Book Reviews

As originally published in The Physiologist
Volume 45, Number 6, December 2002, page 511-514

Methods in Genomic Neuroscience
Cells, Gels, and the Engines of Life. A New, Unifying Approach to Cell Function
Neuropathic Pain: Pathophysiology and Treatment

Methods in Genomic Neuroscience
Hemin R. Chin and Steven O. Moldin (Editors). 
Boca Raton, FL: CRC, 2001, 
321 pp., illus., index, $119.95.
ISBN: 0-8493-2397-5.
    
    With the recent publication of drafts of the human and mouse genome sequences, and advancements in molecular technologies, there could hardly be a more timely volume in the field of neuroscience than Methods in Genomic Neuroscience. Hemin R. Chin and Steven O. Moldin have compiled an excellent collection of chapters that provides an overview of current technologies and their potential for understanding gene-brain-behavior relationships. The volume covers a wide range of topics, from mutagenisis, transgenics and expression profiling, to human genetic analysis. The author list is quite impressive, representing the leaders of each of the respective topics. 
    The book begins with a chapter by Sokolowski and Wahlsten discussing the concepts of gene-environment interactions. Most genetic experiments are performed in a well-controlled environment, precluding the discovery of gene-environment interactions. The authors point out that genetic phenotypes may vary quite dramatically in different environmental contexts. The chapter provides some experimental design and statistical considerations for examining gene-environment interactions and discusses how molecular technologies can be used to elucidate the mechanisms of these interactions. 
    Several chapters discuss techniques for identifying gene loci responsible for particular neurological phenotypes. Wayne Frankel discusses how natural mutants can be used to identify genes involved in neurological processes. This chapter reviews the use of segregation and linkage analysis to map the chromosomal location of mutant alleles, as well as follow-up transgenic strategies for identifying precisely the mutated gene. Lawrence Pinto and Joseph Takahashi discuss similar issues for identifying mutant genes in mutagenisis experiments. Their contribution provides practical information on chemical mutagenisis, including breeding schemes and theoretical considerations for designing genome-wide mutagenisis experiments. Steven Kanes et al. discuss the use of ENU chemical mutagenisis to discover genes relevant to psychiatric disorders. This chapter includes a useful discussion of the various mouse behavioral paradigms used for identifying mutant behavioral phenotypes. Descriptions of breeding schemes for mapping dominant, recessive and modifier loci are included in both mutagenisis chapters.
    Knockout and transgenic mouse techniques are two of the most powerful and commonly used techniques for characterizing gene function. However, from the standpoint of behavioral neuroscience, this technique is fraught with complications arising from developmental and pleiotropic effects of the mutated gene. Mark Mayford and Eric Kandel contribute a chapter discussing the second generation of transgenic mouse technologies; conditional and inducible gene targeting. The use of Crelox and tetracycline inducible systems for creating region-specific and inducible knockout mice are reviewed.
    Gene trap approaches provide another strategy to identify genes involved in specific neurobiological processes. Kevin Mitchell et al present a fascinating example of how this technique can be tailored to focus on genes involved in brain development and wiring. The technique involves randomly inserting into genes a DNA sequence that encodes markers that label the cell body and projections. The sequence disrupts the gene and the marker proteins are expressed in its place. By staining for the markers and comparing fiber pathways in heterozygous and homozygous brains, it is possible to identify genes involved in the wiring of the brain.
    The genomic technology that has received the most fanfare recently is DNA microarray expression analysis. Two chapters in the book are devoted to microarrays and gene profiling. David Lockhart and Carrolee Barlow, and Károly Mirnics et al. provide good general overviews of this technology with a discussion of different types of arrays, their advantages, and a host of useful practical information. Károly Mirnics et al focus their chapter on microarray strategies for studying human tissue and present methodological and analysis details that are specific for expression analysis in human brain tissue. 
    Gene therapy, or gene transfer, is another technology with great potential in neuroscience. Jürgen Hampl offers a description of methods of gene transfer to neural tissue, including viral vectors and grafting transfected cells. Much of this chapter is devoted to potential therapeutic uses of this technology, including disrupting tumor development or increasing dopamine synthesis in Parkinson’s disease. Neural stem cell technology is another potential therapeutic approach for neurodegenerative diseases. Lorenz Studer and Ron McKay’s chapter provides details on deriving neuronal stem cells and in vivo transplantation and functional assessment. CNS stem cells are likely to also be useful for identifying factors involved in neuronal differentiation.
    The final two chapters discuss the approaches and problems in human genetics. These chapters discuss statistical considerations for the use of genome scans and SNP analysis for identifying genes involved in psychiatric or neurological disorders.
    Overall, I found this book to be quite informative and comprehensive. Some of the chapters are quite specific, providing details on methodology and reagents, while others were broader in scope. In general the book is ideal for neuroscientist and physiologist wishing to be kept abreast of the current state-of-art technology in molecular neuroscience. 

