Creating a Physical Biology: The Three-Man Paper and Early Molecular Biologyby Phillip R. Sloan
In 1935 geneticist Nikolai Timoféeff-Ressovsky, radiation physicist Karl G. Zimmer, and quantum physicist Max Delbrück published “On the Nature of Gene Mutation and Gene Structure,” known subsequently as the “Three-Man Paper.” This seminal paper advanced work on the physical exploration of the structure of the gene through… See more details below
In 1935 geneticist Nikolai Timoféeff-Ressovsky, radiation physicist Karl G. Zimmer, and quantum physicist Max Delbrück published “On the Nature of Gene Mutation and Gene Structure,” known subsequently as the “Three-Man Paper.” This seminal paper advanced work on the physical exploration of the structure of the gene through radiation physics and suggested ways in which physics could reveal definite information about gene structure, mutation, and action. Representing a new level of collaboration between physics and biology, it played an important role in the birth of the new field of molecular biology. The paper’s results were popularized for a wide audience in the What is Life? lectures of physicist Erwin Schrödinger in 1944.
Despite its historical impact on the biological sciences, the paper has remained largely inaccessible because it was only published in a short-lived German periodical. Creating a Physical Biology makes the Three Man Paper available in English for the first time. Brandon Fogel’s translation is accompanied by an introductory essay by Fogel and Phillip Sloan and a set of essays by leading historians and philosophers of biology that explore the context, contents, and subsequent influence of the paper, as well as its importance for the wider philosophical analysis of biological reductionism.
Phillip R. Sloan is professor emeritus in the Program of Liberal Studies and the Program in History and Philosophy of Science at the University of Notre Dame. Brandon Fogel is the Collegiate Assistant Professor in the Division of Humanities at the University of Chicago.
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Creating a Physical BiologyThe Three-Man Paper and Early Molecular Biology
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Phillip R. Sloan and Brandon Fogel
The 1935 paper "On the Nature of Gene Mutation and Gene Structure" by Russian Drosophila geneticist Nikolai Timoféeff-Ressovsky (1900–1981) and two Germans, radiation physicist Karl Günther Zimmer (1911–88) and theoretical physicist Max Delbrück (1906–81), is a landmark in the history of the development of biophysics. The paper was commonly known as the "Three-Man Work" or "Three-Man Paper" (Dreimännerwerk, Dreimännerarbeit), from which derives the acronym (3MP) that will be used throughout this volume. Though its particular scientific conclusions would not, at least in specific detail, stand the test of time, the 3MP was an important stimulus in the development of the new molecular biology, both methodologically and conceptually. Through a novel mixture of experimental genetics and chemistry with the most current theoretical physics, used to model the gene as a specifically molecular structure, and utilizing X-ray technology and contemporary "target" theory, the paper demonstrated the potential of such cross-disciplinary collaboration to provide detailed, physicalistic explanations of biological phenomena. Though its historical importance has never been in doubt, the paper has been largely inaccessible, due to its manner of publication. In presenting the first English translation, accompanied by analyses of its historical and philosophical significance, the current volume aims to provide access to this celebrated work and to contextualize its origins.
The 3MP was published in the Reports of the biology section of the Göttingen Academy of Sciences in 1935, a journal that folded after only three issues. Delbrück later commented that to publish it in the Nachrichten at that time was to give it a "funeral first class," although, as Richard Beyler details in his chapter below, this oft-quoted remark is an inaccurate account both of its impact and of its dissemination. In fact, the paper survived its initial publication quite well, through restatements of its arguments in subsequent publications, and physically extending its influence through the circulation of a large number of reprints among a select group of individuals. These reprints were enclosed in a green cover and soon became known as the "Green Pamphlet" (a reproduction of which is the frontispiece of this volume). In 1942, a copy of the Green Pamphlet was lent to Erwin Schrödinger by Paul Ewald, a physicist interested in crystallography who, like Schrödinger, was a refugee from Nazi Europe. Schrödinger drew heavily on the paper for his public lectures of February 1943, published in 1944 in his popular treatise on the nature of life and heredity, What Is Life? It is through that text, often credited with supplying an intellectual impetus for the migration of many physical scientists into biology after World War II, that much of the English-speaking world came to know of the 3MP and its contents. However, as will be developed in detail below, Schrödinger misconstrued the paper's main theoretical conclusions, due to his own theoretical agenda in biophysics. He ignored clearly expressed reservations in the 3MP concerning the complex relationship between developmental and structural genetics in favor of a thoroughgoing reductionism, a position that many would later mistakenly assume was drawn from the 3MP.
The purpose of this introductory discussion is to situate the 3MP within the broader context of issues that surrounded the debates over the relation of physics and biology in the mid-1930s, thereby allowing the reader to appreciate the paper's significance. It will also address some of the enduring philosophical questions that surround the application of physics to biology.
