Professor of Medicine and Vice-Chair for Research, Department of Medicine, University of California, San Diego, School of Medicine

REVIEW

Microcompetition with Foreign DNA and the Origin of Chronic Disease by Hanan Polansky is a provocative and challenging contribution to our understanding of a large number of hitherto mostly unconnected disease states. It rests on a single basic premise – that the existence in the body of specific viral gene sequences competes for an important transcription factor, and by doing so, alters expression of genes that are both positively and negatively regulated by this factor. This so-called “microcompetition” thereby gradually leads to a new steady state for a variety of biological processes that we recognize eventually as disease.

Many diseases that were not previously suspected as being due to infectious processes are emerging as being caused by bacteria and viruses. Thus, the guiding hypothesis in this book is perhaps not wholly novel. However, what is new is the massive extent of the dataset that Dr. Polansky has marshaled to support his arguments, and the rigorous quantitative analyses and modeling he has applied. Likewise, the concept that we should think about chronic viral infections in terms of their protein independent effects represents a paradigm shift that may have important implications for understanding such disease states. These effects also imply a potential ability of viral pathogens to alter host biology in such a way as to cause disease, while yet evading host immune defenses that are directed predominantly towards the protein products of the virus.

The most powerful aspect of this book is that it establishes a series of testable hypotheses. Even if only a portion of the author’s thesis is correct, it would establish wholly new insights into the pathogenesis of chronic disease states, and would have significant implications for treatment and/or prevention. At the very least, the author’s constructs do raise a note of caution for molecular biologists in assessing the results of transfection experiments. Thus, transfection with an ’empty’ vector may not be the innocuous control condition that is commonly assumed if the concepts of microcompetition are validated.

BIOGRAPHY

Dr. Kim Barrett received her PhD from University College London in 1982, for studies that elucidated the extent of functional heterogeneity among mast cell populations in different organs. Following postdoctoral training at the National Institutes of Health, she joined the faculty of the University of California, San Diego, School of Medicine, in 1985, where she is now Professor of Medicine and Vice-Chair for Research in the Department of Medicine. Her research interests have centered on the intestinal epithelium as a critical interface between the host and environment, and implications of epithelial signal transduction for the control of transport and barrier functions. Her work has been supported by continuous funding from the National Institutes of Health, and she has also received funding from the Crohn’s and Colitis Foundation of America. Her findings have shed light on pathogenetic mechanisms underlying infectious diarrheal diseases, cystic fibrosis, and inflammatory bowel diseases, as well as the mechanism underlying beneficial effects of probiotic microorganisms. Her accomplishments have been recognized with several prestigious awards, including the Bowditch Lectureship of the American Physiological Society, the Young Investigator Award of the American Gastroenterological Association and the Gastroenterology Research Group, and the McKenna lectureship of the Canadian Association for Gastroenterology. She has also been the recipient of awards for her contributions to medical and graduate education. Finally, she served a six-year term as Editor-in-Chief of the American Journal of Physiology – Cell Physiology, and is a current member of several additional editorial boards worldwide.

Senior Scientist, National Cancer Institute, NIH

REVIEW

At first, I wish to congratulate Dr. Hanan Polansky for his scientific bravery to take such a unique, novel approach to further stimulate our understanding of the origin and establishment of chronic diseases. The philosophy underscored is an excellent one.

I find the book very challenging as it covers such a wide range of topics such as cell motility, atherosclerosis, autoimmune diseases, cellular signaling, cancer, etc. Therefore, to fully comprehend the underlying common mechanism(s), although explained well, one needs to have reasonable background knowledge in such diverse subjects and an open mind to welcome the thoughts discussed.

With numerous examples and original data from published articles, the author builds the conceptual thinking towards the theme of how endogenous regulatory networks are modulated by foreign genome that enters the host in the form of viral infections or deliberately introduced by various gene transfer methods. For example, the ubiquitous effect of GABP viruses, on par with my research interests, on the sequence of reactions leading to the development of cancer due to compromise of immune surveillance, and on the other hand, hyperactive immune responses leading to the development of autoimmune diseases is very intriguing. The quantitative relationship between sequential events affecting cell motility, antigen uptake, expression of costimulatory molecules, priming of different T cell subpopulations and resulting in opposite outcomes, tolerance versus immunity, is elegantly presented.

The amazing correlation between theoretical predictions and observed in vivo effects seems to bring us a step closer to a deeper understanding of such complex biologic processes. Further experimental research towards validation of the concepts, perhaps in a more direct way, may help develop novel therapeutics for human diseases. From my own perspective, although this book is philosophically sophisticated, it certainly seems to be a stimulator for young students as well experienced minds.

BIOGRAPHY

After obtaining his PhD in Immunology from Madurai University in India, Dr. S. Baskar completed a postdoctoral fellowship in the laboratory of the late Professor Sidney Leskowitz at Tufts University School of Medicine, where he investigated murine T cell responses to synthetic antigens. Later, he studied human T cell responses in allergic patients at Johns Hopkins University and then worked on immunogenetherapy in murine models of cancer at the University of Maryland. At Maryland, he published some pioneering work on T cell costimulation and anti-tumor immunity (e.g. PNAS 1993, JEM 1995). Six years ago, he moved to the National Cancer Institute to pursue an interest in immunotherapy of human cancers. Dr. Baskar is now investigating anti-tumor immunity, primarily T cell responses in patients with B cell malignancy who received experimental custom made vaccines. Some of his major goals include mapping the tumor antigenic epitopes recognized by the T cells in the vaccinated patients, searching for other tumor antigens that may be of potential therapeutic value, and designing better antigen delivery systems, including the use of dendritic cells and recombinant DNA vaccines.

Research Associate, Department of Molecular Genetics, The Forsyth Institute, (Harvard Medical Center Affiliate)

REVIEW

I am very pleased to have read this book by Dr. Hanan Polansky. It proved to be quite challenging and interesting. I started this book knowing little about the theory of microcompetition and finished feeling quite inspired by all the possibilities. Since my background is in biophysics, I appreciated the mathematical models that he used to describe molecular mechanisms of chronic diseases. In my opinion, it provides for a very detailed and precise description for these systems. The book is concisely written, and the extensive data was well-presented to explain the theories. 

Dr. Polansky takes an interesting approach when relating the diseases discussed in this book. He uses a detailed quantitative analysis to explain his theories of microcompetition with foreign DNA. I especially enjoyed how he found links between these different chronic diseases. It was quite thought-provoking.   Although the ideas presented are quite interesting, it takes some chapters a few times to read, to fully grasp the meaning. It would serve as a great teaching tool for graduate students. I believe that this book will provide for an excellent starting ground for new scientists to tackle the world of chronic diseases.

BIOGRAPHY

Dr. Afshin Beheshti studied biophysics at Florida State University. During this time, he conducted research on developing a new model for the mobility versus DNA length dependence during DNA electrophoresis in agarose gels. This research produced a simple model that covered an extensive range of parameters to describe the behavior of the migration of DNA through a matrix. It has never been shown until now, that the migration of DNA during electrophoresis can be described so easily. Potential results show the ability to unify past theories dealing with the migration of DNA. After this time, Dr. Beheshti became interested in the world of oral bacteria. Recently he received a postdoctoral fellowship with the Molecular Genetics department at The Forsyth Institute, which is known as an oral and craniofacial complex located in Boston.  Dr. Behesti’s research pertains to a unique type of uncultivable oral bacteria, referred to as TM7. Bacteria of the TM7 phylotype are thus far unculturable, and no information is available regarding their physiological capacity. Members of the phylotype have been detected in a wide range of ecological niches from human subgingival plaque to soil and marine sediments. Currently, Dr. Beheshti has been able to show that these bacteria are in fact quite cultivable. In the near future a map of its genome will reveal the nature of this mysterious bacteria.

Staff Scientist, National Cancer Institute, NIH

COMMENTS

Dr. Polansky’s book, Microcompetition with Foreign DNA and the Origin of Chronic Disease gives a chance for the reader to think in an unconventional way about the cause of chronic diseases. Dr. Polansky compiled published data and tried to explain in a unique way, how a normal cell reacts after acquiring any foreign DNA, such as viral DNA or mutational alteration within the self-genome. The book covers a wide range of topics but more importantly, includes numerous examples and original data from the published articles. In my opinion, this book will be a valuable resource for medical research and drug design as well as for the field of targeted therapy of a wide variety of diseases, including cancer. I highly recommend this book to the entire scientific community.

BIOGRAPHY

Dr. Tapan K. Bera received his B.S. in Chemistry and his M.S. in Biochemistry from the University of Calcutta, India. He received his PhD in Biochemistry from the University of Calcutta and then moved to the University of California, Berkeley for his postdoctoral training in the Cancer Research Laboratory, Department of Molecular and Cell Biology. He completed his research training at
the National Cancer Institute, NIH, with Dr. Ira Pastan and has held the position of Staff Scientist there since 1999. The main goal of Dr. Bera’s research is to develop an immunotoxin for the treatment of cancer and other diseases.

Vice President for Medical Affairs, Conjer, Inc. and Professor of Clinical Anesthesiology, University of Arizona College of Medicine

REVIEW

The book, Microcompetition with Foreign DNA and the Origin of Chronic Disease, by Hanan Polansky, offers the reader an enjoyable intellectual challenge. This book is a scholarly work of extraordinary magnitude with the presentation of the author’s theory of the relationship between microcompetition with foreign DNA and chronic disease with its origin, progression and resolution.

This is an unusual book. The author sets the tone in the Preface with his thought-provoking, philosophical ideas. Chapters discussing chronic disease processes and outlining treatment by reversal of the abnormal causes are intertwined throughout the book with Technical Note Chapters presenting basic concepts with varying degrees of complexity. 

The book is well-referenced with extensively published work that has been peer- reviewed. The author skillfully presents numerous theoretical predictions combined with scientific observations to emphasize and aid in building and substantiating the conceptual ideas found in the central theme of the book, that good health/chronic disease are related by changes in equilibrium with the basic premise that microcompetition with foreign DNA causes chronic disease. The author’s insights for the theory that he proposes are thought-provoking and somewhat convincing by the magnitude of supporting evidence that is referenced.

Because of the writing style, organization, terminology, scientific and mathematical concepts presented, this is not an easy book to read, especially for the casual scientific reader. This book lacks significant background information. The author assumes that the reader has some basic understanding and knowledge base.

However, this should not be considered a distraction from reading the book. This lack of background information should not discourage anyone who is interested in the topic. For the novice like myself, it will probably require the reader to reread various sections several times, seek other external sources for clarification, and stretch his or her intellectual horizons with discussions with knowledgeable colleagues. 

It is a fine line to walk for the author in presenting background information. Too much would be a distraction from the magnitude of information and concepts presented. The significance of the work would be buried. 

The concepts advanced in this book will serve as a nidus for stimulating further investigations and research towards validation of the complex biological concepts that are presented. It will promote increased interest in new multidisciplinary approaches toward understanding the causes of chronic disease and developing therapeutic strategies for prevention and cure.

The book is designed to be thought-provoking. It is an advanced primer for the knowledgeable scientist and physician.

BIOGRAPHY

Dr. Jerry Calkins is currently the Vice President for Medical Affairs at Conjer, Inc., Professor of Clinical Anesthesiology at the University of Arizona College of Medicine, a member of the medical staff at Mayo Clinic Scottsdale, the Medical Director of the Cardiovascular Science Program at Midwestern University, and an Adjunct Faculty member of the Department of Biomedical Engineering at Arizona State University. He has authored and co-authored over 150 technical articles, book chapters, and other publications. He has written and edited two books and co-edited a four-volume encyclopedia of biomedical devices. He has also served on the editorial staff of professional journals. As an academic anesthesiologist and engineer, he has been involved in clinical care, education, and research. As an educator, he is interested in teaching engineers how physicians use the data that medical devices provide, as well as, teaching physicians how to use medical devices and instruments. His research has focused upon the application and integration of technology into medicine with emphasis in the areas of artificial organs, patient safety, and the reduction of patient risk in the delivery of anesthesia and critical care medicine. More recently, he has extended his interests to include the integration of alternative health care systems into allopathic medicine. He is currently involved in the development of microfluidic respiratory gas analyzers, pulmonary function monitors, metabolic rate monitors, and non-invasive cardiac output monitors. In addition to these interests, he has particular interests in the scientific basis for the mechanisms of acupuncture and the formulation of acupuncture therapy, as well as, the concepts of energy medicine, and the origin of disease.

