A New Insight into Sanger’s Development of Sequencing: From Proteins to DNA, 1943–1977

Fred Sanger, the inventor of the first protein, RNA and DNA sequencing methods, has traditionally been seen as a technical scientist, engaged in laboratory bench work and not interested at all in intellectual debates in biology. In his autobiography and commentaries by fellow researchers, he is portrayed as having a trajectory exclusively dependent on technological progress. The scarce historical scholarship on Sanger partially challenges these accounts by highlighting the importance of professional contacts, institutional and disciplinary moves in his career, spanning from 1940 to 1983. This paper will complement such literature by focusing, for the first time, on the transition of Sanger’s sequencing strategies from degrading to copying the target molecule, which occurred in the late 1960s as he was shifting from protein and RNA to DNA sequencing, shortly after his move from the Department of Biochemistry to the Laboratory of Molecular Biology, both based in Cambridge (UK). Through a reinterpretation of Sanger’s papers and retrospective accounts and a pioneering investigation of his laboratory notebooks, I will claim that sequencing shifted from the working procedures of organic chemistry to those of the emergent molecular biology. I will also argue that sequencing deserves a history in its own right as a practice and not as a technique subordinated to the development of molecular biology or genomics. My proposed history of sequencing leads to a reappraisal of current STS debates on bioinformatics, biotechnology and biomedicine.     

Nicolas Rashevsky's Mathematical Biophysics

This paper explores the work of Nicolas Rashevsky, a Russian émigré theoretical physicist who developed a program in “mathematical biophysics” at the University of Chicago during the 1930s. Stressing the complexity of many biological phenomena, Rashevsky argued that the methods of theoretical physics – namely mathematics – were needed to “simplify” complex biological processes such as cell division and nerve conduction. A maverick of sorts, Rashevsky was a conspicuous figure in the biological community during the 1930s and early 1940s: he participated in several Cold Spring Harbor symposia and received several years of funding from the Rockefeller Foundation. However, in contrast to many other physicists who moved into biology, Rashevsky's work was almost entirely theoretical, and he eventually faced resistance to his mathematical methods. Through an examination of the conceptual, institutional, and scientific context of Rashevsky's work, this paper seeks to understand some of the reasons behind this resistance. This revised version was published online in July 2006 with corrections to the Cover Date.     

How did East German genetics avoid Lysenkoism?

Lysenkoism gained favour in the Soviet Union during the 1930s and 1940s, replacing mendelian genetics. Opponents of Lysenko were dismissed from their jobs, imprisoned and, not infrequently, died. After World War II in some of the East European Soviet satellite states, Lysenkoism became the official genetics supported by the communist authorities, and thus, genetics and biology were set back many years. Yet the uptake of Lysenkoism was not uniform in the Eastern Bloc. The former East Germany (GDR) mostly escaped its influence, owing to the contribution of a few brave individuals and the fact that the country had an open border with the West (West Berlin).     

Genetics: still a discipline?

In the institutional sense of the term "discipline" (laboratories, societies, congresses, curricula, etc.), genetics remains a discipline. In the intellectual sense of the term (consensus on a definite array of concepts, methods and theoretical purposes), it is doubtful that genetics is still a discipline. At first, molecular biology seemed to have introduced an unequivocal structural (or molecular) definition of the gene: a definite sequence of nucleotides that code for a protein. In fact, as it appears in retrospect, this was not the case. Even in 1961, when Jacob and Monod proposed their first model of genetic regulation in bacteria, there was no possibility of constructing a non equivocal concept of the gene. More recent developments in molecular genetics have made this situation worse. There is no possible definition of the gene as a general category. The reasons why biologists keep the word are pragmatic rather than theoretical: communication among scientists, economic interests and ideology.     

Practice and Politics in Japanese Science: Hitoshi Kihara and the Formation of a Genetics Discipline

This paper examines the history of Japanese genetics in the 1920s to 1950s as seen through the work of Hitoshi Kihara, a prominent wheat geneticist as well as a leader in the development of the discipline in Japan. As Kihara’s career illustrates, Japanese genetics developed quickly in the early twentieth century through interactions with biologists outside Japan. The interactions, however, ceased due to the war in the late 1930s, and Japanese geneticists were mostly isolated from outside information until the late 1940s. During the isolation in wartime and under the postwar U.S. Occupation, Kihara adapted to political changes. During wartime, he developed a research institute focusing on applied biology of various crops, which conformed to the national need to address food scarcity. After the war, he led the campaign for the establishment of a national institute of genetics and negotiated with American Occupation officers. The Americans viewed this Japanese effort with suspicion because of the rising popularity of the controversial theory of the Russian agronomist, Trofim Lysenko, in Japan. The institute was approved in 1949 partly because Kihara was able to bridge the gap between the American and Japanese sides. With Kihara’s flexible and generous leadership, Japanese genetics steadily developed, survived the wartime, and recovered quickly in the postwar period. The article discusses Kihara’s interest in cytoplasmic inheritance and his synthetic approach to genetics in this political context, and draws attention to the relation between Kihara’s genetics and agricultural practice in Japan.     

