Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. While several different mathematical and computational methods are developed to study molecular systems at different spatiotemporal (...) scales, there is still a need for methods that bridge the gap between spatially‐detailed and computationally‐efficient approaches. In this review, we summarize the capabilities of agent‐based modeling (ABM) as an emerging molecular systems biology technique that provides researchers with a new tool in exploring the dynamics of molecular systems/pathways in health and disease. (shrink)

Mechanistic models in molecular systems biology are generally mathematical models of the action of networks of biochemical reactions, involving metabolism, signal transduction, and/or gene expression. They can be either simulated numerically or analyzed analytically. Systems biology integrates quantitative molecular data acquisition with mathematical models to design new experiments, discriminate between alternative mechanisms and explain the molecular basis of cellular properties. At the heart of this approach are mechanistic models of molecular networks. We focus on (...) the articulation and development of mechanistic models, identifying five constraints which guide the articulation of models in molecular systems biology. These constraints are not independent of one another, with the result that modeling becomes an iterative process. We illustrate the use of these constraints in the modeling of the mechanism for bistability in the lac operon. (shrink)

The recent dramatic development of molecular neurobiology has focused almost entirely on biological events in individual brain cells, and it seems that many of the goals of such work will soon be attained. Yet, when we attain those goals, we will still have to ask how this information will enable us to understand the properties of brain cell collectivities and their presumptive roles in higher brain functions. Even general ideas about those functions are not yet well defined. Therefore, (...) it seems worthwhile to start studying correlations of the molecular events to these higher functions to help delineate the molecular aspects that need study.It is readily appreciated that we cannot tell what other animal species see, hear, taste, smell and feel when touching something, though we can foresee the time when we will be able to detail the biochemical and biophysical consequences of all inputs to those senses. Thus, however deep our understanding of the biology of those species, we are unable to establish relations between their biological responses to inputs and their presumptive mental perceptions. Even though humans can use language to talk about those perceptions, we cannot even verify whether someone else's perceptions are the same as our own, as with the old question of whether two individuals see the same thing when viewing something blue. Questions about still higher mental functions of human brains are even less accessible to analysis and can be approached at best, by using correlations. In this article are a number of such questions and their current correlation‐level answers. (shrink)

The successes of molecular developmental biology over the last ten years have been particularly impressive in those directions favored by its major paradigms. New technologies have both guided and been guided by the progress of the field. I review briefly some of the major insights into embryonic development that have derived from research in four specific areas: early embryogenesis of various forms; “pattern formation”; evolutionary conservation of regulatory elements; and spatial mechanisms of gene regulation. There remain many (...) major problem areas, some of which may require new orientations to solve. (shrink)

Philosophical discussion of molecular and developmental biology began in the late 1960s with the use of genetics as a test case for models of theory reduction. With this exception, the theory of natural selection remained the main focus of philosophy of biology until the late 1970s. It was controversies in evolutionary theory over punctuated equilibrium and adaptationism that first led philosophers to examine the concept of developmental constraint. Developmental biology also gained in prominence in the 1980s (...) as part of a broader interest in the new sciences of self-organization and complexity. The current literature in the philosophy of molecular and developmental biology has grown out of these earlier discussions under the influence of twenty years of rapid and exciting growth of empirical knowledge. Philosophers have examined the concepts of genetic information and genetic program, competing definitions of the gene itself and competing accounts of the role of the gene as a developmental cause. The debate over the relationship between development and evolution has been enriched by theories and results from the new field of 'evolutionary developmental biology'. Future developments seem likely to include an exchange of ideas with the philosophy of psychology, where debates over the concept of innateness have created an interest in genetics and development. (shrink)

