THE BLACK BOX OF BIOLOGY A History of the Molecular Revolution Michel Morange Translated by Matthew Cobb Cambridge, Massachusetts, and London, England 2020 Copyright © 2020 by Éditions La Découverte, Paris, France This volume is revised and expanded from the first English-language edition, published as A History of Molecular Biology by Harvard University Press. Copyright © 1998 by the President and Fellows of Harvard College First French Edition published as Histoire de la biologie moléculaire Copyright © 1994, 2003 Éditions La Découverte, Paris, France All rights reserved Cover design: Tim Jones Cover artwork: Courtesy of Getty Images 978-0-674-28136-3 (hardcover) 978-0-674-24525-9 (EPUB) 978-0-674-24527-3 (MOBI) 978-0-674-24528-0 (PDF) The Library of Congress has cataloged the printed edition as follows: Names: Morange, Michel, author. | Cobb, Matthew, translator. Title: The black box of biology : a history of the molecular revolution / Michel Morange, translated by Matthew Cobb. Other titles: Histoire de la biologie moléculaire. English Description: Cambridge, Massachusetts : Harvard University Press, 2020. | This volume is revised and expanded from the first English-language edition, published as A History of Molecular Biology by Harvard University Press. Originally published (in French) as Histoire de la biologie moléculaire—Title page verso. | Includes bibliographical references and index. Identifiers: LCCN 2019040562 Subjects: LCSH: Molecular biology—History. Classification: LCC QH506 .M7313 2020 | DDC 572.8—dc23 LC record available at https://lccn.loc.gov/2019040562 Contents Introduction PART ONE THE BIRTH OF MOLECULAR BIOLOGY 1 The Roots of the New Science 2 The One Gene–One Enzyme Hypothesis 3 The Chemical Nature of the Gene 4 The Phage Group 5 The Birth of Bacterial Genetics 6 The Crystallization of the Tobacco Mosaic Virus 7 Enter the Physicists 8 The Influence of the Rockefeller Foundation 9 Physical Techniques in Molecular Biology 10 The Role of Physics PART TWO THE DEVELOPMENT OF MOLECULAR BIOLOGY 11 The Discovery of the Double Helix 12 Deciphering the Genetic Code 13 The Discovery of Messenger RNA 14 The French School PART THREE THE EXPANSION OF MOLECULAR BIOLOGY 15 Normal Science 16 Genetic Engineering 17 Split Genes and Splicing 18 The Discovery of Oncogenes 19 From DNA Polymerase to the Amplification of DNA PART FOUR BEYOND MOLECULAR BIOLOGY? 20 The Molecularization of Biology and Medicine 21 Protein Structure 22 The Rise of Developmental Biology 23 Molecular Biology and Evolution 24 Gene Therapy 25 The Central Place of RNA 26 Epigenetics 27 Sequencing the Human Genome 28 Systems Biology and Synthetic Biology 29 Images, Representations, and Metaphors in Molecular Biology General Conclusion Appendix: Definition of Terms Notes Index Introduction TWO DECADES AGO, when I published A History of Molecular Biology, the predecessor of this book, barely a day went by without the media highlighting another new development in biology—gene therapy, the human genome project, the creation of new varieties of animals and plants by genetic engineering, and even the possibility of cloning a human being. Naturally enough, the public was fascinated. Back then, everyone knew that these developments were the products of molecular biology, which had appeared in the middle of the twentieth century. The endless cycle of new discoveries still continues, but the public is less fascinated and more anxious, and it is not always clear that these developments are the results of the rise of the new science in the middle of the twentieth century. All these advances—such as those enabled by the genome editing system CRISPR—reignite hopes and debates that first emerged decades ago, while all the progress in gene and cell therapies, and new treatments for cancer, are still the more or less direct consequences of the development of molecular biology. Faced with the immense discoveries of the last two decades, and their promised—or threatened—future, I felt it was time to produce a new book. Although this is based on my original History—in particular the first three parts—this is much more than a new edition. The entirely new fourth section deals with developments that were only dreamed of in the late twentieth century, and I have taken the opportunity to extensively revise and update the analysis in the earlier sections. Molecular biology is not the description of biology in terms of molecules —if this were the case, it would include not only biochemistry, but also all those nineteenth century studies in chemistry and physiology that led to the characterization of biological molecules. With such a broad definition, even Pasteur would have been a molecular biologist!1 Rather, molecular biology consists of those techniques and discoveries that make it possible to carry out molecular analyses of the most fundamental biological processes— those involved in the stability, survival, and reproduction of organisms. It is not only a level of observation and explanation of living phenomena, it also provides a method for intervening into those