Assistant Professor of Medicine, Division of Infectious Diseases, Department of Internal Medicine, University of Kentucky

COMMENTS

I appreciate some of the responses you have sent me by other reviewers.  Although I am not finished yet (due to some untimely grant proposals), I am thoroughly enjoying Dr. Polansky’s book, especially the technical notes on signaling and drug-induced molecular disruptions. I can see where many teaching faculty of various basic science graduate school departments will be interested in referencing and even deriving lectures from this collection of writings. Lastly, this book has sparked the interest of some of my current graduate students, and now sharing the book has become somewhat of a competition within our own laboratory.

BIOGRAPHY

Stephen L. Carrithers, PhD is currently an Assistant Professor in Internal Medicine, Division of Infectious Diseases at the University of Kentucky, Chandler Medical Center and a Research Health Science Specialist in the Department of Veterans Affairs. He earned his Doctorate in Biochemistry and Molecular Biology at the University of Louisville, Health Sciences Center and completed his Postdoctoral Fellowship in Clinical Pharmacology at Thomas Jefferson University in Philadelphia followed by a research-training professorship in the Kidney Disease Program, Division of Nephrology, University of Louisville. He has authored over 40 scientific publications and has been awarded grants from the National Institutes of Health, American Cancer Society, American Heart Association, and the Veterans Administration. Dr. Carrithers has also helped start and consult for three biotechnology companies and currently serves as the Director of Molecular Diagnostics for Sequelae, Inc., a biotechnology company located in Lexington, Kentucky that focuses on vaccine development and novel diagnostics for HIV and emerging infectious diseases as well as therapeutics for gastrointestinal and renal disease. He has served as an ad hoc reviewer for various scientific and clinical journals such as the Proceeding of the National Academy of Sciences USA, American Journal of Physiology, and Current Drug Targets Immune, Endocrine & Metabolic Disorders. Dr. Carrithers is the co-inventor of two scientific patents and a series of invention disclosures and is also a member of Marquis Who’s Who in Science and Engineering. Dr. Carrithers’ scientific interests include development of novel anticancer drugs based on targeting specific checkpoints within various intracellular signal transduction cascades and the molecular and physiological mechanisms of natriuretic peptide-hormones.

Chancellor Emeritus, Baylor College of Medicine

COMMENTS

The theory underlying the basic concept concerning the origin of chronic diseases presented by Dr. Polansky is most interesting, indeed fascinating … Perhaps a symposium could be held to provide a forum for further discussions and critiques of this fascinating theory.

BIOGRAPHY

Dr. DeBakey, Chancellor Emeritus of Baylor College of Medicine, has performed more than 60,000 cardiovascular procedures and has trained thousands of surgeons who practice throughout the world. He is a pioneer in cardiovascular surgery and has invented numerous medical devices, techniques, and procedures while contributing to over 1,300 medical publications throughout his career. He was awarded the Lifetime Achievement Award from the United Nations in 1999 and was cited as “Living Legend” by the United States Library of Congress in 2000. His list of awards from institutions around the world is staggering.

Co-Leader, Prevention Program, Barbara Ann Karmanos Cancer Institute, and Professor, Department of Pathology, School of Medicine, Wayne State University

Kenyon G. Daniel, PhD Student

Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University

REVIEW

Unlike many disciplines, the medical sciences seem to lack theories that unify the myriad of observations that are recorded. Most disease studies seem to center around CAUSE: EFFECT: TREATMENT without extensive thought to an overall causality to the disease. Most diseases are treated as unique events that require unique treatments. This book has endeavored to take a large collection of data from a variety of seemingly independent diseases and unify them under a single overriding concept.

The theory proposed by the author is that latent viruses contain promoter sequences that directly compete with host genomic promoter sequences for a limited supply of pre-initiation complexes (PICs). By reducing the available pool of PICs, healthy gene regulation is disrupted, allowing a disease state to  manifest. For example, the author states that in cancer cells, unphosphorylated Rb is of crucial importance for the cellular growth arrest and differentiation. The pool of unphosphorylated Rb protein is principally increased by the creation of new Rb protein (rather than dephosphorylation, or decreased degradation). Cells infected with latent GABP virus compete with endogenous Rb promoter for PICs that results in decreased expression of unphosphorylated Rb and increased cellular proliferation. This concept is expanded to include numerous diseases and is discussed in great detail.

The only problem with this book is the extreme detail that is not coupled with a concise “big picture” summary. The technical notes are filled with mathematical descriptions and an alphabet soup of abbreviations and symbols. This makes those sections somewhat difficult to read. Furthermore, while the author devotes a chapter to what theories are and what the importance of theories is, they fail to briefly and coherently describe their theory. A critical nature of theories is that they are relatively straightforward and simple to understand.  While the theory being described by the book is understandable, the author has not adequately presented the theory such that a reader can quickly determine the nature of their theory. This is a shame since the field really needs more books of this nature and this theory is well-researched and very sound.

Overall, while the book is very difficult to read, it is an important book for a medical researcher to read.  Not only does the book present a strong theory to unify the cause of many diverse disease states, the book itself represents an aspect lacking in the field of medical science, an attempt to unify observations into coherent theories.

BIOGRAPHIES

After receiving his PhD in Chemistry from Rutgers University in 1988, Dr. Q. Ping Dou completed his postdoctoral training in molecular biology and pharmacology at Dana-Farber Cancer Institute and Harvard Medical School (Mentor: Arthur B. Pardee). He was a faculty member of the University of Pittsburgh, University of Pittsburgh Cancer Institute, H. Lee Moffitt Cancer Center & Research Institute, and the University of South Florida before his current positions. Dr. Dou is an expert in the research areas of cell cycle, apoptosis, proteasome and green tea, and has extensive experience in the field of anticancer/chemopreventative drug discovery. His current research focuses on molecular targeting and the cancer-preventative mechanisms of green tea polyphenols, soy isoflavones, tannic acid and other natural products. Dr. Dou also has extensive experience in professional service, including study sections, advisory and editorial boards, and scientific committees.

Kenyon G. Daniel has been involved with science since a very early age and has been fascinated by both chemistry and biology throughout his education. He was awarded a Bachelor of Science degree from the University of South Florida in 2000, and he is currently finishing a PhD in Medical Science. A large amount of Kenyon’s undergraduate studies centered around philosophy, rhetoric, and writing as well as biology. These subjects in conjunction with his doctoral training have created his current outlook on science. Kenyon believes that not only are observations, facts, and experiments necessary but these need to be guided by philosophy. He has worked with Dr. Dou for the past 5 years, and together they have explored cancer and drug discovery in a way that may be unique to most students. Dr. Dou’s guidance of Kenyon’s development has involved as much discussion as experiments, as much computer science as biological science and a healthy dose of philosophy tempered by reality.

Research Fellow, Department of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School

REVIEW

First of all, I want to thank you for giving me the opportunity to review this book. Dr. Polansky presents a theory about microcompetition, which was unknown to me until recently. This theory tries to explain the origin of various diseases that range from autoimmune diseases to atherosclerosis and obesity. Although it is believed that most of the diseases presented are unrelated to each other, Dr. Polansky presents the mechanism of microcompetition with foreign DNA (mainly viral DNA) as a common underlying mechanism that bridges their origin. I think that this idea is very interesting and not only gives you a theory about the pathogenesis and pathophysiology of chronic disease, but also a proposal to treatment. This book is very challenging, and although Dr. Polansky has done a very good job on trying to be thorough, it is rather difficult to read. One has to have a good mathematical background to understand the equations, figures and graphs supporting the model. One has to go back to the list of literature references and do a good amount of reading in order to elucidate and understand the theory in-depth. At this point, I have to congratulate Dr. Polansky for a complete list of literature references.

In conclusion, it is my strong belief that this book, although complex, will engage the motivated reader and give new ideas for further research on the origin of chronic human disease and the options of treatment. Thank you once more for giving me the opportunity to read and give my comments for this book. I believe that it helped me to understand the concept of microcompetition and to get some new ideas for my future research.

BIOGRAPHY

Dr. Harry Elvanides received a B.S. in Biochemistry in 1993 from Aristotle University of Thessaloniki, Greece. In 2000 he earned an MD from Umea University, Sweden. He became a Licensed Physician upon approval from the Swedish/EU Board 2002. Since July 2002, he has worked as a Postdoctoral Research Fellow in Endocrinology in the Department of Medicine at Beth Israel Deaconess Medical Center in Boston. His main scientific interest is the study of obesity and the physiology/pathophysiology of adipokines.

Research Fellow, Department of Cardiology, Children’s Hospital, Department of Cell Biology, Harvard Medical School

REVIEW

Thank you very much for the opportunity to read and review the book by Hanan Polansky. As a trained biotechnologist, I am used to the approach to establish mathematical models for biological processes and believe it is very important for our deeper understanding of molecular mechanisms of diseases.

It was a pleasure to start reading the book. The preface especially caught my attention. It is clearly written and prepares oneself for the following rather complicated technical part due to the large number of mathematical equations. Fortunately, Hanan Polansky provides many examples to clarify the mathematical functions he is carefully introducing in each chapter. In my opinion it is very interesting to read the book, and it is intellectually satisfying. However, the book is very challenging as it covers a wide range of topics such as cell motility, atherosclerosis, autoimmune diseases, cellular signaling, and cancer. Thus, it is very tiring. The organization of the book is also sometimes confusing and maybe too many examples are given.

To my knowledge, Hanan Polansky used a unique, novel approach to further stimulate our understanding of the origin and establishment of chronic diseases. I hope that more attempts will follow to model other important molecular mechanisms. The theory described is very interesting, and the amazing correlation between theoretical predictions and observed in vivo effects seems to validate it. However, it is important to demonstrate that this theory can be used to predict so far not performed experiments and helps to develop novel therapeutics for human diseases.

I am working in the field of heart regeneration, and thus I am familiar with atherosclerosis, obesity and cell cycle studies (cancer). Moreover, I am very interested in understanding cell signaling regarding heart regeneration. Personally, I am also interested in chronic diseases. To be honest, I was surprised to realize by reading the book that all the described diseases might be based on a common cause. It is amazing how Hanan Polansky was able to establish a model describing how chronic diseases are based on the modulation of endogenous regulatory networks by a foreign genome that enters the host in the form of viral infection.

I believe every scientist working with biological systems should read the book to become aware of how important mathematical descriptions of systems are. Moreover, the book demonstrates in a very elegant way how important it is to see the big picture and not to be focused on isolated systems. I find the book very challenging as it covers a wide range of topics such as cell motility, atherosclerosis, autoimmune diseases, cellular signaling, and cancer. Therefore, to fully comprehend the underlying common mechanism(s), although explained well, one needs to have reasonable background knowledge in such diverse subjects. From my own perspective, the idea behind the book certainly seems to be a stimulator for young students. However, I believe the book is too complex as a medical textbook because it is lacking too much basic information needed to understand it.

The book has the potential to impact medical research and drug discovery and time will show. Although the theory was demonstrated very convincingly it might be oversimplifying the problems underlying chronic diseases. Nevertheless, I am convinced that the work of Hanan Polansky will contribute to a deeper understanding of the mechanism of chronic diseases and this brings the field a big step forward.

