The Center for the Biology of Chronic Disease

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Raymond A. Sobel, MD

Associate Professor of Pathology (Neuropathology), Stanford University School of Medicine

REVIEW

This book presents an original and far-reaching hypothesis on mechanisms of chronic diseases. It is a challenging and stimulating read. A full understanding requires a broad medical knowledge of basic mathematical and biochemical principles and familiarity with diverse areas including biophysics, molecular biology, experimental disease models, human epidemiology and nutrition. As I read it, I felt some nostalgia for aspects of my early medical education on subjects from which I am long removed. Dr. Polansky's incorporation of such a broad scientific data base to support his theory is an extraordinary and impressive achievement.

As presented in a single volume, many studies are summarized so concisely that it is occasionally difficult to follow specific arguments, particularly for a reader who finds him/herself in unfamiliar territory. In some instances there are inevitable oversimplifications and one feels that one is reading a catalog of studies. Nevertheless, with perseverance and patience, the read generally can appreciate common themes and is rewarded with new insights.

I cannot state how valid or widely applicable the theory is. Certainly, it is provocative in innumerable ways and its major strengths, as a consequence of Dr. Polansky's scientific erudition, is that it provides explanations for many disparate observations in a remarkable synthesis. Although some of the assertions are likely wrong and only data supporting the argument have been included, the book inspires many testable hypotheses. Therefore, it has considerable scientific merit.

I am particularly interested in multiple sclerosis and human neuropathology. The cause or causes of MS remain elusive. This book suggests a mechanism by which a microorganism infection either initiates the MS disease cascade or promotes chronicity when the process has already been initiated. Indeed, the theory of microcompetition with foreign DNA could be valid for both at different times. Despite innumerable previous attempts to implicate a microorganism infection as a cause of MS, none currently is widely accepted. The theory suggests the possibility that, for example, production of a viral protein would not be necessary to promote the disease. The presence of viral or other microorganism DNA alone, perhaps as a consequence of a prior subclinical infection, could be sufficient to perturb key cellular functions in a chronic time frame. At minimum, this concept deserves further consideration by the MS research community for evaluation of previous and future studies linking CNS infection with MS.

I was also particularly pleased to read about areas in which I have been interested in relation to MS, i.e., ICAM-1/CD18, roles of fibronectin, the extracellular matrix as a site of critical pathological processes, and murine MS models. The theory suggests involvement of foreign DNA microcompetition in a multiplicity of processes in MS that contribute to temporal progression, its considerable phenotypic heterogeneity (even among identical twins), and the dynamic relapses and remissions that most often characterize the disease. Could the variability of MS among individual patients be the result of effects of different GABP viruses or their effects modulating different CNS cells?

On the other hand, there is a large body of literature on the MS model of acute and chronic experimental autoimmune encephalomyelitis (EAE), which indicates that autoimmunity alone could initiate and prolong MS. Further, unlike the viral induced MS murine models cited in the book, Th1 rather than Th2 responses lead to increased rather than decreased disease in EAE. Therefore, significant aspects of experimental and human demyelinating diseases are not readily explained by the arguments advanced in this book. Nevertheless, it provides insights on which to base future investigations.

The concept that the presence of foreign DNA could contribute to disease progression may be particularly relevant to the pathogenesis of other CNS diseases in which a previous infection is known to have occurred. The Post-Polio syndrome is one clear example. Indeed, one might speculate that many neurodegenerative diseases could have similar foreign DNA microcompetition contributing to their chronic courses. Thus, the potential implications of the theory may have even broader implications for human neuropathology than are discussed in this book.

In summary, this is a scholarly and provocative book that proposes a novel theory with broad and important implications for the pathogenesis of numerous important human diseases. It might be intimidating for those without a broad biomedical knowledge base, but would be appropriate for use in a graduate level course or seminar on the biology of chronic diseases or aging.

BIOGRAPHY

Dr. Raymond A. Sobel is a practicing neuropathologist and Associate Professor of Pathology at Stanford University School of Medicine. He has studied mechanisms of immune responses in the central nervous system, particularly as they relate
to multiple sclerosis (MS) and its experimental models, since 1981. Dr. Sobel's work has focused on expression of major histocompatibility complex and
extracellular matrix molecules and immune responses to myelin proteolipid
protein. Dr. Sobel is currently studying mechanisms of the failure of axonal repair/regeneration in MS lesions.

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