systems in order to understand and manipulate them. Although it is not the only possible level at which biological research should be carried out—sometimes it is not even the best one—it clearly represents an important approach to our understanding of the living world. Molecular biology is a result of the meeting of genetics and biochemistry, two branches of biology that developed at the beginning of the twentieth century, each of which had clearly defined research objects: the gene for genetics, and proteins and enzymes for biochemistry. Molecular biology emerged when the relation between these two objects became clearer; scientists identified the gene as a macromolecule (DNA), determined its structure, and described its role in protein synthesis. Strictly speaking, molecular biology is not a new discipline but rather a new way of looking at organisms as reservoirs and transmitters of information.2 This new vision opened up possibilities of action and intervention that were first revealed during the early years of genetic engineering. The techniques necessary for the study of macromolecules were developed between 1920 and 1940, and the new conceptual tools for analyzing biological phenomena were forged between 1940 and 1965. The consequent operational control was acquired between 1972 and 1980 with the development of genetic engineering. In the subsequent decades, molecular biology has completely transformed our understanding of biological phenomena. This book covers the molecular revolution in its entirety, from its earliest days right up to tomorrow. Molecular biology and genetic engineering are too intimately linked for their histories to be separated; genetic engineering cannot be understood without molecular biology, but it was genetic engineering that highlighted the importance of the conceptual changes that molecular biology had produced. The discovery in 1983 of a technique for amplifying DNA, called the polymerase chain reaction (PCR), had its origins in the theoretical framework developed in the 1950s and in the experimental tools devised in the 1970s. Better than any other example, it shows the effectiveness of the theoretical and practical tools forged by biologists in the second half of the twentieth century. Molecular biology was born when geneticists, no longer satisfied with an abstract view of the role of genes, focused their attention on the nature of genes and their mechanism of action. It was also a result of biochemists trying to understand how proteins and enzymes—essential agents of organic specificity—are synthesized and how genes intervene in this process. The end of this history is more difficult to discern. At various points over recent decades, a number of biologists, historians, and philosophers have announced the death of molecular biology. In the last part of this book I briefly describe the key changes that have occurred in the last forty years, exploring how deeply they have affected the framework created by molecular biologists. My conclusion is that we still live within the molecular paradigm,3 and that contemporary biologists use the same conceptual framework that was established more than fifty years ago. Despite the repeated announcements of its demise, molecular biology is still alive and kicking. Parts 1, 2, and 3 contain very detailed descriptions of the experiments that underpinned the development and consolidation of molecular biology. That approach could not be repeated in Part 4 because each new development would have required a book in itself. The chapters in the final part therefore address this recent history in a more synthetic way. This also allows a more direct focus on the major issue that lies at the core of the whole book: whether the “molecularization” of so many biological subdisciplines has transformed molecular biology itself, up to the point where it has disappeared as a discrete subject and been replaced by the emergence of a new form of biology. These final chapters also deal with the key participants in a rather different way. Although the construction of scientific knowledge is always the result of a collective effort, in the first three parts I tried to outline major individual contributions. This was not possible in the fourth part of the book —thousands of researchers would have deserved to be mentioned. The individuals who are named are the authors of articles or experiments that can be seen as landmarks of the transformation of all branches of biology that occurred over the last forty years. A major problem in writing the history of the molecular revolution in the life sciences is the sheer mass of documentation available. Many of those who made this revolution have written their own accounts; there are also a large number of studies by scientists, historians, and philosophers.4 Four books in particular, with very different approaches, have made a major contribution to the history of molecular biology. The British historian Robert Olby wrote a detailed account of the path that led to the discovery of the double helix structure of DNA.5 Horace F.