th century. More important, each author, every chapter, and the editor probe the depth of our understanding of this information beyond the facts, providing ideas and theories about mechanisms of disease, and speculate on the direction that neuroscientific research must and will take in the 21st century.

Roger N. Rosenberg, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235-9036