BIOGRAPHY

Dr. Felix B. Engel studied biotechnology at the Technical University in Berlin, Germany. During this time, he worked on the characterization of replication origins in Schizosaccharomycespompe and developed during his diploma thesis, a selection system for ribozymes that are able to catalyze bimolecular reactions. Afterwards, he became interested in regenerative medicine. At the Max Delbrueck Center for Molecular Medicine, he established during his PhD thesis, a mammalian myocardial cell-free system demonstrating that the mammalian heart is, in principle, able to regenerate. Finally, Dr. Engel joined Mark T. Keating’s group at Harvard Medical School/Children’s Hospital. At the moment, he works on the induction of dedifferentiation and proliferation of mammalian cardiomyocytes as a fundamental mechanism of heart regeneration as Mark Keating’s group has shown previously in zebrafish

REVIEW

I anticipated that the contents of Dr. Polansky’s book would be philosophical and purely subjective. I sat down to read it with such a mental focus, and was completely knocked off my feet by the plethora of data provided in support of his stated theories and observations.

The book is exceedingly well-written and formatted. I confess that not all of the topics were of interest to me or within my field of expertise; however the sections pertaining to inflammation, obesity and malignancy were of the utmost substance. As we charge forward into the future of evidence-based medicine, it is difficult to cast aside novel theories such the concepts of “microcompetition,” particularly when the objective data is so overwhelming.

Dr. Polansky’s work is a completely original and novel examination of the world around us. The style is very tutorial however the complexity of the material makes it difficult to read in sections. A significant amount of abstract thinking and symbolic logic are required to grasp the author’s core message. However, even if the reader is not versed in symbolic logic or mathematical equations, as presented in the first sections of the book; significant information can be gleaned. The structure of the scientific theorem is well-put-forth and the arguments in support are convincing. The author’s arguments are supported by the evidence cited.

Recently, while on an abstract program committee, one of the members of the group noted that it was odd how far we had come when papers were being submitted about HIV+ patients that were developing obesity problems. I had recently read the section on obesity and HIV in Dr. Polansky’s book and found it interesting that independent of any perspective I might hold, others independently were making note of the ‘unusual’ biologic behavior becoming apparent.

The book is suitable for the reader interested in novel biologic theory. It will challenge what we consider to be ‘truisms’ and has the potential to incite new thinking to old problems. Anyone in the biomedical, medical or basic science research fields would benefit from reading it.

It is not suitable as a textbook in a large scale sense. The role of such a work is likely in a “theory of …” class, or an advanced science theory series. While the theorems are well-supported, the vast amount of information already required in the medical curriculum which barely covers significant clinical matters such as nutrition, end of life issues etc., would be overwhelmed by trying to incorporate this book beyond a very superficial level.

Medical research and drug discovery are likely to be impacted by the concepts proposed in this book, similar to the impact that molecular level technologies have enabled us to dissect a more mechanism-based understanding of biology, as opposed to pure association. However, the impact of Dr. Polansky’s book may take some time to be noticed.

Overall, I recommend this book to anyone interested in mechanism-based science and who is able to think “outside the box.” To truly begin to understand some of the radical paradigm shifts proposed by Dr. Polansky it will require that the reader have an open mind beyond the standard explanations that have been accepted by conventional wisdom.

BIOGRAPHY

Joseph Espat, MD, MS, FACS is an Associate Professor in the Departments of Surgery and Pharmacology at the University of Illinois at Chicago. He earned a Bachelors degree in Biology and Philosophy (University of South Florida); MD at the University of Florida, Gainesville, and General surgery training at the University of Florida, Gainesville; Master of Science (University of Illinois); and completed a prestigious Fellowship at the Memorial Sloan Kettering Cancer Center, New York. Dr. Espat is a Fellow of the American College of Surgeons and has authored over a 100 scientific publications. He is a member of the Editorial Board of several scientific journals such as Journal of Parenteral and Enteral Nutrition, Surgical Oncology. He has also been a consultant for several companies. He has obtained various research awards for his work on nutrition and cancer. He is currently Director of Hepatic Regional Therapies Program and research director of the University Of Illinois Laboratories Of Surgical Metabolism

Assistant Professor, Department of Internal Medicine, University of Texas Health Sciences Center-Houston

COMMENTS

The book of Dr. Hanan Polansky presents a theory that explains the origin of many chronic diseases. The title and the content of this book are very attractive to both scientists and clinicians alike. Nevertheless, the book is not easy to read, and while I would highly recommend it to all scientists interested in medical research, I believe that clinicians without any research background may find it difficult to follow. The mathematical models and the symbolic representations used in the book are rigorous and supported by a large body of published data. If validated by future work, this theory could be the basis for
further research in drug development. At this point in time, it would be  premature to translate the theory into treatment options for chronic diseases (and I don’t think that this is what Dr. Polansky had in mind to start with).  Kudos to Dr. Polansky for having the courage to free himself from academia and contribute in such a brilliant way to the understanding of the pathogenesis of chronic diseases.

BIOGRAPHY

Dr. Fabrizia Faustinella holds the position of Assistant Professor in the Division of General Internal Medicine at the University of Texas-Houston. She completed her residency training in Internal Medicine at Baylor College of Medicine in Houston, Texas, where she received the Harry D. McIntosh award for Outstanding Resident in Medicine. Dr. Faustinella received her medical degree from the University of Perugia and her Doctor of Philosophy degree (PhD) from the University of Florence in Italy. She has done research in human genetics at the University of Milano, Italy and at Baylor College of Medicine. She has published numerous articles in the field of research as well as several book chapters. More recently, she has been heavily involved in medical education and in the development of effective teaching strategies for medical students and residents.

Professor, Medical Sciences, University of Puerto Rico

REVIEW

This book on a new theory on the origin of chronic diseases is quite fascinating and full of updated information that fully substantiates the author’s theory.

When I picked up the book, I felt very attracted to it; moreover excited and even amazed by the quantity of data and the in-depth analysis of an array of different studies pertaining to different chronic diseases. Dr. Polansky makes an evidence-based case for his theory for each chronic disease. The book is well written although highly technical and geared toward the scientific community. The book has a series of technical notes to facilitate the author’s explanations and chapters dealing with the different chronic diseases (atherosclerosis, stroke, autoimmune disease, obesity, osteoarthritis, cancer, alopecia) and their related origin to microcompetition with foreign DNA. 

After researching cancer for more than twenty years and actually working on my own theory of the origin of chronic diseases (the bioenergetic theory of the origin of chronic degenerative diseases), I believe my theory is more biological theoretical, while Dr. Polansky’s theory is more of a physical-mathematical answer to the origin of chronic disease. I find Dr. Polansky’s theory very much complementary and in accordance with my own ideas and theory. 

Dr. Polansky’s book does not only scientifically validate his theory but presents possible, attainable solutions to these clinical problems. (Although, I must add that I truly missed the ascorbate molecule as part of the molecular correction of many of the chronic conditions).

I know this book will profoundly impact medical research, drug discovery, as well as natural therapies. I also believe it will benefit the scientific community and society in general by providing further means of treatment for conditions in which only palliative care is available. I think this book is suitable as a clinical textbook for an advanced physiology or physiological biochemistry course. Dr. Polansky’s book and insights are very original with his intriguing, compelling and convincing theory supported by a large body of evidence.

I highly recommend this book to all scientists truly interested in biology, chronic degenerative diseases and evolution.

BIOGRAPHY

Dr. Michael J. Gonzalez is a professor in the Medical Sciences Campus. He earned a Bachelors degree in biology and chemistry (Catholic University), a Masters in Cellular Biology and Biophysics (Nova University) and another Masters in Nutrition and Public Health (University of Puerto Rico). He also has a Doctorate in Health Sciences (Lafayette University) and another Doctorate in Nutritional Biochemistry and Cancer Biology (Michigan State University). He completed a Postdoctoral Fellowship in Geriatrics in the School of Medicine, University of Puerto Rico. Dr. Gonzalez is a Fellow of the American College of Nutrition and has authored over a 100 scientific publications. He is a member of the Editorial Board of several scientific journals such as Biomedicina and the Journal of Orthomolecular Medicine and Alternative Medicine Reviews. He has also been a consultant for several companies and responsible for designing formulations of supplements and pharmaceutical products. He is also a consultant for The Center for the Improvement of Human Functioning. He has obtained various research awards for his work on nutrition and cancer. He is currently Director of RECNAC II project and research director of the InBioMed initiative.

Professor, Department of Biochemistry, University of Saskatchewan, Canada

COMMENTS

This is an excellent book that provides published data from a very different perspective to formulate a generalized theory in terms of stable good health. In this theory, under normal good health conditions, a disturbance to a system returns to the same equilibrium. Any deviation from good health results in chronic disease. The basic concepts are well presented in chapters dealing with “Technical Notes.” These are then explored with published results on chronic diseases. A chapter on treatment outlines reversal from an abnormal equilibrium towards a normal equilibrium. This is an excellent book that describes a good health/chronic disease in terms of dynamic equilibrium with the basic premise “microcompetition with foreign DNA causes chronic diseases.” This is right on the target and deserves to be examined further. I am confident that this theory will be validated with future work. It has already provided stimulus to my thinking, and so far, I agree with the basic concepts outlined in this book. My work was well described and Dr. Polansky deserves a big thank you for this. Thank you again to give me a chance to review the book and to provide comments.

BIOGRAPHY

Dr. Ramji L. Khandelwal obtained his PhD from the University of Manitoba and then was trained as a postdoctoral fellow in the laboratory of Nobel Laureate Dr. Edwin G. Krebs at the University of California, Davis. At present, he is Professor and Head of the Department of Biochemistry at the University of Saskatchewan. His research interests are to delineate aberrations that occur in diseased states, especially in diabetes. He is also working on the interrelationship between insulin and tumor necrosis factor-alpha and how they modulate insulin signaling pathways.

Professor of Medicine (Dermatology), Vanderbilt University School of Medicine

REVIEW

The hypotheses put forward by Dr. Hanan Polansky are intriguing once the complexities of the data presented are analyzed by an initial perusal and a subsequent thoughtful review. Connecting biological, genetic and clinical evidence lead him to construct a conceptual framework of how interacting elements regulate susceptibility, severity and sustainability (chronicity) of human diseases. A fundamental law of interacting forces is a critical limiting element and competition for it in a system determines the ultimate direction and speed of the process, the “rate-limiting step.” In economic theory the “rate-limiting step” often is the availability of capital or resources as determined by multiple interacting forces. In biochemical reactions the availability of a critical substrate or the enzyme responsible for generating that substrate is a “rate-limiting step.”  In molecular genetic terms the availability of a critical binding site in DNA and/or RNA determines the activation or inactivation of a “rate-limiting step.” Professor Polansky proposes that “p300/GABP N-box” interactions are such “rate-limiting steps.” Competition for these sites determines the susceptibility, severity and sustainability involved in selected human chronic diseases states. He does not extend his analyses of “p300/GABP N-Box” interactions in chronic human diseases to the molecular genetics of embryology per se. However, “rate-limiting steps” are always involved in these processes along with the asymmetric spatial and temporal generation of regulatory signaling molecules. The value of Dr. Polansky’s hypothesis is that it can be validated or refuted. “p300/GABP N-box” interactions occur in multiple, experimentally manipulatable single and multiple cell organisms, not just human tissues in vivo and in vitro. How his hypothesis may elucidate the multiple genetic and environmental factors that predispose or make an individual ‘susceptible’ to chronic diseases such as cancer, alopecia and the aging process is truly speculative at this point. His hypothesis provides a different and simplified perspective to understand Darwin’s hypothesis of survival and adaptability. Hopefully Dr. Polansky has found the “Golden Fleece” and not the Siren’s song to reduce complex biological systems to permit comprehensible (erroneous?) analyses. Whatever the ultimate outcome, I recommend his book as a thoughtful, in-depth analysis of seemingly unconnected data to provoke thoughtful discussions by an equally diverse audience.