Despite the transformation in biological practice and theory brought about by discoveries in molecular biology, until recently philosophy of biology continued to focus on evolutionary biology. When the Human Genome Project got underway in the late 1980s and early 1990s, philosophers of biology -- unlike historians and social scientists -- had little to add to the debate. In this landmark collection of essays, Sahotra Sarkar broadens the scope of current discussions of the philosophy of (...) class='Hi'>biology, viewing molecular biology as a unifying perspective on life that complements that of evolutionary biology. His focus is on molecular biology, but the overriding question behind these papers is what molecular biology contributes to all traditional areas of biological research.Molecular biology -- described with some foresight in a 1938 Rockefeller Foundation report as a branch of science in which "delicate modern techniques are being used to investigate ever more minute details" -- and its modeling strategies apparently argue in favor of physical reductionism. Sarkar's first three chapters explore reductionism -- defending it, but cautioning that reduction to molecular interactions is not necessarily a reduction to genetics. The next sections of the book discuss function, exploring how functional explanations pose a problem for reductionism; the informational interpretation of biology and how it interacts with reductionism; and the tension between the unifying framework of molecular biology and the received framework of evolutionary theory. The concluding chapter is an essay in the emerging field of developmental evolution, exploring what molecular biology may contribute to the transformation of evolutionary theory as evolutionary theory takes into account morphogenetic development. (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)

In this fascinating study, the author analyzes the conceptual roots of molecular biology and the social matrix in which it was developed.

One of the most dynamic areas of plant molecular biology is the investigation of the actions of three classes of herbicides: s‐triazines (atrazine, simazine), glyphosate, and sulfonylureas (chlorsulfuron, sulfometuron methyl) (Figure 1). The results of this work are expected to provide the first significant applications of plant biotechnology: directly, in the genetic engineering of crop plants resistant to specific herbicides and, indirectly, in providing a molecular basis for the rational design of new herbicides for specific biological targets.s‐Triazines (...) affect photosynthesis by inhibiting the binding of quinones to the chloroplast membrane QB protein. An s‐triazine resistant QB protein isolated from weeds in fields consistently treated with the herbicide has a serine in place of a glycine in this highly conserved protein. Glyphosate inhibits 5‐enolpyruvyl‐shikimate‐3‐phosphate synthase (EPSP synthase), an enzyme in the aromatic amino acid biosynthetic pathway. Mutagenized bacteria produce a resistant EPSP synthase with a substitution of serine for proline. Sulfonylureas inhibit the acetolactate synthase (ALS) of bacteria, yeast, and higher plants; this enzyme catalyzes the first step in the synthesis of branched chain amino acids. Resistant ALS has been found in bacteria, yeast and tobacco with a proline substituted by serine in yeast ALS. These findings provide a strong basis for developing projected plant biotechnology applications. (shrink)

Molecular biologists exploit information conveyed by mechanistic models for experimental purposes. In this article, I make sense of this aspect of biological practice by developing Keller’s idea of the distinction between ‘models of’ and ‘models for’. ‘Models of (phenomena)’ should be understood as models representing phenomena and are valuable if they explain phenomena. ‘Models for (manipulating phenomena)’ are new types of material manipulations and are important not because of their explanatory force, but because of the interventionist strategies they afford. (...) This is a distinction between aspects of the same model. In molecular biology, models may be treated either as ‘models of’ or as ‘models for’. By analysing the discovery and characterization of restriction–modification systems and their exploitation for DNA cloning and mapping, I identify the differences between treating a model as a ‘model of’ or as a ‘model for’. These lie in the cognitive disposition of the modeller towards the model: a modeller will look at a model as a ‘model of’ if interested in its explanatory force, or as a ‘model for’ if interested in the material manipulations it can possibly afford. (shrink)

Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues has been enabled by recently developed techniques. Ion flows and voltage gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well‐characterized channel mutants. Transmembrane voltage gradients (Vmem) determine anatomical polarity and function (...) as master regulators during appendage regeneration and embryonic left‐right patterning. A state‐of‐the‐art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell‐cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine. (shrink)

