Present at the flood: How structural molecular biology came about: Dickerson, Richard E.

Dickerson, Richard E., Sinauer Associates, Sunderland, Massachusetts, 2005, 307 pp., ISBN 0-87893-168-6, $34.95. This delightful book originated in 2003, according to the author, when his department chair at UCLA suggested that, since the author had delayed his retirement until 2004, he should plan to teach something during the 2003–04 academic year. Because Dr. Dickerson had been a postdoctoral fellow with John Kendrew at Cambridge University during a critical period in the birth of structural molecular biology, he decided to teach a course in the history of this field, with students reading both original papers and the reflections of an active participant in one of the most remarkable periods in the history of science. This modestly sized and eminently readable book, published in paperback, was the result, and it could easily find use as the textbook for similar courses taught by others than Dr. Dickerson. The primary, and nearly sole, emphasis is upon the use of x-ray crystallography to determine the three-dimensional structures of proteins and DNA, and the period covered is the three decades from 1933 to 1963. You won't see anything about NMR in this book, and there is precious little about protein sequence determination, which also came of age during this era. The title is not designed to illustrate the author's participation in the flood of papers, emanating from Cambridge and CalTech, which described the first structural models for DNA and proteins. Rather, it refers to the philosopher John Locke's writings about standards for proof, paraphrased thus: “Had I myself seen the Ark and Noah's Flood, as I saw an overflowing of the Thames River last winter, then I should have no more doubts about the reality of the Biblical Flood than about the overflowing of the Thames.” Through this book, Dickerson aims to confer upon students an awareness of the genesis of molecular biology comparable with the awareness that Locke sought for acceptance of the Biblical flood. The book contains nine chapters, six of which include reprinted papers, including the papers in Nature that are most closely associated with the 1962 Nobel Prizes awarded to John Kendrew, Max Perutz, Francis Crick, James Watson, and Maurice Wilkins. In addition to these scientific pillars are several papers (perhaps a few too many) describing the rise and fall of the cyclol theory of protein structure, advanced primarily by Dorothy Wrinch in the 1930s. Also included are several papers by Erwin Chargaff, in which he describes the significance of his analyses of DNA base composition for development of the DNA model by Watson and Crick and describes in pungent fashion his personal reflections on those gentlemen and their approach to science. Also worth reading is an unpublished whimsical manuscript written in 1953 by Jerry Donohue and the mythical J. Briekopf (“Cheesehead”), entitled “The X-Ray Structural Analysis of α-Globlglobin.” The paper, written just before Perutz's development of multiple isomorphous replacement as a solution to the phase problem, graphically illustrates the difficulties existing at that time in using crystallography to solve the structures of large molecules. The book ends with three appendices, one of which is an appreciation of Irving Geis, who personified the term “molecular art.” Geis, trained originally as an architect, became fascinated by molecular structure, and he created some of the most beautiful representations, both before and after the advent of computer graphics, of the structures of proteins and nucleic acids. Several Geis illustrations grace this book. The main chapters, written by the author, are engagingly written. Chapters 5 and 6 present the clearest descriptions I have ever seen of the use of x-ray diffraction patterns to generate models of macromolecular structure, and the book is worth the price just for that. But the reflections from a different scientific era add a fascinating overlay—descriptions of the computer facilities, which required an overnight vigil while the final 2-Å model of myoglobin was being assembled, and of the difficulties and ingenuity involved in generating three-dimensional physical models of these large molecules. Also of great interest to those concerned about the present uneasy relationships between science and government are Dickerson's descriptions of some events in which the scientific history interfaced with current events of the period. For example, Max Perutz, an Austrian, was declared a German citizen after Britain entered the Second World War and was saved from internment in Canada for the duration only by outcries from the scientific community. And the U. S. House Un-American Activities Committee makes an entrance with its 1952 identification of Linus Pauling as “one of the foremost Americans involved in a ‘campaign to disarm and defeat the United States.’” This led to the cancellation of Pauling's passport, meaning that he could not attend a conference in Britain, at which he would have seen the B-DNA diffraction patterns generated by Rosalind Franklin and Maurice Wilkins and which might have led him to discover the DNA structure before Watson and Crick. Like many scientists, the Dickerson cast of characters injected humor into their work, and this is reflected in the book with liberal applications of limericks, doggerel, and puns—many, I assume, by the author himself, since they are not credited. The most egregious, in my opinion, is “Up the Crick without a Wrinch—a truly apPauling tale, yet one to Bragg about.” Those who use this book as a text should be aware that this is not a comprehensive account of the early days of structural molecular biology. It is appropriate for the focus to be upon Cambridge and Caltech, because of the seminal contributions of Watson, Crick, Perutz, Kendrew, Wilkins, Pauling, and the others but also because of Dickerson's own participation as a member of the Kendrew group while the high-resolution myoglobin model was being assembled. Still, two names that to me were conspicuous by their omission are G. N. Ramachandran and Christian Anfinsen. Ramachandran used x-ray diffraction to propose in 1954 the triple-helical structure of collagen and the concept of coiled coils. When this model was criticized on stereochemical grounds by Crick, among others, Ramachandran in 1963 developed his famous plot, which shows stereochemically acceptable conformations for polypeptide chains and which established the reasonableness of his collagen model. Anfinsen's famous experiment, also carried out in the 1950s, demonstrated that the three-dimensional structure of a protein is determined by its primary structure. Although this reviewer is not a structural biologist, I read this book with particular interest because my own career was beginning toward the end of the historical period covered, and memories kept “flooding” back. As a graduate student in 1960, I prepared for an oral examination on proteins by reading the two papers in the February 13 issue of Nature, by the Kendrew and Perutz groups, on the structures of myoglobin and hemoglobin, respectively. I didn't do very well in the exam, but I passed on the strength of the last question, put to me by the department chair, Hans Neurath—“Chris, have you read the February 13 issue of Nature?” I answered “Yes,” and the exam concluded, to the bemusement of the other committee members, who hadn't yet seen those papers. Later, in 1962, when the Nobel Prize for DNA structure was awarded to Watson, Crick, and Wilkins, I was a postdoc with Seymour Cohen, who had been Erwin Chargaff's first graduate student. Cohen commented that if the award were to be conferred on a third person, in addition to Watson and Crick, that third person should have been Chargaff. The argument has merit, but after reading in this book about Chargaff's impressions of Watson and Crick, I tried to visualize the discomfort that those three gentlemen might have felt had they risen together before the King of Sweden to be honored for the same contribution.

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