BIOGRAPHY

Dr. Lloyd E. King, Jr. received a B.A. in Math from Vanderbilt University in 1961, and an MD in 1967 and a PhD in 1970 from the University of Tennessee, Memphis, TN. From 1968-1969, he worked as a Postdoctoral Fellow in the Department of Anatomy, University of Tennessee Medical Units; from 1971-1976, Instructor, Department of Anatomy, University of Tennessee Medical Units; from 1972-1974, Clinical Associate, Dermatology, VA Hospital, Memphis, TN; from 1973-1976, Instructor, Department of Internal Medicine (Dermatology), University of Tennessee Medical Units; from 1974-1975, Leon Journey Fellowship in Biomedical Research and NIH Special Postdoctoral Fellowships Biochemistry of Cell Membranes, St. Jude Children’s Research Hospital, Memphis, TN; from 1975-1977, Assistant Member (Biochemistry) St Jude Children’s Research Hospital; from 1976-1977, Assistant Professor, Departments of Internal Medicine (Dermatology) and Anatomy, University of Tennessee Center for Health Sciences; from 1977-1982, Associate Professor of Medicine, Chairman, Division of Dermatology, Department of Medicine, Vanderbilt University Medical Center; from 1977-1987, Chief of Dermatology, VA Medical Center, Nashville, TN; from 1982-2002, Professor of Medicine, Chair, Dermatology, Vanderbilt University, Nashville, TN; from 1987-2003, Staff Physician, Director, Photopheresis Center – DVA Medical Center, Nashville, TN; and from 1997-2003, Director, VA Dermatology Diabetes Foot Care Clinic. Currently, Dr. King is a Professor of Medicine (Dermatology), Vanderbilt Dermatology, Nashville, TN. Dr. King has been a committee member of a number of organizations throughout his career. In addition, he has published 209 papers, 42 chapters, and 112 abstracts. In the late 1970s, Dr. King collaborated with Stanley Cohen, PhD, who went on to win a Nobel Prize in medicine in 1986.

Professor, Division of Molecular Life Science, Department of Genetic Information, Tokai University School of Medicine, Japan and Associate Professor, Centre for Bioinformatics and Biological Computing, Murdoch University, Australia

REVIEW

Like many of your previous reviewers, I found this to be a brave and challenging book that provokes, stimulates and inspires. While there is much to praise in the book, I have focused on only a few essential items.

Latent viral infection or viral persistence has long been known to have a role in chronic diseases, but the mechanisms involved from the time of infection to the development of the first symptoms of chronic disease are poorly defined. What are the molecular events (“disruptions to the healthy equilibria”) that move a biological system from “good health” to “chronic disease?” In his book Microcompetition with Foreign DNA and the Origin of Chronic Disease, Hanan Polansky provides us with a highly reasoned explanation of the set of cellular and molecular events that link viral persistence with the onset of chronic disease by way of a single control point, the GABP transcription factor. Essentially, the “healthy equilibrium” is disturbed by microcompetition between the cellular and viral DNA for the GABP transcription factors that are limited in availability for binding. The GABP transcription factor is part of a regulatory gene complex that both induces and suppresses genes. Competition with increased copy numbers of viral DNA for GABP binding can cause the inappropriate expression of GABP regulated cellular genes and initiate chronic disease(s). GABP activity is influenced by exogenous and endogenous factors (agents) acting via the ERK/MAP Kinase or JNK/SAPK signaling pathways. Cellular resistance to the ERK agent and hyper-emia of the agent, such as insulin resistance and hyperinsulinemia in obesity, may also occur due to microcompetition with foreign DNA. Thus, the shift from a healthy to an unhealthy equilibrium is a complex
interaction of various factors acting by way of a single regulatory point, the GABP transcription complex, in microcompetition with foreign DNA. Proposed treatments are given for regulating or curing chronic diseases on the basis of the concepts and models presented within the book. Some of these treatments are already well-known while others are still relatively speculative and require further investigation.

Having worked previously in a variety of research disciplines such as on the enzymology of phosphatases, endocrine regulation of reproductive biology and lactation, viruses and cancer, comparative genomics, immunogenetics and autoimmunity, I very much enjoyed the multidisciplinary aspects of the book. Hanan Polansky has connected the dots from various disciplines and revealed a compelling and unifying theory for the origin of chronic disease. His theory is well-supported by the reinterpretation of a considerable amount of published data. I particularly liked the way a number of different gene products, such as
TF, CD18 and GABP, were used to integrate the different findings of cellular and molecular biology into a logical explanation of chronic disease. I found this book to be a fascinating read and I expect it will help me to reassess and resynthesize some of my own ideas and concepts about the origins of psoriasis, rheumatoid arthritis and atherosclerosis.

But readers, beware. This is not an easy book to understand or appreciate on first reading. The author has produced a book of approximately 543 pages of well-argued cases that most often are highly technical. Each chapter is punctuated with mathematical formulas and functions (signal intensity, adhesion and velocity), symbolic language, conceptual building blocks, models, examples, appendices, velocity curves (skewed-belled shaped and S-shaped curves), transitive deductions, logical summaries, experimental predictions, observations
and conclusions, and numerous examples from a list of 1224 references. The presentation is unusual, the layout eccentric but the content is compelling. It is best read with a computer and the World Wide Web and PubMed close at hand.  All together, the book adds clarity to a highly complex subject even though it may require some rereading and follow-up studies to fully benefit from this thought-provoking and ultimately essential account of the origin of chronic disease.

In the final analysis, it is an extraordinary book and I certainly recommend it to students, clinicians and scientists who are interested in viruses and the origin of chronic disease. Indeed, virologists should now resurrect their RNA/DNA “in situ” hybridization techniques and test some of Hanan Polansky’s predictions.

BIOGRAPHY

Dr. Yurek Kulski obtained his PhD for investigations on the endocrine control of human lactation from the Department of Biochemistry at the University of Western Australia in Australia. He completed two postdoctoral fellowships in the United States. The first was as a Walter-Winchell Postdoctoral Fellow to study the hormonal regulation of breast cancer in the laboratory of Professor Gertrude Buehring in the School of Public Health at the University of California, Berkeley. The other was as a Fogarty Visiting Fellow to study the regulatory control of mammary gland differentiation by growth factors, insulin and glucocorticoids with the late Dr. Yale Topper in the Laboratory of Intermediary Metabolism, NAIDDK, National Institutes of Health in Bethesda. On his return to the University of Western Australia, Dr. Kulski investigated the association between human papillomaviruses and uterine cervical cancer and then worked as a Senior Medical Scientist in the Department of Microbiology and Infectious Diseases, Royal Perth Hospital in Western Australia. Presently, Dr. Kulski has a position as Visiting Research Professor in the Department of Genetic Information, Tokai University School of Medicine in Kanagawa, Japan and in the Centre for Bioinformatics and Biological Computing, School of Information Technology at Murdoch University in Western Australia. His research interests include comparative genomics of the Major Histocompatibility Complex (MHC) region, the role of viruses and the MHC in disease, genetic markers of disease, bioinformatics and disease functional analysis, and the origins of autoimmune diseases such as psoriasis and rheumatoid arthritis. Dr. Kulski has authored more than 100 scientific publications, and he is Scientific Advisor to the Japanese company GenoDive Pharm Inc., whose mission is to identify disease susceptibility genes by genome-wide typing using 30,000 polymorphic satellite markers.

Research Fellow, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital

REVIEW

In his book, Microcompetition with Foreign DNA and the Origin of Chronic Disease, Dr. Hanan Polansky presents a novel theory that links a number of chronic diseases to the presence of foreign DNA in the aging cell. He postulates that DNA sequences that are foreign to the cell, sequences which, in-and-of- themselves may be inert, bind to and titrate transcription factors that are present in limiting quantities in the cell. These foreign sequences include viral promoters, germline or inherited mutations and endogenous sequences that have undergone somatic mutation. All cells are elegantly regulated by transient adjustments in gene expression in response to stress and other stimuli. The initial stimulus leads to the activation of a few key transcription factors, each of which goes on to activate entire regimens of genes whose protein products enable the cellular response. In order to achieve a fine-tuned level of regulation, the response must be proportional to the stimulus. Thus, the key transcription factors must be present in limiting molecular quantities. Polansky’s Theory of Microcompetition presupposes that within a given cell, the presence of a few additional sequences capable of binding to these limiting factors will efficiently compete with their endogenous target promoters, thereby disrupting the balance of downstream gene expression. Polansky suggests diverse mechanisms built on the same theme to explain a range of chronic diseases of aging including atherosclerosis, autoimmunity, obesity, osteoarthritis, cancer and alopecia. His extensive supporting arguments, including incidental data and complex mathematical formulae are quite compelling. The mechanisms that he proposes are original, interesting and amenable to testing. Although it is unlikely that scientists will ever discover a single trigger for the onset of “aging,” Polansky’s theory is notable because it provides a potential basis for the relationship between various aging phenotypes and environmental factors such as viral infection and exposure to mutagens. The theory is especially relevant to phenotypes that manifest gradually or aren’t triggered until many years after the initial insult.

In addition to the concepts that Polansky deals with directly, this book provides a unique foray into the intricate mind of a philosopher, continually challenging the reader through an adventure of the intellect.

Although specialists from a number of diverse fields would appreciate sections of the book relevant to their own work, the beauty of this theory is that it crosses many of the self-imposed boundaries that have traditionally limited the creative thought process. This book could make an excellent foundation for a course in “Skills for Creative Thinking” to be offered to upper level undergraduates or graduate students prior to specialization. However, because most students are likely to be novices in at least some of the areas that are covered in the book, I would recommend that the instructor provide a well-rounded introduction to each section, with a vibrant discussion guaranteed to follow.

All in all, this book makes a great read for the scientist with a far-reaching mind, one who is open to new areas of exploration but not afraid of the rigorous journey.

BIOGRAPHY

Dr. Janice M. LaPlante earned her A.B. degree in Biological Sciences from Indiana University in Bloomington, Indiana. After completing her PhD in Biomedical Science from the University of Connecticut Health Center, specializing in the study of intracellular calcium signaling, she was awarded a fellowship from the National Institute of Aging to study the molecular and cellular basis of aging at Harvard Medical School. Dr. LaPlante is currently a Research Fellow in the Division of Endocrinology, Diabetes and Hypertension at the Brigham and Women’s Hospital. She is part of a multidisciplinary team of scientists from the Neurogenetics Unit of Massachusetts General Hospital and the Harvard Partners Center for Genetics and Genomics, working to clone genes that regulate intracellular calcium signaling and to study their relationship to disease. She is the Principal Investigator of a project to identify the molecular function and cellular role of Mucolipin-1, a lysosomal TRP ion channel that is involved in intracellular membrane trafficking and is the product of MCOLN1, the gene that underlies the neurological disease Mucolipidosis Type IV.

Assistant Professor of Medicine, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine

REVIEW

I have read Dr. Polansky’s book entitled Microcompetition with Foreign DNA and the Origin of Chronic Disease with great interest. His book has caught my attention because we currently do not have any good theory about the origin of chronic diseases, even though we think that we understand quite well, the biological basis or pathogenesis of some individual chronic medical conditions. Upon finishing my reading, I have found that this is an amazingly well-written book. In this book, Dr. Polansky has clearly presented the theory of “microcompetition with foreign DNA.” To support this theory, Dr. Polansky has cited a tremendous amount of evidence, most of which is the most up-to-date throughout the book, and particularly, for several of the most common chronic diseases, such as atherosclerosis-related coronary artery disease and stroke, autoimmune disease, and osteoarthritis. Without going into great length of detail, as several reviewers have done that already, I strongly recommend this book to both clinicians and scientists who are interested in a better understanding of the origin of chronic disease.