This article looks at Deleuze and Guattari's understanding of molecular biology, focusing particularly on their reading of two highly influential works by the eminent French molecular biologists François Jacob and Jacques Monod, La logique du vivant and Le hasard et la nécessité. In these two works, Jacob and Monod present the significance of molecular biology in broadly reductionist terms. What is more, the lac operon model of gene regulation that they propose serves to reinforce the (...) so-called Central Dogma of molecular biology, according to which information passes from DNA to RNA to proteins, with no reverse route. However, Deleuze and Guattari discover intensive potentials within the descriptions of molecular biology offered by both writers. It is argued that Jacob's work in particular, as it has developed in the years since the publication of La logique du vivant in 1970, has itself developed these intensive potentials. (shrink)

Understanding how scientific activities use naming stories to achieve disciplinary status is important not only for insight into the past, but for evaluating current claims that new disciplines are emerging. In order to gain a historical understanding of how new disciplines develop in relation to these baptismal narratives, we compare two recently formed disciplines, systems biology and genomics, with two earlier related life sciences, genetics and molecular biology. These four disciplines span the twentieth century, a period in (...) which the processes of disciplinary demarcation fundamentally changed from those characteristic of the nineteenth century. We outline how the establishment of each discipline relies upon an interplay of factors that include paradigmatic achievements, technological innovation, and social formations. Our focus, however, is the baptism stories that give the new discipline a founding narrative and articulate core problems, general approaches and constitutive methods. The highly plastic process of achieving disciplinary identity is further marked by the openness of disciplinary definition, tension between technological possibilities and the ways in which scientific issues are conceived and approached, synthesis of reductive and integrative strategies, and complex social interactions. The importance – albeit highly variable – of naming stories in these four cases indicates the scope for future studies that focus on failed disciplines or competing names. Further attention to disciplinary histories could, we suggest, give us richer insight into scientific development. (shrink)

Fanconi anaemia (FA) comprises a group of autosomal recessive disorders resulting from mutations in one of eight genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF and FANCG). Although caused by relatively simple mutations, the disease shows a complex phenotype, with a variety of features including developmental abnormalities and ultimately severe anaemia and/or leukemia leading to death in the mid teens. Since 1992 all but two of the genes have been identified, and molecular analysis of their products has revealed a (...) complex mode of action. Many of the proteins form a nuclear multisubunit complex that appears to be involved in the repair of double‐strand DNA breaks. Additionally, at least one of the proteins, FANCC, influences apoptotic pathways in response to oxidative damage. Further analysis of the FANC proteins will provide vital information on normal cell responses to damage and allow therapeutic strategies to be developed that will hopefully supplant bone marrow transplantation. BioEssays 24:439–448, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The Human Genome Project is nearing completion, and shortly we will have access to the complete genetic sequence of an average human being. Hopes are high that the sequence will contribute profoundly to medicine in particular, but also to our understanding of our evolutionary past. Of course, detractors have long insisted that because the HGP represents a victory for formalism in biology, determining the function of DNA sequences will remain an outstanding problem for at least the next several decades. (...) Moreover, it is not clear that having the complete sequence will be significantly useful to biologists seeking to understand gene function in the first place. What can we expect in the postgenomic era? ;I reject the very idea that a complete, encapsulated sequence of a human genome is foundational to biological understanding. I set my investigation within the framework of the ancient debate between preformationists and epigenecists. I survey and conceptually analyze arguments on both sides, especially as they relate to the separation of genetics and embryology in the early part of the twentieth century. I identify modern variants of both preformationism and epigenesis, and note their reconciliation in the form of a Modern Consensus on development established after the neo-Darwinian Synthesis in biology in the 1940s. ;Drawing on recent work in molecular and developmental biology, I challenge the seeming intuitiveness of the Modern Consensus and its subsumption of developmental concerns under the aegis of molecular genetics. I then propose and defend an alternative synthesis of preformationism and epigenesis, and of genetics and developmental biology, according to which development does not reduce to mere gene activation. I underscore the practical benefit of my perspective through a lengthy discussion of the psychiatric genetics approach to schizophrenia. (shrink)

