Although molecular biology has meant different things at different times, the term is often associated with a tendency to view cellular causation as conforming to simple linear schemas in which macro-scale effects are specified by micro-scale structures. The early achievements of molecular biologists were important for the formation of such an outlook, one to which the discovery of recombinant DNA techniques, and a number of other findings, gave new life even after the complexity of genotype–phenotype
relations had become apparent. Against this (...) background we outline how a range of scientific developments and conceptual considerations can be regarded as enabling and perhaps necessitating contemporary systems approaches. We suggest that philosophical ideas have a valuable part to play in making sense of complex scientific and disciplinary issues. (shrink)

One observes regulation at every biological level. Organisms, cells, and biochemical processes operate efficiently, normally wasting neither material nor energy, and adjusting their functions to external influences. Nature evidently has evolved mechanisms specifically dedicated to regulation at many levels. What is the molecular basis of this control?In the 1950s these molecular control mechanisms began to be explored seriously. The discoveries of feedback inhibition of enzyme activity were important because they gave an initial example of how regulation is achieved at the (...) molecular level. We showed that certain enzymes are composed of two parts, one for catalysis and another distinct part present only to regulate this catalysis. Catalytic activity can be either stimulated or inhibited when a small molecule in the environment combines with the enzyme's regulatory site. In particular, a final product of a metabolic pathway generates a feedback loop which automatically limits its own excessive production, by combining with the regulatory site of an early enzyme in that pathway. Later studies showed that catalytic and regulatory structures of some enzymes could be separated physically.The discovery of regulatory sites and their interaction with molecules unrelated to their substrates was the basis for the generalized allosteric concept. This concept extends the regulatory site idea to a wide variety of processes such as control of gene expression, hormone action, and cellular growth. (shrink)

The Pajama (Pardee, Jacob, Monod) experiment provided a breakthrough in our understanding of the molecular mechanisms by which gene expression is regulated. Today, twenty‐five years later it provides a paradigm for thinking about problems of gene expression, such as growth regulation and differentiation. From this experiment emerged entities such as repressors, regulatory genes, the operon as a group of jointly controlled genes, and messenger RNA.

Steve Fuller has argued that a scientific discovery will not be recognized unless it can be justified within the history of the relevant science. He cites Mendel's work on genetics, which was not recognized until thirty-five years after its publication, as an example. This essay argues that Mendel's work comes out of the tradition of work by both agricultural breeders and academics in nineteenth century Austria. Thus, Fuller is mistaken, and one must look elsewhere for the neglect of Mendel's work. (...) This essay also places Mendel's work within the philosophy of Jan Comenius, whose work was very likely known to Mendel.--------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- -----------------------------------------------. (shrink)

We argue that the physics of complex materials and self-organizing processes should be made central to the biology of form. Rather than being encoded in genes, form emerges when cells and certain of their molecules mobilize physical forces, effects, and processes in a multicellular context. What is inherited from one generation to the next are not genetic programs for constructing organisms, but generative mechanisms of morphogenesis and pattern formation and the initial and boundary conditions for reproducing the specific traits of (...) a taxon. There is no inherent antagonism between this “physicalist” perspective and genetics, since physics acts on matter, and gene products are essential material components of living systems whose variability affects the systems’ parameters. We make this notion concrete by summarizing the concept of “dynamical patterning modules” (DPMs; Newman and Bhat, Phys Biol 5:1–14, 2008; Int J Dev Biol 53:693–705, 2009), an explicit physico-genetic framework for the origin and evolution of multicellular form in animals, as well as (when differences in interaction toolkit genes and applicable physical processes are taken into account) in multicellular plants (Hernández-Hernández et al., Int J Dev Biol 56:661–674, 2012). DPMs provide the missing link between development and evolution by revealing how genes acting in concert with physics can generate and transform morphology in a heritable fashion. (shrink)