This book is highly relevant to my work. I like the “microcompetition” part of the theory in particular. First, as a geriatrician (physician specialized in providing clinical care for older adults), I see older patients with multiple and complex chronic diseases all the time. Understanding the origin of chronic disease will certainly help me to treat, and better off to prevent, these chronic diseases for my patients. In addition to the theory of “microcompetition with foreign DNA” on the origin of chronic disease discussed in this book, here I describe, from a different angle, several levels of “microcompetition” in older patients. At the biological level, multiple chronic diseases and other stressors compete for limited physiologic reserve that older patients have, such as nutrition (including micronutrients) and immune defense mechanisms, leading to the development of other chronic conditions or the worsening of existing chronic conditions. From the patient’s perspective, multiple chronic diseases and their crippling effects and associated costs compete for patients’ already reduced functional level and financial resources, leading to further functional decline and disability, as well as to patients’ inability to actively participate (both financially and physically) in prevention and treatment of chronic diseases. From the clinician’s perspective, setting the treatment priority from multiple competing chronic conditions for the patients is one of the most challenging tasks that clinicians face everyday. Secondly, as a physician/scientist, my research interest is focused on frailty in older adults. Frail older adults, with multiple chronic conditions and further impaired physiologic reserve, are particularly vulnerable to adverse clinical outcomes from acute illnesses as well as chronic diseases. The “microcompetition with foreign DNA” theory provides a provocative, yet potential, hypothetical mechanism that may contribute to the development of frailty, an important chronic condition in older adults. Managing frailty and it’s associated adverse clinical outcomes in older adults is indeed the heart and soul of geriatric medicine. As the population ages in this country and around the world, providing the best clinical care to frail older adults in a cost-effective manor is becoming the most pressing priority for the whole medical community.

BIOGRAPHY

Before he immigrated to the United States, Dr. Sean X. Leng obtained his MD at Jiangxi Medical College in Jiangxi Province and practiced in Allergy and Clinical Immunology at Peking Union Medical College Hospital in Beijing, the People’s Republic of China. He then obtained a PhD in Molecular Virology and Immunology at Texas A&M University followed by a two-year postdoctoral research fellowship in cytokine research at Yale University School of Medicine. Dr. Leng then came back to clinical training in Internal Medicine at St. Luke’s-Roosevelt Hospital Center, a Columbia University College of Physicians and Surgeons’ training program in New York City followed by a two-year clinical and research fellowship in Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine. Currently, Dr. Leng is an Assistant Professor of Medicine in the Division of Geriatric Medicine and Gerontology, Department of Medicine, the Johns Hopkins University School of Medicine. In addition to his clinical practice of geriatric medicine, his research at Hopkins has been focused on the frailty syndrome in older adults. Dr. Leng has had significant scientific findings on the role of inflammation, cytokines, and immune and endocrine dysregulations in the pathogenesis of frailty either published or in press in several prominent peer-reviewed journals in geriatric medicine and aging research, such as the Journal of the American Geriatric Society (JAGS 50:1268-1271, 2002), Journal of Gerontology Medical Sciences, Mechanisms of Aging and Development, and Aging Clinical and Experimental Research.

Tufts University School of Medicine

REVIEW

To be honest, it took me three attempts to read this book. The first attempt resulted in frustration and confusion. The unusual writing style, complex terminology, and volume of information was daunting. I put the book aside, but the seeds of curiosity had been planted, and intriguing ideas took root. They began to grow, and soon I was forced to return to my reading. My second attempt was far more productive but nevertheless challenging. I went through all seven chapters of technical notes. It was a slow process, not because of the numerous mathematical equations (which were straightforward and well-supported) but because I found myself repeatedly distracted by independent thoughts and ideas triggered by the content of the book. I would read a sentence or two and immediately attach my own observations to the proposed frame, and test the fit; I was amazed by the serendipities. My third attempt was joyous; the book served its purpose – it made me think differently! What had first seemed cumbersome technical notations became transparent when I connected them to the work I perform daily. I also realized that the area of my research interest – mathematical modeling of disease temporality – would benefit greatly by applying the fruitful ideas presented in Dr. Polansky’s book.

The general underpinning of this work is to outline a foundation for understanding mechanisms behind the origins of chronic diseases and provide a methodology for investigating complex biological systems. The foundation laid out is an elegant set of fundamental concepts and operational rules for their connection, which form a unique language of complex systems. By applying this language, Dr. Polansky’s theory of microcompetition and chronic disease initiation, progression and resolution, was delivered with amazing elegance and ease.

Understanding complex living systems is an enterprise that is interdisciplinary in its nature; to effectively communicate ideas, facts, and inferences, a common language is a must. Dr. Polansky’s work compellingly demonstrates a framework that could bring together researchers from different fields. His proposed theory will work its magic by clarifying ambiguous definitions, identifying similarities and differences in various biological processes, and discovering new pathways. 

I consider this book a guide for recognizing scientific puzzles, solving them, and collecting pieces for future ones. This book is a well-justified manual of fascinating algorithms for putting seemingly disconnected observations into a multi-dimensional framework for understanding chronic disease etiology. The content of the book is presented in an array of logical sequences of conceptual building blocks, corresponding models, anticipated outcomes, and collections of observations. While challenging to read initially, the book stimulates constructive thinking and teaches one to look for the unexpected while leaving room for creativity and imagination.

I believe that Dr. Polansky’s book will catalyze the scientific learning process, promote interdisciplinary cross-fertilization, stimulate development of treatment strategies and drug discovery, and leave the reader inspired.

Thank you for the opportunity to review Dr. Polansky’s book and provide commentary.

BIOGRAPHY

Dr. Elena N. Naumova, PhD, is an associate professor in the Department of Family Medicine and Community Health, Tufts University School of Medicine.  Educated in Novosibirsk, Russia, she continued her advanced studies at the Bauman Technical University in Moscow, focusing on design of expert systems in immunology. Her research emphasizes the creation and application of mathematical/statistical tools to understand disease temporality, and evaluate influences of intermediate events on spatial and temporal disease patterns. Her research interests include development of analytical tools for time series and longitudinal data analysis applied to disease surveillance, exposure assessment, and growth studies. Her research activities span a broad range of research programs in infectious disease, environmental epidemiology, immunology and developmental biology. Dr. Naumova is currently working on several large NIH-funded studies and teaches biostatistics and data visualization courses in the Graduate Programs in Public Health at Tufts University. 

Research Associate, Human Gene Therapy Center, University of Pittsburgh Medical Center

COMMENTS

Thanks for providing me the opportunity to benefit from Dr. Polansky’s excellent research, articulated brilliantly in his book, Microcompetition with Foreign DNA and the Origin of Chronic Disease. Permit me to describe the book as the pool of philosophically and mathematically credible theories of the origin of chronic diseases and cancer. It has provided the research community with many things to ponder, validate and implement in the future. As a young investigator, I found these theories stimulating and inspiring. Previous observation with people living with HIV treated and untreated with AZT and 3TC is consistent with the findings in this book. The aspect of GABP virus is very impressive and consistent with my understanding of chronic diseases. I have also found this book useful in my current effort to provide efficient platforms for delivery of therapeutic genes to target organs. Dr. Polansky’s book is an excellent companion for all clinical investigators as well as students of Physiology, Biochemistry, Pharmacology, Pathology and Alternative (Natural) Medicine. Please extend my congratulations to Dr. Polansky.

BIOGRAPHY

Dr. Edward Nwanegbo had his medical training at the University of Nigeria. As a research physician he conducted HIV Prospective studies, New Anti-malaria (LAPDAP) Pharmacokinectics studies, and Immunogenecity and Safety of Malaria vaccine trials for the Medical Research Council station in The Gambia West Africa. Dr. Nwanegbo is presently working on pre-existing immunity to adenoviral
vectors, adenoviral clinical gene therapy applications, and HIV and SARS vaccines.

Marc Pouliot, PhD

Associate Professor, Department of Anatomy and Physiology, Faculty of Medicine, Université Laval, Canada

REVIEW

Dr. Polansky’s book presents a theory by which viruses are held as causative agents of a number of chronic conditions including, obesity, cancer, apnea and autoimmune diseases, which appear otherwise unrelated.

Viruses use the infected cell’s resources to their advantage. Energy and resources (for example, transcription factors) are diverted in order to transcribe and translate the virus’s genes at the expense of the host. This has been known for a long time; however, Dr. Polansky goes one step further by suggesting that this diversion of cellular energy and resources causes a sufficient disequilibrium, responsible at least in part for the onset of a number of clinical chronic conditions.

Strong points:

First of all, I would like to congratulate the author for putting together such an impressive collection of data and most importantly, for being able to delineate functional links between distinct sets of data. This is a well-organized, highly rigorous presented theory. The concept of microcompetition will change our approach in the study of chronic diseases and will furthermore give scientists a higher level of understanding in biology. Presentation of this concept undoubtedly provides a new set of opportunities for attacking chronic diseases. The idea that viruses are the cause of chronic diseases is not new, but the  evidence put forward in this work, the molecular observations, analyses 
and conclusions certainly are. They lead the way to new approaches in chronic disease treatment.

In my opinion, this book could be of great use to fundamental researchers. Investigators of specific areas will find well-presented concepts which transform our way of thinking about chronic diseases, the implication of viruses in biology and health in general. This work will eventually also have an impact on medical research and drug discovery, although realistically not in the near future; these areas not being typical bearers of new ideas.

This is a very good theory, one that makes a lot of sense and one that helps a lot in terms of trying to identify possible causes for chronic diseases. Time will tell, but regardless of being proved right or wrong, this theory has the merit of changing our current way of thinking, and this is probably the greatest contribution a new theory can bring.

Personal suggestions:

The main idea put forward in this book is superb. In my opinion, this work might have served a higher number of people, for example students, if the concept of microcompetition had been presented in a more “casual” way. At times, I had the feeling of reading an extensive PhD thesis, with explanations and multiple references for almost every concept presented. While there is no doubt whatsoever that explanations are rigorous and well-documented, most of them were written in such a way that only the people who are already familiar with these concepts would understand. Usefulness of a book can sometimes be found in presenting a concept which initiated people understand and explaining that concept to the uninitiated. This book is more “from initiated to initiated.” This is not to say that the structure of the book is not good, far from it; it is a superb piece of work, just less open to masses than it could have been.

I hope these short comments may be of use. In finishing, thank you for the opportunity of reading this book. It was a great (and sometimes challenging) experience, which helped in crystallizing some of the ideas I had about viruses and their possible role in biology.

BIOGRAPHY

Dr. Marc Pouliot received his PhD in Cellular & Molecular Biology from Laval University in 1994, then did his postdoctoral training at the Royal Adelaide Hospital (Australia, 1994-1996), Laval University Hospital (Canada, 1996-1997) and Brigham & Women’s Hospital (Boston 1997-1999). He is currently an associate professor in the Centre de Recherche en Rhumatologie et Immunologie, affiliated with the Department of Anatomy-Physiology (Medicine), Laval University. In the past five years, Dr. Pouliot published 9 peer-reviewed papers, 29 abstracts and has given 13 presentations upon invitation.

Assistant Professor, Department of Biochemistry, University of Mississippi Medical Center

REVIEW

It was a pleasure to read and review the book, Microcompetition with Foreign DNA and the Origin of Chronic Disease by Hanan Polansky. In this book, Dr. Polansky presents the concept of microcompetition, a new biological mechanism on the origin of chronic diseases. The book covers a wide range of important topics, such as autoimmune disease, osteoarthritis, coronary artery disease,  stroke, cellular signaling, cell motility and cancer. The book is well-written and basic concepts are clearly presented. To support his theory, Dr. Polansky has included original data from the published articles and numerous examples.

The technical notes on cancer are especially interesting. In this chapter, Dr. Polansky clearly explains how a normal cell may react after acquiring any foreign DNA, such as viral DNA. He describes microcompetition, a new biological mechanism, and shows that disruption of this mechanism decreases cell differentiation and increases cell proliferation leading to cancer. That microcompetition with foreign DNA may be the prevalent cause of cancer is supported by frequent detection of viral genomes in human tumors. As one example which supports his theory, Dr. Polansky stated that the frequency observed decrease in Fas transcription in various cancer is consistent with the predicted effect of microcompetition with foreign DNA on Fas transcription and cancer. Other examples include progressive decrease in BRCA1 transcription, detection of protein free, the carcinogenic effect of epigenic carcinogens and replication defective viral genomes in many tumors. Therefore, microcompetition with foreign DNA may explain in a unique way, many otherwise unexplained observations reported in cancer literature.