Double‐minute chromosomes play a critical role in tumor cell genetics where they are frequently associated with the overexpression of oncogene products. They have been observed for many years in light microscopic examinations of metaphase chromosomes from tumor cells, but their origin remains unknown and is the subject of considerable speculation. However, molecular details of their structure and organization can now be described in conjunction with the microscopic examinations, to allow an evaluation of the various models that have been developed (...) to explain the genesis of double‐minutes. The evidence now favors simple models that invoke chromosome breakage and circularization of very large acentric chromosome fragments, permitting unequal segregation of the genes on the fragment during cell division. If there is selection for overexpression of one of the genes on the fragment, daughter cells with more fragments will grow faster than daughter cells with fewer fragments, and over time the population of cells will come to contain many double‐minutes per cell. (shrink)

Between November 30th and December 2nd, 2015, the Jacques Loeb Centre for the History and Philosophy of the Life Sciences at Ben-Gurion University of the Negev in Beer Sheva held its Eighth International Workshop under the title “From Genome to Gene: Causality, Synthesis and Evolution”. Eric Davidson, the founder of the concept of developmental Gene Regulatory Networks, had regularly attended the previous meetings, and his participation in this one was expected, but he suddenly passed away 3 months before. In this (...) paper, we provide an introduction and overview on five papers that were presented at the workshop and examine the importance of genomes and gene regulatory networks in extant biology, developmental biology, evolutionary biology and medicine, as well as a collection of remembrances of Eric Davidson, of his personality as well as of his scientific contributions. Historical perspectives are provided, and the ethical issues raised by the new tools developed to modify the genome are also discussed. (shrink)

I have not attempted to provide here an analysis of the methodology of molecular biology or molecular genetics which would demonstrate at what specific points a more reductionist aim would make sense as a research strategy. This, I believe, would require a much deeper analysis of scientific growth than philosophy of science has been able to provide thus far. What I have tried to show is that a straightforward reductionist strategy cannot be said to be follwed in (...) important cases of theory development in molecular biology, and that in at least one important case, the Jacob-Monod operon theory, the methodology followed was more biological than chemical. It should be noted in closing, however, that since biological systems are thought by molecular biologists to be nothing but chemical systems, in the long run detailed investigations of such systems will be in full accord with the dictates suggested by the general reduction model. (shrink)

Thomas Kuhn described the progress of science as comprising occasional paradigm shifts separated by interludes of ‘normal science’. The paradigm that has held sway since the inception of molecular biology is that genes (mainly) encode proteins. In parallel, theoreticians posited that mutation is random, inferred that most of the genome in complex organisms is non‐functional, and asserted that somatic information is not communicated to the germline. However, many anomalies appeared, particularly in plants and animals: the strange genetic phenomena (...) of paramutation and transvection; introns; repetitive sequences; a complex epigenome; lack of scaling of (protein‐coding) genes and increase in ‘noncoding’ sequences with developmental complexity; genetic loci termed ‘enhancers’ that control spatiotemporal gene expression patterns during development; and a plethora of ‘intergenic’, overlapping, antisense and intronic transcripts. These observations suggest that the original conception of genetic information was deficient and that most genes in complex organisms specify regulatory RNAs, some of which convey intergenerational information. Also see the video abstract here: https://youtu.be/qxeGwahBANw. (shrink)

In recent times, the exponential growth of sequenced genomes and structural knowledge of proteins, as well as the development of computational tools and controlled vocabularies to deal with this growth, has fueled a demand for conceptual clarification regarding the concept of function in molecular biology. In this article, we will attempt to develop an account of function fit to deal with the conceptual/philosophical problems in that domain, but which can be extended to other areas of biology. (...) To provide this account, we will argue for three theses: (1) some authors have confused metatheoretical issues (about the meaning and application criteria of terms) with metaphysical ones (about teleology); this led them to (2) look for explicit definitions of “function”, in terms of necessary and sufficient criteria of application, in order to make the concept of function eliminable; however, (3) if one leaves metaphysical worries aside and focuses on functional attribution practices, it is more adequate to say that the concept of function has an open texture. That is, that a multiplicity of application criteria is available, none of which is sufficient nor necessary to attribute a function to a trait, and which only in concert form a clear picture. We distinguish this thesis from some usual forms of pluralism. Finally, we will illustrate this account with a historical reconstruction of the ascription of a water transport function to aquaporins. (shrink)