'Molecules and monkeys': George Gaylord Simpson and the challenge of molecular evolution

In this paper, I analyze George Gaylord Simpson's response to the molecularization of evolutionary biology from his unique perspective as a paleontologist. I do so by exploring his views on early attempts to reconstruct phylogenetic relationships among primates using molecular data. Particular attention is paid to Simpson's role in the evolutionary synthesis of the 1930s and 1940s, as well as his concerns about the rise of molecular biology as a powerful discipline and world-view in the 1960s. I argue that Simpson's belief in the supremacy of natural selection as the primary driving force of evolution, as well as his view that biology was a historical science that seeks ultimate causes and highlights contingency, prevented him from acknowledging that the study of molecular evolution was an inherently valuable part of the life sciences.     

“The Real Point is Control”: The Reception of Barbara McClintock's Controlling Elements

In the standard narrative of her life, Barbara McClintock discovered genetic transposition in the 1940s but no one believed her. She was ignored until molecular biologists of the 1970s “rediscovered” transposition and vindicated her heretical discovery. New archival documents, as well as interviews and close reading of published papers, belie this narrative. Transposition was accepted immediately by both maize and bacterial geneticists. Maize geneticists confirmed it repeatedly in the early 1950s and by the late 1950s it was considered a classic discovery. But for McClintock, movable elements were part of an elaborate system of genetic control that she hypothesized to explain development and differentiation. This theory was highly speculative and was not widely accepted, even by those who had discovered transposition independently. When Jacob and Monod presented their alternative model for gene regulation, the operon, her controller argument was discarded as incorrect. Transposition, however, was soon discovered in microorganisms and by the late 1970s was recognized as a phenomenon of biomedical importance. For McClintock, the award of the 1983 Nobel Prize to her for the discovery of movable genetic elements, long treated as a legitimation, may well have been bittersweet. This new look at McClintock's experiments and theory has implications for the intellectual history of biology, the social history of American genetics, and McClintock's role in the historiography of women in science. This revised version was published online in July 2006 with corrections to the Cover Date.     

The Forgotten Promise of Thiamin: Merck, Caltech Biologists, and Plant Hormones in a 1930s Biotechnology Project

The physiology of plant hormones was one of the most dynamic fields in experimental biology in the 1930s, and an important part of T. H. Morgan's influential life science division at the California Institute of Technology. I describe one episode of plant physiology research at the institution in which faculty member James Bonner discovered that the B vitamin thiamin is a plant growth regulator, and then worked in close collaboration with the Merck pharmaceutical firm to develop it as a growth-boosting agrichemical. This episode allows one to draw continuities between certain fields of life science in the United States circa 1940 and the biotechnology industry today, and also foregrounds a number of similarities between plant physiology of the late 1930s and the molecular biology of the period. This revised version was published online in July 2006 with corrections to the Cover Date.     

基因打靶技术的研究进展

基因打靶技术是一项新兴的分子生物学技术,是利用外源DNA与受体细胞染色体DNA上的同源序列之间发生重组,并整合在预定位点上,从而改变细胞遗传特性的方法。它的产生是遗传工程领域的一次革命,为发育生物学、分子遗传学、免疫学及医学等学科提供了一个全新的、强有力的研究手段。目前基因打靶技术在研究基因的结构和功能、表达与调控,转基因及基因治疗等方面均取得了进展。但基因打靶技术仍存在一些问题,主要是打靶的效率太低。本文综述了基因打靶技术的原理、操作程序并对提高基因打靶效率的可能途径进行了探讨。 Progress on Gene Targeting LIU Hong-quan1,DAI Ji-xun1,YU Wen-gong2,YANG Kun-feng1 1.Ocean University of Qingdao,College of Marine Life Sciences,Qingdao 266003,China; 2.Institute of Marine Drugs and Foods,Qingdao 266003,China Abstract:Gene targeting is a rising technology in molecular biology,which is defined as the introduction of exogeneous DNA to specific site in genome by homologous recombination,and consequently change the hereditary character of the cell.This technology provides a new and powerful means for research in developmental biology,molecular genetics,immunology and medicine.Progresses have been made in exploring gene structure and function,gene expression and regulation,transgene and gene therapy with the application of gene targeting.But there are some problems in gene targeting,especially for the low efficiency.This article just provided a review of the principle and program of gene targeting,and discussed the possible approaches to increase the efficiency of gene targeting. Key words：gene targeting;homologous recombination;targeting vector;targeting efficiency     