In summary, Dr. Polansky’s book illustrates how microcompetition with foreign DNA may cause a variety of chronic diseases, and it will contribute to our deeper understanding of the origin and molecular mechanisms of chronic diseases.

BIOGRAPHY

Dr. Drazen Raucher received a B.S. in Mathematics and Physics in 1988 from the University of Osijeck, Osijeck, Croatia. In 1995, he received a PhD in Molecular Biophysics from the Institute of Molecular Biophysics at Florida State University. From 1995-99, he was a Postdoctoral Fellow in Cell Biology at Duke University in the Department of Cell Biology. Dr. Raucher was then awarded an Assistant Research Professor position in the Department of Cell Biology and eventually taught in the Department of Biomedical Engineering at Duke from 2000-01. Currently, he is an Assistant Professor in the Department of Biochemistry at the University of Mississippi Medical Center in Jackson, Mississippi, a position he has held since 2002. Dr. Raucher has published 13 peer-reviewed papers.

Professor and Chair of Virology, Institute for Virology, Johannes Gutenberg University, Germany

COMMENTS

I received the book and it was of interest for me to read of my group’s work in an unexpected context! I actually really like to see that our findings are useful for other scientists and contribute a piece to a unifying hypothesis on the origin of chronic disease. As specialists for cytomegalovirus immunology, even though cytomegalovirus causes chronic disease, we were unable to put our data into such a context. I must admit that I’m not a specialist for mathematical models and I’m far from understanding all parts of this book–Hanan Polansky must be a genius and time will show whether he will become the “Einstein” of the theory of chronic disease … I noted that our work was described correctly and precisely, which tells me that Dr. Polansky is really a bright scientist; I frequently find my work cited in papers by colleagues who have either not read a sentence of our work or who are unable to understand. So, congrats to Dr. Polansky.

BIOGRAPHY

Dr. Matthias Johannes Reddehase was trained in biology, chemistry, and physics at the University of Heidelberg, Germany. He then studied for a PhD with Professor Ulrich H. Koszinowski at the Federal Research Center for Virus Diseases of Animals in Tuebingen, Germany. After a position as a research associate at the University of Ulm, Germany, Dr. Reddehase was appointed in 1994 to a full professor and director of the Institute for Virology at the Medical Faculty of the Johannes Gutenberg-University, Mainz, Germany. Since the time he has joined Koszinowski’s group, his research has focused on pathogenesis, immune control, and latency of murine cytomegalovirus in the specific context of experimental bone marrow transplantation. Major recent contributions of his laboratory were to the immune control of cytomegalovirus pneumonia and to the identification of antigenic peptides that elicit a protective antiviral immune response.

Marion Covington Distinguished Chair, Chairman of the Department of Medicine, University of North Carolina

COMMENTS

This text formulates an interesting hypothesis, potentially linking a number of chronic diseases through a common mechanism. Dr. Polansky has brought together threads from a number of high profile, disease-specific areas of
investigation in a manner that is of interest to a broad group of scientists. The detailed consideration of topics ranging from cytokine activation to intracellular signaling to lipid metabolism is impressive. Although well written, the text is not for the timid or the novice. It will, however be very useful for scientists considering broad, comprehensive funding initiatives, and may be of interest to seminar groups studying disease origins. Overall, for scientists who can think “outside the box,” this is a fascinating series of thoughts on the origin of chronic diseases.

BIOGRAPHY

Marschall S. Runge, MD, PhD is the Marion Covington Distinguished Chair and Chairman of the Department of Medicine at the University of North Carolina. He obtained his PhD in Molecular Biology from Vanderbilt University and his MD from Johns Hopkins University. He completed his medical residency at the Johns Hopkins Hospital and his cardiology fellowship training at the Massachusetts General Hospital. At the MGH, Dr. Runge trained with Edgar Haber, beginning what was a long-term collaboration on the role of thrombosis in vascular biology. When Dr. Haber left to become President of Bristol-Myers Squibb, Dr. Runge joined the faculty at Emory University as an Associate Professor. There he became interested in reactive oxygen species and their role in vascular pathology and atherosclerosis. He was recruited from Emory to the University of Texas Medical Branch in Galveston as Chief of Cardiology and Director of the Sealy Center for Molecular Cardiology. Then he was recruited by UNC in 2000. Dr. Runge has been continuously funded by the NHLBI since his fellowship at the MGH. He served as a member of the Experimental Cardiovascular Sciences Study Section of the NIH for five years, the last year (2002-2003) as Chair of the Study Section. He has published over 150 peer-reviewed manuscripts in the areas described above and is a renowned leader in vascular biology. He is also an editor of two clinical texts: Netter’s Internal Medicine and Netter’s Cardiology (to be published in 2004) and two upcoming basic science texts: the Principles of Molecular Cardiology and the Principles of Molecular Medicine (Second Edition).

Professor Emeritus, Department of Pathology, School of Medicine, Oregon Health and Science University

REVIEW

Polansky presents a fascinating perspective on disease as a consequence of our interactions with other species. This work clarifies our perspective on such interactions. For instance, until now, we have mostly, if not virtually entirely, considered the diseases resulting from such interactions as being a consequence of the xeno-species’ phenotypic properties – whether these be talon or toxin. It is a natural and logical step, in the molecular paradigm, to assume there are underlying genomic elements controlling these pathogenic phenotypic properties. To some extent, we have come to some understanding along those lines, though most of such understanding explicates in terms of non-genomic molecules.

Now comes Polansky who proposes that, in addition to pathogenic phenotypic and molecular interactions, we must consider genotypic interactions. At least, genotypic in the sense of DNA, various types of RNA, as well as the more proximate molecules. Further, the interaction is genotype to genotype and does not involve either our or the xeno-phenotype, at least initially.

In fact, the author’s precepts more or less define chronic disease as being the result of genotype-to-genotype interactions. By inference and deduction, the author at the same time at least implies that acute and subacute disease is more often the result of phenotype-to-phenotype interactions. I generalize, of course, but do so to place into perspective the new disease paradigm proposed.

… My suspicion is that the author “has it right.” Now, to convince the skeptics, enter the minds of the thinkers, and make aware the student. Probably any one book cannot do all of this and, probably, each audience will require focused attention and specialized presentation.

… I believe that all biomedical researchers in virtually all endeavors would benefit from reading the book. In addition, the concepts need to be integrated into the medical curriculum, as well as studies for biomedical research students.

BIOGRAPHY

Dr. Waldemar A. Schmidt received both his medical degree and doctorate from the University of Oregon Medical School in Portland in 1969. Afterwards, he completed his residency training in Anatomic Pathology from Oregon Health & Science University. Dr. Schmidt’s special areas of interest are cytopathology and Ob/Gyn pathology, and he is board certified in Anatomic Pathology and Cytopathology. He is currently Professor Emeritus of Pathology at OHSU and heads the Cascadia Placenta Registry.

Senior Staff Scientist, Lee Hartwell’s Laboratory, Fred Hutchinson Cancer Research Center

REVIEW

Hanan Polansky’s book challenges the current views of chronic disease and
commands respect for its daring originality. To comprehend this document, a broad spectrum of scientific skills is required, since mathematical tools are extensively used to interpret a wide range of published data in light of the microcompetition paradigm. Reading Hanan Polansky’s book stirs multiple concepts and brings up all the excitement that good science can offer: unmapped thought patterns, puzzling questions, aching doubts and glints of light at the end of a dark corridor.

Hanan Polansky’s book also underscores paradigms as filters for perception. Although the amount of cited literature is impressive and probably sufficient to make a point toward the validity of the microcompetition concept, the author processed through his own mental strainer, data generated by others. During this handling surfaced perilous stretches or simplifications of concepts and physiological mechanisms, as for example in immunology. I feel that the author’s new theory would have gained strength by acknowledging data for which microcompetition could not be demonstrated. In conclusion, I would recommend the reading of this book to scientists wanting to challenge themselves and to take a peek out-of-the-box.

BIOGRAPHY

Dr. Nathalie Scholler received a PhD in Immunology with High Honors in 1995 from Peter S. Linsley’s laboratory at Bristol Myers Squibb P.R.I. in Seattle, Washington. From 1995-1997, she completed a Postdoctoral Fellowship in the same laboratory. Afterwards, from 1997-2001, she worked as a Staff Research Scientist in the laboratory of Ingegerd Hellstrom in the Tumor Immunology Department of the Pacific Northwest Research Institute in Seattle. Dr. Scholler then worked as a Senior Research Scientist in the Biochemistry Department of Seattle Genetics Inc. in Bothell, Washington from 2002-2003. She is currently a Senior Staff Scientist in the laboratory of Lee Hartwell (Nobel Laureate in Medicine 2001) at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Scholler’s primary research interests are investigating the immune response to cancer and developing diagnostic tests for cancer’s early detection. Dr. Scholler is a member of the American Society of Gene Therapy, the American Association for the Advancement of Science, and the American Association of Immunologists.

Assistant Professor, Emeritus, Department of Anesthesiology, College of Medicine, University of Kentucky

COMMENTS

While reading the book I concluded that Dr. Polansky has presented an interesting and potentially useful theory for predicting the origin of a variety of chronic diseases. This book, however, is not an easy read without background material. Having said that, I think the book is intriguing, convincing and supported by evidence. I think others have had somewhat similar ideas concerning other disease states but not with regard to microcompetition with foreign DNA (cf Martin, William R. Ass. Res. Nerv. Ment. Dis. 46:206-225, 1968). I think the book could prove useful in generating ideas for experimental approaches in the area of both acute and chronic pain and will probably stimulate a different approach to research in many chronic diseases.

I don’t think the book would be suitable for a medical textbook but will be useful to professors in preparing lectures and as adjunct reading for some graduate students, Postdocs, and researchers in drug discovery and medical research. For sure, I will continue to study this book and to share it with my colleagues.

BIOGRAPHY

Dr. Jewell W. Sloan received a B.S. in Anatomy & Physiology and a PhD in Pharmacology, both from the University of Kentucky. She spent many years in research with the NIMH in the area of the pharmacodynamics of drug abuse (mainly opioids) and later with the NIDA Addiction Research Center in Lexington, Kentucky under the Directorship of Harris Isbell, MD, and later William R. Martin, MD. When the Addiction Research Center moved to Baltimore, Dr. Sloan elected to stay in Lexington and retired as a Supervisory Research Chemist. She then joined the Department of Pharmacology (William R. Martin, MD, Chair) at the University of Kentucky, obtained a PhD, and received a faculty appointment as an Assistant Professor. She later joined the University of Kentucky’s Department of Anesthesiology where she served as Director of Research for seven years before retiring and obtaining an Emeritus appointment two years ago. Dr. Sloan’s research at the University of Kentucky continued in the area of drug abuse, focusing on nicotine and the dependency producing properties of the sedative hypnotics (mainly benzodiazepines) and studies of drugs and drug combinations useful in the treatment of acute and chronic pain in male and female subjects. Dr. Sloan has over 80 publications in peer reviewed journals and book chapters where she is the author or co-author and over 85 abstracts.

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.

Assistant Professor, Department of Physiology, University of Texas Southwestern Medical School

COMMENTS

Although the book is rather technically difficult due to the large number of mathematical equations it puts forth to substantiate the theory of microcompetition, it is a very thought-provoking read. It gives one an opportunity to think about the relationship between the workings of many biological systems and perhaps the underlying cause of some pathophysiologies. Rather than draw conclusions for the reader, it allows one to draw our own conclusions based on the parts one chooses to accept based on the evidence provided. I found the chapters on autoimmune disease and obesity to be two of the most compelling due to their thoroughness and clarity. Finally, since you specifically asked about my feedback regarding how my work was cited, it was done in an accurate manner.