This paper argues that the consensus physicalist antireductionism in the philosophy of biology cannot accommodate the research strategy or indeed the recent findings of molecular developmental biology. After describing Wolperts programmatic claims on its behalf, and recent work by Gehring and others to identify the molecular determinants of development, the paper attempts to identify the relationship between evolutionary and developmental biology by reconciling two apparently conflicting accounts of bio-function – Wrights and Nagels (as elaborated (...) by Cummins). Finally, the paper seeks a way of defending the two central theses of physicalist antireductionism in the light of the research program of molecular developmental biology, by sharply reducing their metaphysical force. (shrink)

RESUMEN: Abir-Am ha criticado la visión estándar de que la Fundación Rockefeller (FR) jugó un papel central en el surgimiento de la biología molecular durante la década de 1960. En su opinión, la FR aceleró la molecularización de las ciencias de la vida, pero no intervino de manera directa en el surgimiento de la biología molecular como disciplina. Aquí sostengo que esta crítica tiene consecuencias mayores a las que sospechó su autora y muestro que la tesis de la (...) centralidad de la FR en el desarrollo de la biología molecular no se puede desmantelar sin alterar también la visión de la biologia molecular como una disciplina orientada a la resolución de problemas predefinidos.ABSTRACT: Abir-Am has critiqued the standard view that the Rockefeller Foundation (RF) played a central role in the development of molecular biology during the 1960s. In her view, the RF accelerated the molecularization of the life sciences, but it did not directly contribute to building molecular biology’s disciplinary identity. Here I argue that Abir-Am’s critique has more consequences than she envisioned, and I show that the thesis of the centrality of the RF cannot be dismantled without also altering the view of molecular biology as a field oriented towards the solution of predefined problems. (shrink)

Thanks to the extensive use of recombinant DNA technology and immunological methods, much insight into cellular functions of the human malaria parasite Plasmodium falciparum has been gained since it was learnt ten years ago how to grow this organism in culture. The amino acid sequence of over a dozen surface proteins of the parasite and of several proteins the parasite excretes into its most important host cell, the erythrocyte, have been determined. Interestingly many of these proteins show blocks of repeated (...) amino acids. Several proteins have been shown to be involved in specific aspects of the complex hostparasite interaction, such as penetration of host cells or increased stickiness of infected red blood cells in the blood vessels. Some of the proteins described here may be protective antigens and may become important in vaccine development. (shrink)

A number of roles have been ascribed to poly(ADP‐ribose) polymerase* including involvement in DNA repair, cell proliferation, differentiation and transformation. Cloning of the gene has allowed the development of molecular biological approaches to elucidate the structure and the function(s) of this highly conserved enzyme. This article will review the recent results obtained in this field.

This paper proposes an experiment-based methodology for both classical genetics and molecular biology by integrating Lindley Darden’s mechanism-centered approach and C. Kenneth Waters’s phenomenon-centered approach. We argue that the methodology basing on experiments offers a satisfactory account of the development of the two biological disciplines. The methodology considers discovery of new mechanisms, investigation of new phenomena, and construction of new theories together, in which experiments play a central role. Experimentation connects the three type of conduct, which work (...) as both ends and means, occurring in a circular way and constituting an overall process of scientific practice from classical genetics to molecular biology. (shrink)

Ancient DNA has been discovered in many types of preserved biological material, including bones, mummies, museum skins, insects in amber and plant fossils, and has become an important research tool in disciplines as diverse as archaeology, conservation biology and forensic science. In archaeology, ancient DNA can contribute both to the interpretation of individual sites and to the development of hypotheses about past populations. Site interpretation is aided by DNA‐based sex typing of fragmentary human bones, and by the use (...) of genetic techniques to assess the degree of kinship between the remains of different individuals. On a broader scale, population migrations can be traced by studying genetic markers in ancient DNA, as in recent studies of the colonisation of the Pacific islands, while ancient DNA in preserved plant remains can provide information on the development of agriculture. (shrink)