His Own Synthesis: Corn, Edgar Anderson, and Evolutionary Theory in the 1940s

Tracing the contributions of Edgar Anderson (1897--1969) of the Missouri Botanical Garden to the important discussions in evolutionary biology in the 1940s, this paper argues that Anderson turned to corn research rather than play a more prominent role in what is now known as the Evolutionary Synthesis. His biosystematic studies of Iris and Tradescantia in the 1930s reflected such Synthesis concerns as the species question and population thinking. He shared the 1941 Jesup Lectures with Ernst Mayr. But rather than preparing his lectures as a potentially key text in the Synthesis, Anderson began researching Zea mays -- its taxonomy, its origin, and its agronomic role. In this study, Anderson drew on the disciplines of taxonomy, morphology, genetics, geography, anthropology, archaeology, and agronomy among others in his own creative synthesis. Though his maize research in the 1940s represented the most sustained work of his career, Anderson was also drawn in many directions during his professional life. For example, he enjoyed teaching, working with amateurs, and popular writing. This revised version was published online in July 2006 with corrections to the Cover Date.     

Molecular biology in the French tradition? Redefining local traditions and disciplinary patterns

Conclusion The first part of this paper has shown that the development of regulatory genetics and the lactose operon model stemmed from laboratory cultures rooted in local traditions. A "physiological" culture may be recognized in the Pasteurian context. The institutional continuity provided the basis for a tenuous link between Pasteur, Lwoff, and Monod. My claim is that the "national" value of regulatory and physiological genetics is an artifact produced in the course of the legitimization process accompanying the institutionalisation of the discipline. In the 1960s, the lactose operon model was turned into a "flag-object," a symbol of the new culture. The work done by the Pasteurian group became therefore the most important, if not the only, exemplar of molecular biology in France.The second part o f the paper described the origins of general patterns that dominated the building of molecular biology in France. The study of the relationships between molecular biologists and biochemists or immunologists revealed the existence of alternatives to the development of operon research, or to the convergence with molecular biology. Both examples uncover specific paths leading to achievements that might be viewed as international trends: the expansion of RNA and translation studies, and the development of cellular immunology. They illustrate two possible patterns of linking local settings and disciplinary traditions: an oligopolistic situation where a few groups or one institution dominate an entire field, and the emergence of "collective" trends through collaboration networks or schools.     

Flow cytometry: technical description and some applications in France

After reviewing basic technical considerations, we discuss some applications of flow cytometry in French laboratories. This methodology is used in several areas: oncology, cellular pharmacotoxicology, molecular biology and genetics, immunology, as well as cellular biology and physiology. We also examine the evolution of this technique in two directions: on the one hand, the appearance of increasingly sophisticated instruments; on the other, the development of less expensive and less complicated apparatuses principally directed at clinical applications.     

Molecular immunology: At the border of centuries and at the interface of disciplines

This is a special issue of the journal Molekulyarnaya biologiya (Molecular Biology) focusing on topical problems in molecular immunology, virology, and the related fields of science, including molecular genetics, biochemistry, and cell biology. Several reviews are offered to the attention of our readers, as well as original experimental papers. This issue was prepared on a tight schedule and, certainly, cannot pretend to cover all the areas of the state-of-the-art science.     

A Particular Synthesis: Aleksandr Promptov and Speciation in Birds

During the 1930s, Aleksandr Promptov—a student of the founder of Russian population genetics Sergei Chetverikov—developed an elaborate concept of speciation in birds. He conducted field investigations aimed at giving a naturalistic content to the theoretical formulations and laboratory models of evolutionary processes advanced within the framework of population genetics, placing particular emphasis on the evolutionary role of bird behavior. Yet, although highly synthetic in combining biogeographical, taxonomic, genetic, ecological, and behavioral studies, Promptov’s speciation concept was ignored by the architects of the 1930s and 1940s evolutionary synthesis, including Theodosius Dobzhnasky, Ernst Mayr, and Julian Huxley. In this article, I argue that the story of Promptov’s concept and its reception by other evolutionists challenges the traditional presentation of the synthesis as a singular, international process of the unification of biology, which led to the creation of a universal synthetic theory of evolution. It suggests that during the same time period, within largely the same theoretical framework, there were multiple, intrinsically local, attempts at creating synthetic evolutionary concepts. These concepts were often quite particular—in their taxonomic applicability, in their explanations of various evolutionary factors, and in the range of disciplines unified in the synthesis. Apparently, these concepts ran contrary to the universal aspirations of the synthesis architects, and as a result, they were disregarded, first by the architects and later by historians of the evolutionary synthesis.     