BIOGRAPHY

Dr. Tansey arrived at U.T. Southwestern after working in the biotech industry in California where she led a multi-disciplinary team of scientists in developing biochemical and cell-based assays to screen computationally designed protein variants for biotherapeutic applications. She conducted postdoctoral studies at U.T. Southwestern and Washington University of St. Louis. At Washington, she was a major contributor to several projects involving GFL action and signal transduction pathways. As a postdoctoral fellow, she has been published in distinguished peer-reviewed journals such as Journal of Neuroscience, Neuron, Journal of Biological Chemistry, and Journal of Cell Biology. Currently, the focus of her laboratory is to investigate the cellular and biochemical mechanisms that regulate RET signal propagation and termination and how alterations in these lead to compromised neuronal survival or transformation.

Associate Professor, Vice-Chairman for Education, Department of Pharmacology, Ohio State University

COMMENTS

Who would benefit from reading the book? I believe that advanced graduate students in biochemistry or molecular biology may be benefited by reading this book especially if they use some of these chapters for having a debate during the Journal Club. The book also provides good topics for the PhD thesis of more than a dozen students in Theoretical Biology!

BIOGRAPHY

Gopi A. Tejwani received his PhD degree in Biochemistry from the All-India Institute of Medical Sciences, in New Delhi, in 1973 and subsequently traveled to the United States for postdoctoral training under B.L. Horecker at the Roche Institute of Molecular Biology, Nutley, New Jersey. Dr. Tejwani has been on the faculty of The Ohio State University in Columbus, Ohio since 1978, where he does research in neuropharmacology and teaches graduate and medical students. Dr. Tejwani has published more than 80 original research papers in biochemistry, enzymology and neuropharmacology. He has presented his research work at international meetings in more than twenty countries. At present, Dr. Tejwani is an Associate Professor and Vice-Chairman for Education in the Department of Pharmacology at the College of Medicine and Public Health at Ohio State. In his free time, Dr. Tejwani collects and shares family jokes. He has recently published two joke books, Party Jokes and Jokes for Friends. He can be contacted via email at <tejwani.1@osu.edu>.

Assistant Professor, Department of Microbiology and Immunology, University of Texas Medical Branch

REVIEW

Author Hanan Polansky has added an excellent book that bridges the gap between a number of chronic diseases (traditionally believed to be unrelated), with a theory that elucidates the common mechanism underlying their origin. Microcompetition with Foreign DNA and the Origin of Chronic Disease was not quite as accessible as some other books that I have read, but it is certainly worth the extra effort even if much of the evidence found in the book requires additional reading from other bibliographic sources.

The text is very well-organized. The book spent a great deal of time on a series of technical notes that help the reader understand the basis of the theory. Even though this book is packed with mathematical equations, figures and graphs, the author clearly described their use throughout a series of biologically relevant situations. These technical notes are followed by a series of individual chapters dealing with a number of chronic diseases ranging from atherosclerosis, autoimmune disease, cancer, osteoarthritis, and obesity, where it’s presented very clearly how microcompetition with foreign DNA causes these chronic diseases. Excellent diagrams enable the reader to understand complicated concepts. Dr. Polansky includes a long list of references, which provide support for the theory described.

The writer takes you through the basic knowledge of each chronic disease and the series of observations reported by multiple researchers in each particular field. Along the way, Dr. Polansky details the theory of microcompetition with foreign DNA, which tries to explain the fundamentals of these human diseases. Furthermore, a series of simple methods of treatment are described that are likely to be effective.

As I said, this particular work requires more effort than others I have read, and the enjoyment or aversion you have to math will play a role in how much pleasure this read will bring. However, even if the formulas leave you cold, the potential to explain the regulation of many genes and therefore the molecular basis of a wide range of important human diseases, are guaranteed to fascinate.

BIOGRAPHY

Alfredo G. Torres, PhD is an assistant Professor in the Department of Microbiology and Immunology and Department of Pathology at the University of Texas Medical Branch. He was trained in the laboratories of Dr. Shelley Payne (UT Austin) and Dr. Jim Kaper (University of Maryland) where he became interested in pathogenic Escherichia coli. The main goal in Dr. Torres’ laboratory is to understand the global mechanisms of colonization by E. coli O157:H7 and related pathogens during infection of the human intestine and determine the role that E. coli is playing in the development of inflammatory bowel disease.

Lab Manager/Associate Scientist, Schepens Eye Research Institute (Harvard Medical Center Affiliate)

REVIEW

Dr. Hanan Polansky’s, Microcompetition with Foreign DNA and the Origin of Chronic Disease is a fascinating work. The book presents a unifying theory that identifies the origin of several chronic diseases such as atherosclerosis, stroke, cancer, obesity, diabetes, multiple sclerosis, lupus, thyroiditis, osteoarthritis, rheumatoid arthritis, and alopecia. The author builds the theory on 1224 cited publications: empirical papers written by over 5000 researchers working on the fields of wide varieties of chronic diseases. From the huge amount of scientific observations, Dr. Polansky draws a very challenging conclusion. The book is well-researched and well-written, in spite of the numerous mathematical models and lack of background information that would increase the volume of the book significantly. Therefore, one has to have relatively solid knowledge in related fields to fully appreciate the work.

The theory is unique and inspires us to look at scientific data from a completely different prospective. I liked the chapter about obesity (a very serious problem in the USA) best. The microcompetition model of obesity provides a revolutionary and novel explanation of previously unexplained observations reported in the literature. These include decreased expression of hormone sensitive lipase, hypertrophy, and hyperplasia of adyposites, catecholamine resistance, insulin resistance, leptine resistance, hyperinsulinemia, hyperletinemia, the high level of serum zink and copper, and the high level of serum estradiol in obesity, and the effectiveness of IL-1beta and TNFalpha and LPS in attenuating symptoms of obesity in animal models and in humans.

I read the book in different intervals. There were chapters that I returned to and sections (mostly mathematical models) that I did not follow in-depth. In summary, this is an intellectually challenging book that I warmly recommend to medical and graduate students. It could also profoundly affect the biotech and pharmaceutical industry focusing on rational drug design efforts.

I was honored to be one of the reviewers of Dr. Polansky’s book, Microcompetition with Foreign DNA and the Origin of Chronic Disease. This is an extremely challenging and stimulating book to read and accept. I want to congratulate Dr. Polansky for his novel work that deepens our understanding of the origin of chronic diseases.

BIOGRAPHY

Ildiko Toth, PhD is a Lab Manager/Associate Scientist at Schepens Eye Research Institute in Boston. She graduated from Attila Jozsef University in Szeged, Hungary as a Biology major and received her PhD in Biochemistry, studying membrane-bound enzymes. She was a Postdoctoral Fellow of Genetics & Molecular Biology at Harvard University in Boston, where she identified a novel enzyme complex and studied the regulation of the corresponding genes. After completing her training, she joined BioTechnica International, Inc., an agricultural biotech company in Cambridge, where she initiated a new project to transform crops using particle gun and DNA imbibition methods that resulted in patents. After BioTechnica International, Inc. ceased to exist, she continued her research at Tufts School of Medicine, then at Harvard Medical School in Boston. Dr. Toth studied the effect of vitamin C, hypoxia and gallium on cellular iron homeostasis and worked out several cell model systems to study Cideroblastic anemia, bladder cancer using erythroleukemia, hepatoma and different cancer cell lines. She has several publications in EMBO Journal and the Journal of Biological Chemistry, book chapters, patents, and laboratory manuals. She has been an invited speaker at national and international meetings and has organized several events.

Professor, Department of Radiology, Feinberg School of Medicine, Northwestern University

REVIEW

Dr. Polansky’s book Microcompetition with Foreign DNA and the Origin of Chronic Disease is actually a long scientific paper that explains and justifies his theory of microcompetition with foreign DNA as the origin of multiple different chronic diseases including cancer, arthritis, obesity, atherosclerosis, and others.  The book is based in the concept that exogenous DNAs compete with normal cellular DNA for limiting transcription factors and thus influence the transcription rate of essential genes; when this occurs over a prolonged period of time, disease results. The concept is established, not through independent new studies but rather through a vast review of the literature covering over 1200 references in diverse fields of science including cancer biology, atherosclerosis, immunology, molecular biology, and others. While evidence for this concept is certainly found in much of the literature in single examples and through transgenic animal and transfection studies, there has been no unifying presentation of the microcompetition model as relating to such a large range of human diseases. 

In general, this volume provides a deep analysis of particular data supporting microcompetition for DNA sequences requiring GA-rich binding proteins for transcription. Some models relating to cell mobility, trucking models for LDL clearance, and other mechanisms are also presented, but these are important only insofar as they provide a background for supporting the microcompetition model. Nevertheless, the presentation of these other models was somewhat confusing, and it was difficult to discern whether acceptance of those models was actually essential for the microcompetition work. Regardless of the concerns, this provided interesting reading and certainly the suggested mechanisms warrant further consideration.

The DNA microcompetition model, which is the major focus of the work, is well-presented and argued in the volume. The analysis presented in this volume involves an in-depth focus on specific experiments that have been extensively examined and even re-drawn and re-calculated in an effort to establish the relationship between the literature and the DNA microcompetition model. It is clear from the presentation that the model is well-supported in the literature and fits naturally into existing molecular data. What was difficult to discern from the volume is whether Dr. Polansky actually believes that GA-rich binding proteins are the most important transcription factors for this microcompetition as a cause of disease, or whether other transcription factors are also important, making this a combinatorial process with a higher level of complexity than that actually presented in the volume itself.

This treatise is also interesting as a novel form of scientific theory presentation that may become more important in an age when the literature is so overwhelming that most investigators focus more on abstracts than on the meat of papers. This type of exploration of a theory based on the literature in an effort to provide unifying models could provide a new approach to biomedical questions that has not really been done well to date.

The book was written as a scientific paper, which made constant concentration an essential ingredient for understanding the work. This was on the one hand exhausting, and on the other hand satisfying and challenging. Dr. Polansky is to be commended for this volume, with its ideas and approach that are likely to influence the biomedical community for years to come.

BIOGRAPHY

Dr. Gayle E. Woloschak received a B.S. in Biological Sciences from Youngstown State University, Youngstown, OH in 1976 and a PhD in Microbiology from the Medical College of Ohio, Toledo, OH. From 1980-1983, she worked as a Postdoctoral Research Fellow in Immunology and Molecular Biology at the Mayo Clinic in Rochester, MN. During the mid-eighties, Dr. Woloschak worked as an Associate Consultant and Assistant Professor in the Department of Immunology and Department of Biochemistry and Molecular Biology at the Mayo Clinic/Mayo Graduate School of Medicine. From 1987-1992, Gayle worked as an Assistant Molecular Biologist at the Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, Argonne, IL. From 1992-2001, she was promoted to Molecular Biologist, Group Leader, Biosciences Division, Argonne National Laboratory. Dr. Woloschak has been a Member of the NIH Radiation Study Section, the U.S. Army Prostate Cancer Study Section, and the DOE study section for Low Dose Radiation proposals. From 2000-2003, she was the Vice-Chairman for the American Cancer Society-Illinois Research Committee. Currently, Dr. Woloschak is a Member, Microarry Core Facility Oversight Committee, University of Chicago; Senior Molecular Biologist, Bioscience Division, Argonne National Laboratory; Senior Fellow, Nanosciences Consortium, Argonne National Laboratory-University of Chicago; and Member, NCI Program Project Review Subcommittee D. Dr. Woloschak is currently a full Professor in the Department of Radiology, The Feinberg School of Medicine, Northwestern University. She has contributed to 102 peer-reviewed publications.

MORE REVIEWS

Professor, Department of Pharmacology, Baylor College of Medicine

REVIEW

This book provides an expansive review of a prodigious amount of published scientific data and results, but from a unifying perspective that puts forth the hypothesis that many chronic conditions and diseases are caused by a molecular imbalance introduced by foreign DNA, which is introduced by viruses.

While the role of viruses in infectious disease and their causative role in the development of cancer are not new ideas, the shift in emphasis for causation from viral protein to viral DNA represents a different view. The predictions made, the mathematical rigor provided for the models proposed and the proposed role that viruses may play in bringing about a range of subclinical chronic health problems is most fascinating.