1900 was a remarkable year for science. Several ground-breaking events took place, in physics, biology and psychology. Planck introduced the quantum concept, the work of Mendel was rediscovered, and Sigmund Freud published The Interpretation of Dreams . These events heralded the emergence of completely new areas of inquiry, all of which greatly affected the intellectual landscape of the 20 th century, namely quantum physics, genetics and psychoanalysis. What do these developments have in common? Can we discern a family likeness, (...) a basic affinity between them, so that we can use the one to deepen our understanding of the other? One common denominator is that they open up realms of inquiry that are significantly different from the world of everyday experience, namely the realm of elementary particles, of genes and genomes, and of the unconscious. But to what extent can we meaningfully argue, for instance, that the genome is the biological unconscious, and the unconscious the psychic genome? To address these questions, I will build on the work of two key intellectual figures who have explored the affinities of these developments in depth, namely Erwin Schrödinger (a quantum physicist and avid reader of Schopenhauer who initiated molecular biology) and Jacques Lacan (who reframed the specificity of psychoanalysis with the help of 20 th century science: the era of structural linguistics, but also of quantum physics, molecular biology, bioinformatics and DNA). (shrink)

In 1973-1974 Stanley N. Cohen of Stanford and Herbert W. Boyer of the University of California, San Francisco, developed a laboratory process for joining and replicating DNA from different species. In 1974 Stanford and UC applied for a patent on the recombinant DNA process; the U.S. Patent Office granted it in 1980. This essay describes how the patenting procedure was shaped by the concurrent recombinant DNA controversy, tension over the commercialization of academic biology, governmental deliberations over the regulation of (...) genetic engineering research, and national expectations for high technology as a boost to the American economy. The essay concludes with a discussion of the patent as a turning point in the commercialization of molecular biology and a harbinger of the social and ethical issues associated with biotechnology today. (shrink)

In 1809--the year of Charles Darwin's birth--Jean-Baptiste Lamarck published Philosophie zoologique, the first comprehensive and systematic theory of biological evolution. The Lamarckian approach emphasizes the generation of developmental variations; Darwinism stresses selection. Lamarck's ideas were eventually eclipsed by Darwinian concepts, especially after the emergence of the Modern Synthesis in the twentieth century. The different approaches--which can be seen as complementary rather than mutually exclusive--have important implications for the kinds of questions biologists ask and for the type of research they conduct. (...) Lamarckism has been evolving--or, in Lamarckian terminology, transforming--since Philosophie zoologique's description of biological processes mediated by "subtle fluids." Essays in this book focus on new developments in biology that make Lamarck's ideas relevant not only to modern empirical and theoretical research but also to problems in the philosophy of biology. Contributors discuss the historical transformations of Lamarckism from the 1820s to the 1940s, and the different understandings of Lamarck and Lamarckism; the Modern Synthesis and its emphasis on Mendelian genetics; theoretical and experimental research on such "Lamarckian" topics as plasticity, soft (epigenetic) inheritance, and individuality; and the importance of a developmental approach to evolution in the philosophy of biology. The book shows the advantages of a "Lamarckian" perspective on evolution. Indeed, the development-oriented approach it presents is becoming central to current evolutionary studies--as can be seen in the burgeoning field of Evo-Devo. Transformations of Lamarckism makes a unique contribution to this research. (shrink)

The transmission of electrical impulses in nerve and muscle cells depends fundamentally on the operation of specific ion channels in their membranes. Recent technical advances in electrical recording from cell membranes have permitted the analysis of the properties of single ion channels and the measurement of gating currents. The results have revealed considerable complexities, in particular in the operation of voltage‐gated sodium channels, and in the relationships between the several open and closed states of the channels. An important new (...) class='Hi'>development is the cloning and analysis of the structural genes for the acetylcholine receptor and sodium channel protein, which promises to yield fresh insights into the functioning of these proteins. (shrink)