Cell biologists sort things out: Analysis and purification of intracellular organelles by flow cytometry

Flow cytometry was established originally for measuring DNA content and for the analysis of cell-surface markers in combination with cell sorting. During the past two decades, it has added new dimensions to various areas of immunology and medicine. Increased sensitivity and precision of flow cytometers, accompanied by the development of new fluorescent dyes and probes, has led to new applications in molecular cell biology and genetics. This article focuses on applications of flow cytometry in analysis and sorting of intracellular organelles.     

Postcolonial Ecologies of Parasite and Host: Making Parasitism Cosmopolitan

The interest of F. Macfarlane Burnet in host–parasite interactions grew through the 1920s and 1930s, culminating in his book, Biological Aspects of Infectious Disease (1940), often regarded as the founding text of disease ecology. Our knowledge of the influences on Burnet’s ecological thinking is still incomplete. Burnet later attributed much of his conceptual development to his reading of British theoretical biology, especially the work of Julian Huxley and Charles Elton, and regretted he did not study Theobald Smith’s Parasitism and Disease (1934) until after he had formulated his ideas. Scholars also have adduced Burnet’s fascination with natural history and the clinical and public health demands on his research effort, among other influences. I want to consider here additional contributions to Burnet’s ecological thinking, focusing on his intellectual milieu, placing his research in a settler society with exceptional expertise in environmental studies and pest management. In part, an ‘‘ecological turn’’ in Australian science in the 1930s, derived to a degree from British colonial scientific investments, shaped Burnet’s conceptual development. This raises the question of whether we might characterize, in postcolonial fashion, disease ecology, and other studies of parasitism, as successful settler colonial or dominion science.     

Recent science and its exploration: the case of molecular biology

This paper is about the interaction and the intertwinement between history of science as a historical process and history of science as the historiography of this process, taking molecular biology as an example. In the first part, two historical shifts are briefly characterized that appear to have punctuated the emergence of molecular biology between the 1930s and the 1980s, one connected to a new generation of analytical apparatus, the other to properly molecular tools. The second part concentrates on the historiography of this development. Basically, it distinguishes three phases. The first phase was largely dominated by accounts of the actors themselves. The second coincided with the general ‘practical turn’ in history of science at large, and today’s historical appropriations of the molecularization of the life sciences appear to be marked by the changing disciplinary status of the science under review. In a closing remark, an argument is made for differentiating between long-range, middle-range and short-range perspectives in dealing with the history of the sciences.     

On the impact on biochemical research of the discovery of stable isotopes: the outcome of the serendipic meeting of a refugee with the discoverer of heavy isotopes at Columbia University

As late as the 1930s, approaches to biochemical research not only were rather primitive, but a certain amount of mysticism still surrounded the biochemical events that occur in the living cell. To a great extent, this was due to the lack of techniques needed to uncover the subtle reactions in the living cell. In the early 1930s, an accidental meeting of two scientists revolutionized approaches in biochemical studies and led to the scientific explosion in molecular biology that has occurred during the last few decades. The dark political storm in Germany deposited Dr. Rudolf Schoenheimer on the New York shore, where he met Professor Urey, who recently had discovered "heavy" hydrogen. Schoenheimer suggested that biological compounds tagged with heavy atoms of hydrogen would enable investigators to follow their metabolic pathways. This intellectual leap revolutionized the thinking and design of experiments and made it possible to uncover the myriad reactions that occur in the living cell.     

Timeline: Neurospora: a model of model microbes

In the 1940s, studies with Neurospora pioneered the use of microorganisms in genetic analysis and provided the foundations for biochemical genetics and molecular biology. What has happened since this orange mould was used to show that genes control metabolic reactions? How did it come to be the fungal counterpart of Drosophila? We describe its continued use during the heyday of research with Escherichia coli and yeast, and its emergence as a biological model for higher fungi.