Following some historiographical reflections and a brief biographical sketch of the three authors, a discussion of the concept of the gene around 1930 will provide a background against which the paper can be read. These perspectives will supply a framework for the more detailed studies of the paper's historical and conceptual contexts in the chapters that follow.
Writing the History of Molecular Biology
Some attention to historiographical concerns is required in discussing the historical importance of the 3MP. A particular pitfall is the "presentism" of viewing phage and DNA research as the apotheosis of molecular biology; in such a view, the beginnings of modern biophysics are mere prehistory to the discovery of the structure of DNA in 1953.6 But the early visions of the new molecular approach to biology were not limited to investigations of genetic phenomena, and as developed in detail in this volume, the paper emerged from a rich context of radiation research, medical physics, and other explorations of biophysics in the 1920s and 1930s. The first appearance of the term "molecular biology," in a report to the Rockefeller Foundation in 1938 by Warren Weaver, the director of the Natural Sciences Division of the Rockefeller Foundation from 1932 to 1955, refers to "the studies ... in a relatively new field ... in which delicate modern techniques are being used to investigate ever more minute details of certain life processes." To encourage this, the Rockefeller Foundation during Weaver's tenure supplied much of the primary research funding for biophysical research both in the United States and abroad in the pre–World War II period.
In the earliest intellectual histories of molecular biology, published in the 1960s, the 3MP was included unproblematically as part of the "origins" of modern molecular biology, as we see one of its authors, Karl Zimmer do in his retrospective discussion of the target theory. Likewise, Donald Fleming gives it a similar importance in a well-known analysis of the impact of the cross-disciplinary migration of physicists into biology. Nonetheless, recent detailed scholarly work on the history of molecular biology has restricted the designator "molecular" to the post–World War II period, with its origins closely related to a complex interaction of institutional developments, technological inventions, and new experimental practices arising in the 1950s and 1960s. Two recent examples of this new historiography illustrate this trend: Soraya de Chadarevian's study of the transformation of the Medical Research Council Unit for the Study of the Molecular Structure of Biological Systems at Cambridge University, which changed its name to the MRC Unit for Molecular Biology only in 1957, has highlighted the institutional factors in the definition of "molecular" biology. A similar study is that of Bruno Strasser on the postwar development of biophysics at the University of Geneva, which details the transformation in 1963 of the Laboratoire de biophysique, previously devoted to electron microscopy, into a new Institut de biologie moléculaire. These transformations are also located within the broader transnational "molecularization" of biology after World War II, with the first journal bearing this name, the Journal of Molecular Biology, commencing publication in 1959. The shift in this recent historiography away from history of scientific ideas toward local microhistory, with emphasis on the material history of instruments (e.g., the electron microscope), on new techniques of analysis, and on experimental practices within laboratory groups, in interaction with funding agencies and local political contexts, has required new ways of approaching the 3MP.
Another historiographical issue concerns the attempt to identify the "origins" of a discipline by identification with certain key figures or even with key papers. As exemplified particularly by the now-famous Watson and Crick papers of 1953, much of the identification of such significance is retrospective, coming some time after the events themselves. In the case of the 3MP, it can be argued that it was the retrospective reading of Schrödinger's later popularized presentation of important aspects of the paper in 1944, rather than the paper itself, that has played this role in "origins" stories. As detailed in Richard Beyler's chapter, the central theory of the 3MP, the target theory, did not, in fact, survive intact. But aspects of this theory were elaborated upon and institutionalized in a series of developments that preceded Schrödinger's exposition.
The 3MP intersects with several issues that have been of concern in the historiographical analysis of contemporary biophysics. First, it is the product of an "intellectual migration" from physics into biology by two of its authors, Max Delbrück and Karl Zimmer, the first moving from high-level theoretical physics, and the other from experimental radiology. These migrations were not those of refugee scientists driven from Europe by the rise of totalitarianism and moving into biology, the familiar story told in the better-known "origins" story of the history of molecular biology. Rather, their discipline jumping occurred within the general confines of a single complex institution, the Kaiser Wilhelm Society (Kaiser-Wilhelm Gesellschaft) in Berlin.
The paper is also a result of major technological developments of the 1920s and 1930s, specifically the technology for producing artificial mutations in fruit flies through techniques of irradiation with X-rays and beta and gamma radiation. This required developments of precise techniques for targeting flies in varying stages of development, for administering specific quantities of radiation, and for measuring the outcomes by way of interbreeding experiments. The difficulties in solving these technical questions are easily overlooked. The development of special containers was required, as well as means of conducting precise radiation experiments on a small volume of biological material. The collaboration of Timoféeff-Ressovsky and Zimmer began in the early 1930s with techniques developed by others, particularly Hermann Muller, yet they attained a new level of quantitative precision through development of specific means of managing the flies in radiation experiments and administering different wavelengths of radiation.