Model organisms became an indispensable part of experimental systems in molecular developmental and cell biology, constructed to investigate physiological and pathological processes. They are thought to play a crucial role for the elucidation of gene function, complementing the sequencing of the genomes of humans and other organisms. Accordingly, historians and philosophers paid considerable attention to various issues concerning this aspect of experimental biology. With respect to the representational features of model organisms, that is, their status as models, (...) the main focus was on generalization of phenomena investigated in such experimental systems. Model organisms have been said to be models for other organisms or a higher taxon. This, however, presupposes a representation of the phenomenon in question. I will argue that prior to generalization, model organisms allow researchers to built generative material models of phenomena – structures, processes or the mechanisms that explain them – through their integration in experimental set-ups that carve out the phenomena from the whole organism and thus represent them. I will use the history of zebrafish biology to show how model organism systems, from around 1970 on, were developed to construct material models of molecular mechanisms explaining developmental or physiological processes. (shrink)

Genes in Development is a collection of 13 stimulating essays on "post genomic" approaches to the concept of the gene. At the risk of caricaturing some complex balances, the contributors tend to be skeptical about genetic determinism, the central dogma of molecular biology, reductionism, genes as programs and the concept of the gene as a DNA sequence. They tend to like emergent properties, complexity theory, the parity thesis for developmental resources, developmental systems theory, and membranes. But within (...) this broad weltanschauung the essays in Genes in Development vary widely in their interests and emphases––from the history of twentieth century genetics to the social and ethical issues raised by contemporary genetics––which makes for an attractive and valuable collection. (shrink)

This paper is devoted to an examination of the discovery, characterization, and analysis of the functions of microRNAs, which also serves as a vehicle for demonstrating the importance of exploratory experimentation in current (post-genomic) molecular biology. The material on microRNAs is important in its own right: it provides important insight into the extreme complexity of regulatory networks involving components made of DNA, RNA, and protein. These networks play a central role in regulating development of multicellular organisms and (...) illustrate the importance of epigenetic as well as genetic systems in evolution and development. The examination of these matters yields principled arguments for the historicity of the functions of key biological molecules and for the indispensability of exploratory experimentation in contemporary molecular biology as well as some insight into the complex interplay between exploratory experimentation and hypothesis-driven science. This latter result is not only important for philosophy of science, but also of practical importance for the evaluation of grant proposals, although the elaboration of this latter claim must be left for another occasion. (shrink)

The comprehension of living organisms in all their complexity poses a major challenge to the biological sciences. Recently, systems biology has been proposed as a new candidate in the development of such a comprehension. The main objective of this paper is to address what systems biology is and how it is practised. To this end, the basic tools of a systems biological approach are explored and illustrated. In addition, it is questioned whether systems biology ‘revolutionizes’ (...) class='Hi'>molecular biology and ‘transcends’ its assumed reductionism. The strength of this claim appears to depend on how molecular and systems biology are characterised and on how reductionism is interpreted. Doing credit to molecular biology and to methodological reductionism, it is argued that the distinction between molecular and systems biology is gradual rather than sharp. As such, the classical challenge in biology to manage, interpret and integrate biological data into functional wholes is further intensified by systems biology’s use of modelling and bioinformatics, and by its scale enlargement. (shrink)

In 1937, a group of researchers in Nazi Germany began investigating tobacco mosaic virus with the hope of using the virus as a model system for understanding gene behavior in higher organisms. They soon developed a creative and interdisciplinary work style and were able to continue their research in the postwar era, when they made significant contributions to the history of molecular biology. This group is significant for two major reasons. First, it provides an example of how researchers (...) were able to produce excellent scientific research in the midst of dictatorship and war. Coupled with the group's ongoing success in postwar Germany, the German TMV investigators provide a dramatic example of how scientific communities deal with adversity as well as rapid political and social change. Second, since the researchers focused heavily on TMV, their story allows us to analyze how an experimental system other than phage contributed to the emergence of molecular biology. (shrink)