François Jacob’s The Logic of Life: A History of Heredity has shown an enduring relevance for the history and philosophy of biology. In this article, resisting the received view that regards this book merely as an application of Foucault’s archaeological method, I reconstruct a silent debate between François Jacob and Jacques Monod. More precisely, I argue that Jacob’s history of biology offers a riposte to Monod’s claims in Chance and Necessity. First, I show that the distinction between a “history of (...) ideas” and a “history of objects” captures two ways of looking at the history of science that characterize Monod’s and Jacob’s own approaches. Next, I present Monod’s search for a “theory of the natural selection of ideas.” Then I argue that the concept of “integron,” introduced by Jacob in his conclusion, covertly undermines Monod’s argument for the use of evolutionary models of cultural and scientific change. These contrasting perspectives shed new light on why the Nobel colaureates and former colleagues expressed little interest in each other’s books. More generally, the Monod-Jacob divide illustrates the use and rejection of biological models in writing the history of science and the importance of situating Jacob within his own milieu. (shrink)

In 1948, a dynamic junior member of the Johns Hopkins Biology Department, William McElroy, became the first director of the McCollum—Pratt Institute for the Investigation of Micronutrient Elements. The Institute was founded at the university to further studies into the practicalities of animal nutrition. Ultimately, however, the Institute reflected McElroy's vision that all biological problems, including nutrition, could be best investigated through basic biochemical and enzymes studies. The Institute quickly became a hub of biochemical research over the following decade, producing (...) foundational work on metabolism and a respected series of symposia. In this paper, I argue that McElroy's biochemical vantage on biology also permeated the traditionally morphological and embryological Biology Department at Hopkins. Largely due to the activity of McElroy and the Institute, the faculty, course offerings, and research underwent a radical reorientation toward biochemistry and molecular biology in the 1950s, even while maintaining a commitment to developmental biology. While the history of postwar biology is often told as the ascendancy of the "new" biology over "traditional" biology, the case of McElroy and the McCollum—Pratt Institute affords an opportunity for historical examination of biochemical and molecular science as a lens through which all branches of biology at an institution were reconceived and unified. (shrink)

This essay recognizes that the interactions that define medical care are problematic and that narrative is invoked to overcome these strains. Being grounded in science, medicine, too, might be influenced by a particular world-view that arose in the natural philosophy of the Scientific Revolution. If narrative responds to this sort of medicine, it may retain traces of this mindset. A feminist approach responds to this viewpoint and may used beneficially to analyze both the story of medicine and the stories within (...) medicine. Tensions discussed from this perspective are those between sickness and health and those between patient and provider; also questioned are suitable form(s) of narrative and whose narratives are valued. Suggestions for broadening narrative to address these issues include letting the body speak for itself, overcoming the power differential in the patient/provider interaction and using standpoints to foster a more equal and just medical system. (shrink)

In 1958, Francis Crick distinguished the flow of information from the flow of matter and the flow of energy in the mechanism of protein synthesis. Crick’s claims about information flow and coding in molecular biology are viewed from the perspective of a new characterization of mechanisms and from the perspective of information as holding a key to distinguishing work in molecular biology from that of biochemistry in the 1950s–1970s . Flow of matter from beginning to end does not occur in (...) the protein synthesis mechanism; flow of information does. The flow of information and coding in molecular biological mechanisms are distinguished, on the one hand, from formal information theory, and, on the other, from information as used in cognitive neuroscience, where information and representation are often coupled. (shrink)

Current philosophical and legal bioethical reflection on reprogenetics provides little more than a rationalization of the interests of science. There are two reasons for this. First, bioethicists attempt to address ethical issues in a “language of precision” that characterizes science, and this works against analogical and narratological modes of discourse that have traditionally provided guidance for understanding human nature and purpose. Second, the current ethical and legal debate is framed by a public/private distinction that banishes robust norms to the private (...) realm, and leaves a minimalist public discourse of harm avoidance that is insufficient for regulating the science. In this essay, I argue that Mark Hanson's account of anxiety provides a valuable starting point for addressing deficiencies in the current philosophical and legal debate, and it highlights the need for a theological discourse on genetic enhancements. Through an assessment of Joel Shumann's criticism of the public/private distinction, I show how the needed theological discourse should be situated in the context of robust communities, and how such a communitarian inter-ethic is compatible with a variant of liberalism. Finally, I critically assess James Keenan's account of virtue and perfection, in order to outline what a sufficient discourse on reproductive and genetic enhancements requires. (shrink)

