Present at the Flood: A First Person Guided Tour through the Early Literature in Structural Biology

The challenge with reading the primary scientific literature from several decades ago is that while the main conclusions are familiar, many other aspects of the paper are not. This is true even for papers as historically important as Pauling's report of the α-helix model or the structure of hemoglobin reported by Perutz. How many recently trained graduate students are familiar with the colloidal theory of proteins or Pauling's 5.1 residue-per-turn model of a protein helix? The difficulty with reading these older papers is that they often refute incorrect hypotheses that have largely been forgotten, use methods that are no longer employed, or accept assumptions that have been disavowed. Such challenges, which are particularly daunting in structural biology, can make this important early literature inaccessible, causing new generations of structural biologists to collectively miss the boat, or, should I say, miss the ark, on the intellectual journey that led to our current understanding of macromolecules.Richard Dickerson's recent book, Present at the Flood: How Structural Molecular Biology Came About, centers on reprints of the key papers in protein and DNA structure determination published during the period from 1933 to 1963. These begin with the structural transition of keratin between the relaxed and the stretched state (α versus β, names eventually given to the secondary structure elements they represent) and conclude with the three-dimensional structures of hemoglobin and myoglobin. Collectively, they constitute many of the seminal papers in the revolution of macromolecular structural biology. All 40 papers are presented in their original typesetting with their original figures. The papers are reproduced as they would be if photocopied from the local library, including partial text from unrelated papers that preceded or followed the paper of interest. Most of the papers are complete, while some of the longer ones have been edited to include only that portion most relevant to a modern reader.This primary literature is organized into eight chapters. Dickerson introduces each chapter by providing the scientific and historical background needed to understand each set of papers. These introductions include a summary of what the authors got right and what they got wrong, the state of scientific thought when the work was published, and several anecdotal stories about the contributing scientists. Particularly useful, because the method is used much less frequently today than in the 1950s, are several diagrams that describe the X-ray diffraction patterns of fibers. Understanding the data resulting from this method makes accessible the original literature reporting the α-helix and β sheet structures of proteins and the DNA double helix. With Dickerson's introduction, the reader can identify the features of Wilkens' and Franklin's diffraction data that led Watson and Crick to propose an antiparallel duplex with a 3.4 A repeat and appreciate why Pauling waited three years before publishing his model of the α-helix, a model that he originally discovered while sick in bed (a model that Dickerson points out was made from D-amino acids with a left-handed helix-the mirror image of the actual helix present within proteins)? Unlike a scientific history book, Present at the Flood is a primer for the scientific literature. In many cases, particularly in the chapter focused on DNA, Dickerson assumes the reader is already familiar with the history and focuses exclusively on the intellectual development of the science and a few humorous insider tidbits about the scientists.The book is particularly well-suited for classroom instruction. In fact, the text grew out of a graduate course in structural biology that Dickerson teaches at UCLA. His text provides most of the relevant literature in one convenient location and facilitates classroom discussion by including a set of focused conversation questions at the end of each chapter. It also provides a valuable introduction for non-structural biologists interested in the development of X-ray crystallography. For example, Dickerson guides the non-specialist through the method of multiple isomorphous replacement developed by Perutz for determination of the hemoglobin structure.The papers selected are not just those with the correct answers. Dickerson recognized that much can be learned about the scientific process by reading papers with conclusions that have stood the test of time as well as those presenting models that have not. He has included Wrinch's 1936 paper on the cyclol structure of proteins and Pauling's attempt to model DNA as an inside-out triple helix. The race for the DNA structure exemplifies how the introductory commentary provides the context for reading the primary literature. Dickerson explains that three different labs built a three-stranded DNA helix and discusses which features in the fiber diffraction data led to this errant conclusion.Interestingly, and quite amusingly, not all of the papers reprinted in Present at the Flood were published in reputable scientific journals. One of the manuscripts was actually rejected by the Journal of Irreproducible Results but finally finds publication in this book. This report was a witty parody prepared by Jerry Donohue in 1953 entitled “The X-Ray Structure Analysis of α-Globlglobin.” Old scientific jokes, like old science, require an insider's interpretation, so Dickerson has included a table to identify the aliases of the people who appear in the manuscript. However, the model of Donohue's w-helix paper chain drawn on the 0.001 μ yard scale and the electron density duck found in his Patterson projection require no such augmentation.Even a passing familiarity with some classic literature can have benefits. I recently gave a tour of Yale's Center for Structural Biology to some nonscientific visitors to the department. On our way into the facility, we passed Harold Wycoff's somewhat dusty model of sperm whale myoglobin, which marks the entrance to the Center. I have walked by this model at least twice a day for more than ten years, but had not stopped to ask the obvious question posed to me during that tour: “Why did they select sperm whale as their source of myoglobin?” Only when I read the 1958 Nature paper authored by Kendrew, Wycoff, and coworkers, included in this collection, did I know the answer. Unlike hemoglobin, which has a role in oxygen transport, the role of myoglobin is in oxygen storage, an important function for diving animals such as whales, where the protein is particularly abundant.Providing historical and logical tidbits about the scientific process will undoubtedly improve my tour of the science facility, but more importantly, it will improve my scientific teaching. An underlying premise of the book is a reminder to the reader that science is a process. Dickerson manages to create a sense of how the developing structural biology community leaped and stumbled toward the modern incarnation of the field. What we know about protein and nucleic acids structure did not fall from the sky, like the rain on Noah's ark depicted on the book's cover, as a consecutive, discrete series of seminal discoveries by infallible scientists. Instead, like science today, these discoveries were made in fits and starts, in moments of inspiration and moments of error. It is encouraging to see that even the pioneers of structural molecular biology pursued dead ends, published mistakes in the literature, and were unwilling or unable to unlock the meaning of their hard-won data. All students should understand the rhythms of discovery, and Dickerson's book organizes this historically important primary literature for study and instruction using just such an approach.View Large Image | View Hi-Res Image | Download PowerPoint Slide