Larry Young
Emory University

Cells, Gels, and the Engines of Life. A New, Unifying Approach to Cell Function
Gerald H. Pollack. 
Seattle, WA: Ebner and Sons, 2001, 320 pp., $55.00.
ISBN: 0962689513.

    Glancing at the first paragraph of this book, I winced: uh-oh, here come the epicycles. The story of Galileo’s experimental extirpation of the Ptolemaic epicycles seems always to foreshadow the pronouncements of scientific revolutionaries claiming that the accepted view of something big—physics, biology, whatever—is rotten at its core and requires a radical paradigm-shift (another familiar mantra in such circumstances). It’s the core of cell physiology that Gerald Pollack sets out to extirpate here. He views the idea of a continuous lipid bilayer membrane, and the pumps, channels, and permeases that reside therein, as biological epicycles, “postulates put forth to rescue attractive theories that otherwise would have collapsed...” Pollack thinks that everyone has got everything wrong. Cells are not bounded by lipid membranes acting as permeability barriers; energy-consuming solute pumps, such as the Na/K ATPase or the H+-coupled ATP synthase, do not exist as such; cellular electrical potentials do not arise from selective ion flows down transmembrane gradients; muscle contraction does not proceed from ATP hydrolysis-driven conformational changes in the myosin head. 
    These ideas are, in the author’s phrase “orthogonal to convention;” indeed, the book is a new exposition of the old “association-induction hypothesis” put forth by G.N. Ling, who has been promoting it vociferously for the past four decades (see http://www.gilbertling.org for the flavor of that discourse). What does this theory say? First, that cell water exists in a non-aqueous state, highly ordered by protein surfaces, and is, thus, a poor solvent for hydrophilic solutes like ions. Second, that cytoplasmic proteins are delicately organized into a gel with a high density of charged groups that selectively bind ions. Third, that this protein-water gel is poised to undergo highly co-operative and very long-range “phase transitions” in response to the binding of ions like Ca++, ATP-3, etc. Finally, that extracellular solutes exist in thermodynamic equilibrium with this cellular gel, not in an energy-consuming steady state. Cyto-plasmic Na+ is low not because it is pumped out of the cell, but because cellular water is a poor solvent; K+ is high because of specific binding to negatively charged sites on cellular proteins. Thus, the cell is pictured as an exquisite kind of ion-exchanger, in which the interplay of solute binding to sites and exclusion from cell water, both equilibrium processes controllable by ligand-induced pancytoplasmic phase transitions, underlies all cellular behavior.
    Pollack re-interprets many familiar physiological phenomena in terms of this picture. For example, ion channel proteins act not as transmembrane diffusion pathways, but as surface receptors which undergo conformational changes and, as a result, cause long-range phase transitions in the cytoplasm, transitions that alter the phase-boundary potential between cellular gel and extracellular solution. Likewise, kinesin does not “walk” along microtubules but rather “surfs” along waves of conformational changes in the microtubule, suspended within a traveling halo of water-structure disassembly linked to binding of ATP. Mitochondria act not as chemiosmotic machines but rather as platforms from which ATP shuttles to nearby cytoplasmic proteins, where it delivers energy by binding and provoking local phase transitions.
    These are pretty wild notions, and Pollack takes pains to explain why we should embrace them, abandoning our familiar view of cell membranes, why the standard view fails so badly as to demand such a complete revision. With appropriate attribution to Ling, he describes three really big problems with the membrane theory.
    1. The Na+ pump violates the laws of thermodynamics by requiring a much larger (>10-fold) free energy expenditure than is available in ATP hydrolysis.
    2. Cellular function is maintained under conditions in which lipid membranes are disrupted by mechanical insult, detergents, organic solvents, or other outrages to hydrophobic integrity.
    3. Cellular electrical behavior is inconsistent with the ionic theory based on selective transmembrane permeability.