Whether Polansky has truly achieved the goal he set for himself, i.e., to apply the scientific method to a host of biological findings in a manner similar to that achieved by Watson and Crick, remains to be answered by others. It is not known whether time will tell us that microcompetition is an equivalent in theoretical construction to the structure proposed for DNA.

Clearly, this is not a “light read” and will tax the concentration and stamina of even the most gifted scientific minds. I believe that reading, studying and discussing the hypotheses and predictions that Polansky has put forth are useful exercises, much like practicing the Hanon musical exercises can be useful for an aspiring pianist.

The value of Polansky’s thinking and his reorganization of others’ work truly must be tested in the laboratory. While I personally found some of the examples provided in the chapter on treatment to fall short of my expectations, the value of the hypotheses and predictions put forth may have more immediate value. For example, they could be integrated into the world of bioinformatics as it is currently being applied to drug design and drug discovery.

In summary, Polansky challenges the reader to examine and reexamine the results provided in a wide variety of scientific reports that have been published by chemists, biochemists, biologists, cell biologists, molecular biologists, geneticists and physicians. If he achieves this goal, then he has probably met his mark.

BIOGRAPHY

Dr. Lynn C. Yeoman took his baccalaureate training in chemistry at DePauw University and received his doctorate in biochemistry from the University of Illinois at Urbana-Champaign. After completing a postdoctoral fellowship in Cancer Biology at Baylor College of Medicine, Dr. Yeoman joined the faculty and subsequently rose to the rank of Full Professor. During his career as a research scientist and educator, Dr. Yeoman has authored 167 publications, invited papers, review articles and book chapters. He served as Associate Director for Cell and Molecular Biology in the Oncology Drug Discovery Program at Bristol-Myers Squibb Co. in Wallingford, Connecticut. A Faculty Associate in Baylor’s Huffington Center on Aging since 1995, he is also a Professor of Pharmacology and Medicine. In addition, Dr. Yeoman is the Director of the College’s Integrated Problem Solving (Problem-Based Learning) course, the Curriculum Database Program and also serves as Executive Director of the College’s Education Resource Center. Dr. Yeoman currently serves as Chairman of the CATCHUM Project’s Problem-Based Learning Task Force, a National Cancer Institute funded program in cancer prevention education at the University of Texas Medical Branch, Galveston. He also serves as Chairman of the United States Pharmacopeia’s Committee of Experts on Biotechnology and Natural Therapeutics and is a member of the Complex Actives Division Executive Committee. Dr. Yeoman is a member of the Center for Clinical Pharmacology planning team; a founding member of the Board of the Clinical Pharmacology Consortium of the Texas Medical Center; and a member of the Board of Advisors of ProteEx, Inc., a proteomics biotechnology corporation located in The Woodlands, Texas. He is listed in numerous biographical publications, including Who’s Who in the World, and recently received both the 2003 Distinguished Faculty Award from the Baylor Medical Alumni Association and the 2003 Fulbright & Jaworski L.L.P. Faculty Excellence Award for Educational Research from Baylor College of Medicine.

Section Head, Cellular and Molecular Immunology Section, Laboratory of Experimental Immunology, National Cancer Institute, NIH

REVIEW

Dr. Hanan Polansky has taken theoretical biology to a new level with his book, Microcompetition with Foreign DNA and the Origin of Chronic Disease. In this book, Dr. Polansky develops his hypothesis that through the introduction of foreign DNA into cells via viruses, there is competition within the cell for specific transcription factors. This competition significantly alters gene expression, especially of the Tissue Factor gene, resulting in the triggering of many chronic diseases, including cancer. The hypothesis is of significant interest and will not
be foreign to today’s molecular biologists, as most scientists that have performed transfection experiments in tissue culture realize that competition for transcription factors may occur when two or more plasmids are co-transfected.  Indeed, the rapidly growing use of interfering RNAs is in itself a form of microcompetition resulting in inhibition of specific targets. Thus the basic theory put forward by Dr. Polansky will have champions in the experimental biology community. Throughout the book, Dr. Polansky does a good job of demonstrating how existing data supports his theories. In the chapter on cancer, I found particularly interesting, Dr. Polansky’s explanation that data obtained in transfection experiments with “empty” vectors in comparison to non-transfected cells, showing higher growth rates and tumor volumes, is due to the microcompetition from foreign DNA (i.e. the empty vector) through sequestering of p300 and resulting in decreased transcription of the Rb gene.

While the idea of microcompetition with foreign DNA as an explanation for all chronic diseases is intriguing, it does not address all aspects of chronic disease (e.g. why some diseases are more prevalent in females) and may be overly reductionistic in nature. Nevertheless, Dr. Polansky presents his theories in a manner that provides bench scientists with ways to test his theories experimentally, and this book will be thought-provoking for all those who read it. However, the book itself is not an “easy” read and probably is best-suited for an advanced graduate level course. Chapters need to be read a number of times for more thorough appreciation of the theories and the inclusion of numerous biological ‘equations’ tends to make it a bit hard to sometimes grasp the bigger picture. The book could be improved by having more simplified pathways in the beginning of each chapter to better illustrate the major hypotheses being presented.

In summary, Dr. Polansky is to be applauded for his attempt to provide a unifying basis for chronic diseases. His theories are stimulating and offer a basis for experimental testing and possible treatment. It is worth the time for the experimental biologists to consider his ideas by reading this book and determine if the theories presented will hold up to carefully designed laboratory experiments.

BIOGRAPHY

Howard A. Young received a B.S. in Microbiology from the University of
Massachusetts and his PhD from the Department of Microbiology, University
of Washington. He joined the National Cancer Institute in 1983 as a Cancer
Expert in the Laboratory of Molecular Immunoregulation and in 1989 became
Head, Cellular and Molecular Immunology Section, Laboratory of Experimental
Immunology. He is the President-elect of the International Society of Interferon and Cytokine Research (term 2004-2005) and is a member of the American Association of Immunologists, the American Association for the Advancement of Science, the American Society for Biochemistry and Molecular Biology, the American Society for Microbiology and the DNA Methylation Society. He has received an NIH Merit Award for his efforts in support of the Werner Kirsten Student Intern Program, the NCI Quality of Worklife Award (1999) and the NIH Director’s Award for Mentoring (2000). He has chaired the NIH Cytokine Interest Group, the NCI-Frederick-Ft. Detrick Spring Research Festival and the Immunology Division of the American Society for Microbiology (1997-1998) and currently co-chairs the NIH Immunology Interest Group. His research focuses on the regulation of gene expression in the immune system with a special emphasis on Natural Killer cells.

linical Professor of Medicine, Indiana University School of Medicine

REVIEW

This is a remarkable work. A process for the genesis of chronic diseases, whose etiologies are very poorly understood, is postulated and substantiated with evidence from the biological literature (from microcellular events to their phenotypic expression). The author creates the forest from the trees and presents us with a picture of a cohesive, unique, biologically plausible phenomenon, which may be the root cause of many of the afflictions of humankind.

A detailed quantitative biophysical model of biochemical competition, cell motility and cell signaling is presented as the framework within which the processes of disease pathogenesis are described. Evidence from human and animal studies is then used as examples of the various stages within this process of disease development.

The unique feature of this work is that the author presents a testable model for his hypothesis. Although ample supporting literature is provided to substantiate his ideas, further, directed research which tests the microcompetition phenomenon can now be performed. An understanding of this process at the subcellular level can then provide the impetus to develop highly targeted drug therapies aimed at reversing the respective microcellular events leading to phenotypic disease.

This work will undoubtedly stimulate new thinking and generate new insights and new classes of drug therapies can be developed. It is useful as a graduate text in an advanced biological sciences or biophysical sciences curriculum. The mathematical models presented could potentially be “computerized” to generate a “working digital model” of the physiology. These models could then be verified by comparison with empirical data from real experiments and tweaked as necessary.

I was particularly intrigued by the sections on atherosclerosis and autoimmune disease, which helps to fuel my own suspicions that many of the common rheumatologic and autoimmune diseases are actually chronic viral or prion infections from as yet undetected agents.

BIOGRAPHY

Dr. Atif Zafar holds a Bachelor of Science degree in Biological Sciences and Mathematics from the State University of New York at Buffalo and completed medical school in 1994 at the same institution. He trained in Internal Medicine at the University of Cincinnati from 1994 to 1997. He then completed a fellowship in Medical Informatics at the Regenstrief Institute for Health Care in Indianapolis, IN. He is a Board Certified Internist currently in practice at the Indiana University Medical Center and is the Information Technology Director of a national Primary Care research support group funded by a subsidiary of Health and Human Services called the Agency for Healthcare Research Quality. His research interests include electronic capture of patient-physician encounter data, improvement of medical errors and patient safety through information technology and electronic medical education. His clinical research involves novel treatment approaches to sepsis syndromes, including HELLP, early Gram Negative septicemia and multi-organ failure states. He is also involved with research aimed at addressing the epidemic of HIV and AIDS in the rural West African state of Kenya, where he is applying information technology strategies to assist physicians with the care of HIV-infected patients by providing point-of-care guidelines, results and advice. He was the 2001 recipient of the prestigious George W. Thorn Award from the University at Buffalo, given to a graduate under 40 who has made important national and international contributions in his or her field. Dr. Zafar makes his home in Carmel, Indiana.

Research Associate, Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill

REVIEW

I have to admit it is not an easy book to read. But I found it to be immensely rewarding and thought-provoking. I thank you for giving me the opportunity to be among the first group of people who get their hands on this novel book.

Dr. Polansky in the book proposed an intriguing theory that competition for limited transcription factors between the host transcription units and those of foreign origin e.g., viruses, is the underlying cause for a number of chronic diseases, such as cancer, obesity, autoimmune disease, etc. The proposed theories are well-reasoned and abundantly supported by experimental data. It helps to explain many dilemmas encountered during clinical studies. I found that the theory is groundbreaking and will likely open doors to many exciting research areas and treatment options.

Compared to physical or chemical sciences, biology and medicine lag behind and remain experimental disciplines, which are heavy on experimental data but thin on applicable theories that could guide future directions. In this sense, Dr. Polansky’s book is nothing short of revolutionary. It makes people stand back from their daily experiments, and start to look at the whole picture, and to view biology as an interacting and interconnected system. On the other hand, the book may be a step ahead of itself, meaning the field is not yet mature enough to embrace these mathematical theories proposed in the book.

I work in the field of gene therapy, in which up to now, the most efficient gene delivery vehicles have been of viral origin, with retrovirus and adenovirus-based vectors being the most dominant players. In the minds of people concerned about the safety of these approaches, insertional mutagenesis into the host genome by retroviruses and acute immune reactions to adenoviruses rank on the top of the list. I have yet seen anyone in the field who realizes that the introduced foreign DNA associated with the delivery vector may have a profound impact on human health through microcompetition for host transcriptional factors. The major impact of this book on many specialties including gene therapy will be felt strongly in the coming years.

If I have to point out the shortcomings of the book, I do feel that the author bet too much on the N-box/GABP system, since we know that transcriptional controls of human genes are far more complicated and our understanding far from complete. Also, the author could have spent a few more pages on treatment sections of chronic diseases.

Thanks again for giving me the opportunity to review the book.

BIOGRAPHY

Dr. Liqun Zhang received her undergraduate degree in 1991 from Tsinghua University, Beijing, China, studying in the Department of Biological Sciences and Biotechnology. From 1991-1997 she studied at the University of Maryland at Baltimore, School of Medicine, Division of Human Genetics. Here, she earned a PhD for studying the molecular characterization of mouse thromboxane synthase gene under Dr. Rong-Fong Shen. From 1997-2002, Dr. Zhang completed a postdoctoral fellowship at the University of North Carolina at Chapel Hill at the Cystic Fibrosis/Pulmonary Research and Treatment Center under Richard C. Boucher, MD. She is currently a Research Associate at the same center. Dr. Zhang is a member of the American Society of Microbiology and has contributed to five peer-reviewed journal articles, 11 abstracts, one book chapter, and one patent.