The 3MP's origins also involve specific institutional issues associated with the interplay of distinct institutes within the Kaiser Wilhelm Society in the early 1930s; these are outlined in the Sloan chapter in this volume. The research for the paper was funded by the Emergency Fund for German Science, established through the initiative of Max Planck, Fritz Haber, and Ernst von Harnack in 1920, which served as a major agency for interwar German scientific research. Finally, the paper's origins and character cannot be fully understood without attention to the political conditions created by the rapid nazification of Germany after January 1933, which displaced numerous German academics for either ethnic or political reasons and resulted in the creation of the ephemeral interdisciplinary discussion seminar organized by Max Delbrück that ran from 1934 to 1937. It was from this seminar that the 3MP emerged. Different aspects of these issues will be explored in several chapters of this book.
If we must acknowledge important microhistorical and detailed historiographical concerns that surround the concept of "molecular" biology as a discipline, there are also "big picture" issues connected with origins of modern biophysics, whether the designator "molecular" biology is applied or not, that bear on the 3MP. The intellectual project of ontological reductionism—the claim that life can be fully explained through the categories of the physical sciences—has major implications for the understanding of human identity, the nature of "life," and the many social and political issues surrounding the relations of organismic biology to analytic biology. It eventually involves the status of consciousness itself. These issues, with contemporary as well as historical interest, inevitably lead us back to an examination of the history of efforts to connect the biological and the physical sciences. The interaction of these domains, though centuries old, developed novel features and built on new assumptions in the 1920s and 1930s, when new forms of interaction between physics and biology developed, spurred by the efforts of a group of individuals, primarily Germanspeaking, to bring together the new quantum mechanics with traditional issues of biological function, the philosophy of biology, and even psychology. For some, the resulting theoretical advances promised to provide the conceptual resolution of the long controversy over mechanism and vitalism that was particularly heated in the period after the inauguration of neovitalism by embryologist-turned-philosopher Hans Driesch (1867–1941). Although such hopes were not quite fulfilled, examination of this dynamic theoretical discourse can help clarify the motivations of key players who managed to achieve various institutional realignments. It is within the larger intellectual nexus of the 1930s that one major measure of significance of the 3MP lies, and in this book we illuminate some of this little-known history, centering on this key early moment in what would become a vast cross-disciplinary conversation.
The biographies of Timoféeff-Ressovsky, Zimmer, and Delbrück are enmeshed in the tumultuous political and social events of the 1930s and 1940s. Nikolai Vladimirovich Timoféeff-Ressovsky, often rendered in German publications as Nikolai W., the largest contributor to the 3MP in terms of length, was the best-known scientist of the three in 1935. He was originally a population geneticist who was one of the early introducers of the neosynthetic theory into Germany in the late 1920s. By the mid-1930s he had also become known as a leading experimental Drosophila geneticist whose important papers, appearing in Russian, German, and English, had already introduced some of the fundamental concepts that are discussed in the first section of the 3MP.
Timoféeff-Ressovsky studied biology as an undergraduate at Moscow University under the population geneticist Sergei Chetverikov (1880–1959), although the Russian civil war prevented him from actually completing the degree. After the revolution, despite having no advanced degrees, he secured a position at the research institute of Nikolai Kol'tsov (1872–1940). In 1925 he was invited to join the Kaiser Wilhelm Institute (KWI) for Brain Research (Hirnforschung), located in the far northeast Berlin suburb of Buch, following extended contact with its director, Oskar Vogt (1870–1959), who had come to Moscow to study the brain of the recently deceased Vladimir Lenin.
Timoféeff-Ressovsky was to assist Vogt in developing a theory of the genetic basis of hereditary mental disorder; the active research group he assembled in Buch, which included several political refugees, survived through the end of World War II.
Although ordered to return to the Soviet Union in 1937, Timoféeff-Ressovsky made a fateful decision to remain in Nazi Germany, due largely to the rise of Lysenkoism under Stalin. Despite the outbreak of war between Germany and the Soviet Union in June of 1941, he continued his work at the KWI without significant interruption. His activity during the war period has been the subject of conflicting scholarship. One group has regarded him as a firm anti-Nazi who worked to shelter several people in his unit and whose son, Dmitri, died in the Mauthausen concentration camp following arrest for anti-Nazi activities. Others have pointed out the several compromises he evidently made with the Nazi regime that could indicate sympathy with its eugenicist policies. After the war he was arrested by the Soviet authorities, charged with being an enemy collaborator, and sentenced to ten years of hard labor in the Gulag prison camps; he spent time there with Aleksandr Solzhenitsyn and appears in the Gulag Archipelago leading informal scientific seminars.
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