It is not my purpose to critique the theory itself, which I consider nonsense. Rather, I aim to review Pollack’s exegesis of this theory to his intended audience: interested scientists with little background in biology. Pollack writes in a most engaging style—vivid, colorful, and enthusiastic. His prose is crystal-clear, he never equivocates, and he puts great effort into making the central points and basic logic stand out from the background. Eschewing the resentful tone so often associated with ignored scientific heretics, Pollack instead relishes the role of mischievous contrarian, and, as a result, the book is a fun read. Moreover, the pages are festooned with David Olsen’s imaginative illustrations that acutely illuminate the unfamiliar ideas offered. But the skillful writing fails to compensate for the intellectual flaccidity of the exposition. This would be an appallingly bad place for a biological novice to begin. I will cite a few characteristic examples of broad, breathless assertions that melt away upon even superficial examination and that mislead the biologically naive reader. 
    1. The reader is told authoritatively that the Na+ pump violates the laws of thermodynamics (p. 18), but is not informed that the experiments leading to this conclusion have never appeared in a peer-reviewed publication, only in Ling’s monograph, which summarizes work he carried out in the 1950s. Likewise, consider the citation (p. 34) casting doubt on the existence of a continuous lipid membrane, in which ion permeability was unaffected by depletion of membrane lipids. The citation is to a 1960 general review of red cell ion permeability containing a short description of an unpublished experiment in which the passive permeability increased by only 20% after about 10% of red cell lipids “should” have been extracted by exposure to alumina (lipids were not actually measured). Does this result tell you that the cell membrane doesn’t form a permeability barrier?
    2. The novice biologist is reminded (p. 41) that certain organisms, such as the wooly bear caterpillar, survive in ultra-cold climates, and then told that this means that the freezing point of cellular water is much depressed, as though it is in a non-aqueous state. In fact, water in most cells freezes slightly below 0oC, and the cold-resistance of arctic insects, which specifically arises from fascinating antifreeze proteins, is an exception. Is this conflation of a special property of an extremophile with a general property of all cells a sly rhetorical device or merely an honest howler? I don’t know, but in either case, the student will end up undereducated.
    3. Asserting that the number of proposed pumps is impossibly large, Pollack fingers an outwardly directed tetracycline pump in bacteria (p 17) as a particularly egregious ad hoc epicycle invoked to patch up the faltering membrane idea. Inviting his audience to join him in throwing up his hands, he argues that such a pump is a priori ridiculous. How can you have a new pump for every new compound synthesized by organic chemists? Pollack leaves it there, without even a whisper about the exciting, vigorous, and medically compelling field of multidrug resistance transporters, several of which have recently been seen at atomic resolution. Regardless of whether this is simple negligence or determined tendentiousness, the naive student at whom the book is aimed has missed out on something awfully interesting.
    Examples like this—in politics it’s called “disinformation”—pervade the book. It seems clear why Pollack explicitly directs his exposition at “those with minimal background in biology”—nobody who knows the facts will swallow this stuff. In our scientific infancy in grad school, each of us dreamed of someday smashing received wisdom to smithereens, like Galileo or Darwin (neither of whom had set out with any such intention). Eventually, we all end up settling in to doing “normal science,” not because we are pathetic failures but because we become genuinely fascinated with the demanding details of specific problems. After reading this book, though, I wonder if it’s unhealthy to have these dreams of glory at all and whether it might be best just to ban Thomas Kuhn and Karl Popper from the children’s section of the library. 