Since the 1930s, scientists studying the neurological disease scrapie had assumed that the infectious agent was a virus. By the mid 1960s, however, several unconventional properties had arisen that were difficult to reconcile with the standard viral model. Evidence for nucleic acid within the pathogen was lacking, and some researchers considered the possibility that the infectious agent consisted solely of protein. In 1982, Stanley Prusiner coined the term `prion' to emphasize the agent's proteinaceous nature. This infectious protein hypothesis was denounced (...) by many scientists as `heretical'.This two-part essay asks why the concept of an infectious protein was considered controversial. Some biologists justified their evaluation of this hypothesis on the grounds that an infectious protein contradicted the `central dogma of molecular biology'. Others referred to vague theoretical constraints such as molecular biology's `theoretical structure' or `framework'. Examination of the objections raised by researchers reveals exactly what generalizations were being challenged by a protein model of infection.This two-part survey of scrapie and prion research reaches several conclusions: A theoretical framework is present in molecular biology, exerting its influence in hypothesis formation and evaluation; This framework consists of several related, yet separable, generalizations or `elements', including Francis Crick's Central Dogma and Sequence Hypothesis, plus notions concerning infection, replication, protein synthesis, and protein folding; The term `central dogma' has stretched beyond Crick's original 1958 definition to encompass at least two other `framework elements': replication and protein synthesis; and From the study of scrapie and related diseases, biological information has been delineated into at least two classes: sequential and what I call `conformational'.In Part I of this essay, a brief review of the central dogma was given, and the developments in scrapie research from 1965 to 1972 were traced. This section summarized many of the puzzling, non-virus-like properties of the scrapie agent. Alternative hypotheses to the viral explanation were presented, including early versions of a protein-only hypothesis. Part II of this essay will follow the developments in scrapie and prion research from the mid-1970s through 1991. The growing prominence of a protein-only model of infection will be countered by continued objections from many researchers to a pathogen devoid of nucleic acid. These objections will help illuminate those generalizations in molecular biology that were indeed challenged by a protein-only model of infection. (shrink)

The Bermuda Principles for DNA sequence data sharing are an enduring legacy of the Human Genome Project. They were adopted by the HGP at a strategy meeting in Bermuda in February of 1996 and implemented in formal policies by early 1998, mandating daily release of HGP-funded DNA sequences into the public domain. The idea of daily sharing, we argue, emanated directly from strategies for large, goal-directed molecular biology projects first tested within the “community” of C. elegans researchers, and were introduced (...) and defended for the HGP by the nematode biologists John Sulston and Robert Waterston. In the C. elegans community, and subsequently in the HGP, daily sharing served the pragmatic goals of quality control and project coordination. Yet in the HGP human genome, we also argue, the Bermuda Principles addressed concerns about gene patents impeding scientific advancement, and were aspirational and flexible in implementation and justification. They endured as an archetype for how rapid data sharing could be realized and rationalized, and permitted adaptation to the needs of various scientific communities. Yet in addition to the support of Sulston and Waterston, their adoption also depended on the clout of administrators at the US National Institutes of Health and the UK nonprofit charity the Wellcome Trust, which together funded 90% of the HGP human sequencing effort. The other nations wishing to remain in the HGP consortium had to accommodate to the Bermuda Principles, requiring exceptions from incompatible existing or pending data access policies for publicly funded research in Germany, Japan, and France. We begin this story in 1963, with the biologist Sydney Brenner’s proposal for a nematode research program at the Laboratory of Molecular Biology at the University of Cambridge. We continue through 2003, with the completion of the HGP human reference genome, and conclude with observations about policy and the historiography of molecular biology. (shrink)

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. (shrink)

Shannon's theory lays the foundation for understanding the flow of information from world into brain: There must be a set of possible messages. Brain structure determines what they are. Many messages convey quantitative facts. It is impossible to consider how neural tissue processes these numbers without first considering how it encodes them.

