Book Review

Handbook of Gene Level Diagnostics in Clinical Practice

N Engl J Med 1993; 329:586-587August 19, 1993

Article

Handbook of Gene Level Diagnostics in Clinical Practice
By Victor A. Bernstam. 695 pp. Boca Raton, Fla., CRC Press, 1992. $99.50. ISBN: 0-8493-6824-3

This remarkable book can be seen as heralding the coming of age of the “first wave” of the new era of molecular medicine -- DNA-based diagnostics (the imminent second wave being gene therapy). Forty years after the elucidation of the double helical structure of DNA by Watson and Crick, their aesthetically beautiful molecule is now finding a place as an accepted analyte (and reagent) in clinical laboratories. This new-found power to uncover diagnoses at the molecular level, even before the appearance of symptoms or before birth, promises to revolutionize the practice of medicine. Yet at present the discipline is considered arcane, practiced by a small and heterogeneous group of molecular biologists, pathologists, geneticists, oncologists, and microbiologists. Although rapid advances in molecular diagnostics are reported in an array of journals, there has been a conspicuous dearth of practical, comprehensive handbooks equally accessible to the laboratorians who perform these tests and the clinicians who order them.

The present work fills that gap to an extent one would not have thought possible. Indeed, the designation “handbook” is too modest; except that the entries are not alphabetized, it can really be considered an encyclopedia, the first in this important discipline. Even a partial listing of the topics and applications covered would consume far more space than is available here. Suffice it to say that almost every relevant tumor, genetic disease, and infectious agent of contemporary clinical interest -- and for which there is any applied molecular or genetic information -- is included. Dr. Victor A. Bernstam has made a superhuman effort to distill the key facts from thousands of research papers to compile summary information on the clinical applications of these discoveries. One would have thought it nearly impossible for a single writer to have such a broad command of the literature in so many unrelated fields of medicine and molecular biology. Yet in this era of multiauthored works, Bernstam's sole authorship imparts a satisfying consistency of style to the text, with minimal redundancy between chapters even when the topics overlap. The book is not a laboratory manual, but the thorough references guide the interested reader to the relevant original article or vendor source. The highlighting of key terms and phrases in boldface is helpful and prevents the densely packed pages from becoming dull expanses of gray.

The book begins with a detailed review of the many diagnostic techniques that employ nucleic acid hybridization, their respective power and pitfalls, and considerations of quality assurance relevant to each. Even such recent innovations as quantitative polymerase chain reaction, ligase chain reaction, RNA amplification by 3SR and Qbeta replicase, in situ hybridization, and single-strand-conformation polymorphism are incorporated (Figure 1Figure 1Molecular Diagnosis of Cytomegalovirus (CMV) by in Situ Hybridization.). Also included throughout the text are references to ancillary techniques, such as flow cytometry, cytogenetics, and immunochemical assays, driving home the lesson that clinical molecular biologic tests are never performed in a vacuum but must always be evaluated with all other clinical and laboratory data available on the patient. In addition there are discussions of sequence-tagged sites and other strategies relevant to the Human Genome Project, which will be the source of tomorrow's diagnostic probes. Bernstam then proceeds into the myriad clinical applications, with chapters organized generally around an organ-systems approach. At first this may seem strange, since so many of the topics involve multisystem diseases, but in an age when cancer is coming to be thought of as a genetic disease and DNA fingerprinting is being applied to microorganisms, it would be just as problematic to try to divide the book according to clinical disciplines.

Considering how rapidly this field is advancing -- even during the brief time it has taken to write this review, the discoveries of three new genes of profound diagnostic importance were announced (amyotrophic lateral sclerosis, Huntington's disease, and inherited colon cancer) -- the book is about as up to date as anyone could reasonably expect. Most of the references date from 1989-1991, with a fair number from as late as 1992. Nor is the book merely an uncritical, robotic cataloguing of citations. The exposition of such topics as DNA fingerprinting and tumor-suppressor genes is lengthy and well reasoned, whereas current controversies about the clinical usefulness of human papillomavirus subtyping in cervical dysplasia, amplification studies of the HER-2/neu oncogene in breast cancer, and the population-based screening of carriers for mutations of the cystic fibrosis gene are laid out in detail and without bias.

Obviously, though, no hardcover book can remain entirely timely for long in so fast-moving a field. With even the Food and Drug Administration lagging in its evaluation of DNA-based testing products, it will probably fall to the respective professional societies to monitor the clinical implications of emerging molecular tests. The newly incorporated American College of Medical Genetics has already expressed a determination to do this for the inherited disorders, whereas the College of American Pathologists and the American Association of Blood Banks, among others, have standing committees overseeing the applications of interest to them (molecular oncology, molecular microbiology, identity testing, and the like). Bernstam's book, essentially a snapshot of what is current in DNA diagnostics in 1992, provides a firm foundation for their continuing work.

Like other books from this publisher, this one has a rather steep price, although in this case it is not unwarranted in view of the abundantly packed contents. Those concerned, however, can opt for the author's more frugal companion volume, Pocket Guide to Gene Level Diagnostics (Boca Raton, Fla.: CRC Press, 1992; $45), which covers the same topics more concisely and includes features not found in the larger book, such as lists of DNA reference laboratories and reagent vendors, licensing issues, and draft guidelines on quality assurance.

The Handbook is the first truly comprehensive overview of all aspects of DNA diagnostics to appear in a field whose diverse and sometimes isolated practitioners desperately need such a unifying intellectual approach. It will be of immense use not only to laboratory workers but also to clinicians and trainees in all medical specialties, from emergency medicine to psychiatry, if only to heighten awareness of the panoply of tests available to them as the molecular revolution begins to influence their workup of patients. The amazing panorama of molecular diagnostics in this book bodes well for the nascent field of molecular medicine and suggests that it may not be too long before Dr. Bernstam can herald the “second wave” with a Handbook of Gene Level Therapeutics in Clinical Practice.

Wayne W. Grody, M.D., Ph.D.
UCLA School of Medicine, Los Angeles, CA 90024