Christopher Miller
Howard Hughes Medical Institute
Brandeis University

Neuropathic Pain: Pathophysiology and Treatment
Per T. Hansson, Howard L. Fields, Raymond G. Hill, Paolo Marchettini (Editors), Progress in Pain Research and Management, Volume 21
Seattle, WA: IASP, 2001, 277 pp., illus., index, $79.00. 
ISBN 0-931092-38-8.

    The past ten years have seen a significant increase in basic and clinical research focusing on conditions, which can be placed under the umbrella of neuropathic pain. In spite of a multidisciplinary strategy involving researches from around the world there remains significant shortcomings in our ability to treat patients with this condition. For this reason it is understandable why the International Association for the Study of Pain (IASP) has chosen this topic as the focus of another outstanding contribution in their series devoted to progress in pain research and management. Considering the fact that an estimated 5% of all patients with traumatic nerve injury suffer from pain, 8% of stroke patients suffer from central neuropathic pain, as do 28% of patients with multiple sclerosis, 40% of patients with Parkinson’s disease, and 75% of patients with syringomyelia or spinal cord injury, it is easy to appreciate the importance of this topic. Although research in the field of neuropathic pain is progressing rapidly, the contents of this volume provides a valuable overview along with descriptions of recently emerging information within the field of neuropathic pain. This book represents a state-of-the-art summary of two symposia held in conjunction with the World Congress on Pain held in August 1999. The volume contains contributions from an internationally recognized list of clinical and basic science experts who address the latest clinical and scientific knowledge dealing with the pathophysiology, diagnosis and treatment of neuropathic pain. 
    The monograph can be divided into three sections, the first dealing with the clinical characteristics of neuropathic pain (Chapter 1); the second with basic research and putative mechanisms of neuropathic pain (Chapters 2-8); and the third with treatment strategies (Chapters 9-13). 
    The opening chapter by Hansson provides an outstanding summary of the clinical characteristics of neuropathic pain, as well as a commentary on the current state of diagnostic and treatment strategies for this condition. This chapter also establishes the clinical dimensions of different neuropathic pain states. A timely perspective on the relevance of current animal models and behavioral outcome measures in studying the complexities of neuropathic pain is also provided. Emerging from this chapter is the recommendation that a continuing dialogue is needed between pain clinicians and pain scientists to enhance research related to the underlying mechanisms of neuropathic pain. The opening chapter is followed by a series of seven chapters focusing on the pathophysiology and possible mechanisms of neuropathic pain. These chapters focus on experimental studies dealing with sodium channels, cytokines, peripheral and central sensitization, plastic changes in chronic pain states and the role of descending facilitatory pathways in neuropathic pain. Chapter 5 by Dickenson and colleagues provides an excellent summary of the central changes that are thought to play a critical role in the pathophysiology underlying the onset and persistence of chronic pain resulting from injury to the peripheral or central nervous system. Porreca and colleagues (Chapter 6) add to the proposed underlying mechanisms of neuropathic pain in their description of bulbospinal facilitatory influences on spinal pain processing. Their contribution describes a novel component to the mechanism of neuropathic pain and typifies the way contributors have provided insightful interpretations of their work. This chapter challenges existing views on the mechanisms responsible for the onset and maintenance of neuropathic pain. Based on a comparison of research in animal models and human studies the role of the sympathetic nervous system in neuropathic pain is provided by Janig and Baron (Chapter 7). The predictability of animal models and their relevance to the human condition is discussed. Chapter 8 describes the use of postherpetic neuralgia as a potential model for the study of neuropathic pain. 
    Effective, long-term treatment of neuropathic pain represents one of the biggest challenges in medicine today. Chapters 9-13 deal with treatment strategies and focus on the use of antidepressants, anticonvulsants, opoids, local anesthetics and electrical stimulation. An important consideration in this section of the book is whether research related to mechanisms of neuropathic pain represents a viable strategy for identifying future targets of therapeutic intervention. Mechanism-based approaches for the treatment of neuropathic pain including blockade of calcium and sodium channels, inhibition of cytokine production, and the use of opioids are discussed. An important underlying theme of these chapters is the fact that in spite of progress in predicting the diagnosis of different neuropathic pain conditions what is lacking is a way to predict the success of different therapeutic interventions. The concluding chapter (14) provides an integrated discussion focusing on the current state of scientific and clinical knowledge related to neuropathic pain and a perspective on what to expect in the future. 
    In conclusion this volume consists of short chapters dealing with the major components of topics related to the clinical characteristics, mechanisms and treatment of neuropathic pain. Each chapter is well-referenced and provides an outstanding state-of-the-art review of research and clinical practice related to this condition. The volume offers the reader a fundamental view of the landscape as well as an account of recently emerging information in basic and clinical areas of neuropathic pain. The contributors have emphasized the importance of increasing our understanding of the mechanisms and clinical characteristics of various conditions in hopes of promoting the development of novel treatments. The book represents a wealth of high quality information for the basic scientist, as well as health professionals, interested in neuropathic pain and emphasizes the importance of current and future research efforts directed towards understanding the pathophysiology and identification of potential therapeutic targets. This volume is an outstanding reference for those interested in the field of neuropathic pain. It contains a comprehensive index, meets the high standards of the IASP Press, and will serve as valuable reading for the established as well as beginning researcher in the field of neuropathic pain. 

Robert P. Yezierski
University of Florida

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