During the 1960s, Howard M. Temin (1934-1994), dared to advocate a "heretical" hypothesis that appeared to be at variance with the central dogma of molecular biology, understood by many to imply that information transfer in nature occurred only from DNA to RNA. Temin's provirus hypothesis offered a simple explanation of both virus replication and viral-induced cancer and stated that Rous sarcoma virus, an RNA virus, is replicated via a DNA intermediate. Popular accounts of this scientific episode, written after the discovery (...) of an RNA-directed DNA polymerase in 1970, tend to describe the reaction to his proposition as ardent opposition. Typically these accounts use a 'molecular biology' standpoint emphasizing the central dogma's part in its rejection. In this article, however, this episode will be examined from a joint perspective of virology and experimental cancer research. From this perspective it is clear that Temin's work was well within the epistemological and methodological boundaries of virology and cancer research. Still, scientists did have reasons to doubt the provirus hypothesis, but these do not seem to be good enough to either justify an account that portrays Temin as a renegade or his ideas as heretical. (shrink)

Recent completion of the human genome sequence is a spectacular achievement of the 20th-century biology. This achievement has opened the door for future revolutions in biological and medical sciences. By learning about the gene sequences and the individual genetic differences, scientists hope to understand the molecular basis of the normal state and the diseased state of life on one hand, and individualize medicine on the other hand. However, the human genome sequencing project was not an isolated, spectacular undertaking. Rather, it (...) was a natural extension and the culmination of the advances in the science and techniques of molecular biology. The present article is an attempt to summarize these major landmarks in the history of DNA research, beginning from the identification of “nuclein.”. (shrink)

The recent historiography of molecular biology features key technologies, instruments and materials, which offer a different view of the field and its turning points than preceding intellectual and institutional histories. Radioisotopes, in this vein, became essential tools in postwar life science research, including molecular biology, and are here analyzed through their use in experiments on bacteriophage. Isotopes were especially well suited for studying the dynamics of chemical transformation over time, through metabolic pathways or life cycles. Scientists labeled phage with phosphorus-32 (...) in order to trace the transfer of genetic material between parent and progeny in virus reproduction. Initial studies of this type did not resolve the mechanism of generational transfer but unexpectedly gave rise to a new style of molecular radiobiology based on the inactivation of phage by the radioactive decay of incorporated phosphorus-32. These ‘suicide experiments’, a preoccupation of phage researchers in the mid-1950s, reveal how molecular biologists interacted with the traditions and practices of radiation geneticists as well as those of biochemists as they were seeking to demarcate a new field. The routine use of radiolabels to visualize nucleic acids emerged as an enduring feature of molecular biological experimentation. (shrink)

This paper explores multiple experimental interventions in molecular biology. By “multiple,” we mean that molecular biologists often use different modes of experimental interventions in a series of experiments for one and the same subject. In performing such a series of experiment, scientists may use different modes of interventions to realize plural goals such as testing given hypotheses and exploring novel phenomena. In order to illustrate this claim, we develop a framework of multiple modes of experimental interventions to analyze a series (...) of experiments for a single subject. Our argument begins with a brief characterization of Craver and Darden’s taxonomy of experiments, because the taxonomy they have made implies various modes of interventions. We propose to extract two interventional directions and two interventional effects from their taxonomy as the basis of classification. The vertical or inter-level direction means that an intervention is performed between different levels of organization and the horizontal or inter-stage direction means that an intervention is performed between different stages of a mechanism. Interventions may produce an excitatory or an inhibitory effect. As a consequence, we can classify modes of interventions according to different directions and effects. We illustrate our claims by doing a case study of the PaJaMo experiment, which is a series of experiments for a single subject. The final goal in this paper is to provide a taxonomy of characteristics of experimentation in which the PaJaMo experiment is adequately located. (shrink)