The comprehension of living organisms in all their complexity poses a major challenge to the biological sciences. Recently, systems biology has been proposed as a new candidate in the development of such a comprehension. The main objective of this paper is to address what systems biology is and how it is practised. To this end, the basic tools of a systems biological approach are explored and illustrated. In addition, it is questioned whether systems biology ‘revolutionizes’ (...) class='Hi'>molecular biology and ‘transcends’ its assumed reductionism. The strength of this claim appears to depend on how molecular and systems biology are characterised and on how reductionism is interpreted. Doing credit to molecular biology and to methodological reductionism, it is argued that the distinction between molecular and systems biology is gradual rather than sharp. As such, the classical challenge in biology to manage, interpret and integrate biological data into functional wholes is further intensified by systems biology’s use of modelling and bioinformatics, and by its scale enlargement. (shrink)

Biologists and historians often present natural history and molecular biology as distinct, perhaps conflicting, fields in biological research. Such accounts, although supported by abundant evidence, overlook important areas of overlap between these areas. Focusing upon examples drawn particularly from systematics and molecular evolution, I argue that naturalists and molecular biologists often share questions, methods, and forms of explanation. Acknowledging these interdisciplinary efforts provides a more balanced account of the development of biology during the post-World (...) War II era. (shrink)

In light of scientific advances such as genomics, predictive diagnostics, genetically engineered agriculture, nuclear transfer cloning, and the manipulation of stem cells, the idea that genes carry predetermined molecular programs or blueprints is pervasive. Yet new scientific discoveries—such as rna transcripts of single genes that can lead to the production of different compounds from the same pieces of dna—challenge the concept of the gene alone as the dominant factor in biological development. Increasingly aware of the tension between certain (...) empirical results and interpretations of those results based on the orthodox view of genetic determinism, a growing number of scientists urge a rethinking of what a gene is and how it works. In this collection, a group of internationally renowned scientists present some prominent alternative approaches to understanding the role of dna in the construction and function of biological organisms. Contributors discuss alternatives to the programmatic view of dna, including the developmental systems approach, methodical culturalism, the molecular process concept of the gene, the hermeneutic theory of description, and process structuralist biology. None of the approaches cast doubt on the notion that dna is tremendously important to biological life on earth; rather, contributors examine different ideas of how dna should be represented, evaluated, and explained. Just as ideas about genetic codes have reached far beyond the realm of science, the reconceptualizations of genetic theory in this volume have broad implications for ethics, philosophy, and the social sciences. Contributors. Thomas Bürglin, Brian C. Goodwin, James Griesemer, Paul Griffiths, Jesper Hoffmeyer, Evelyn Fox Keller, Gerd B. Müller, Eva M. Neumann-Held, Stuart A. Newman, Susan Oyama, Christoph Rehmann-Sutter, Sahotra Sarkar, Jackie Leach Scully, Gerry Webster, Ulrich Wolf. (shrink)

Caenorhabditis elegans is a tiny worm that has become the focus of a large number of worldwide research projects examining its genetics, development, neuroscience, and behavior. Recently several groups of investigators have begun to tie together the behavior of the organism and the underlying genes, neural circuits, and molecular processes implemented in those circuits. Behavior is quintessentially organismal—it is the organism as a whole that moves and mates—but the explanations are devised at the molecular and neurocircuit levels, (...) and tested in populations using protocols that span many levels of aggregation. Following a brief review of the main relevant features of C. elegans, I describe some of these circuits, and then discuss two contrasting approaches in behavioral genetics and neural network analysis of the worm. Finally, I outline the rudiments of a “field and focus” explanation model using the two contrasting approaches. (shrink)

It was no accident that the first neuroscience community, the Neurosciences Research Program (NRP), took shape in the 1960s at MIT, the birthplace of cybernetics. Francis O. Schmitt, known as the founding father of the NRP, was a famous biologist and an avid reader of cybernetics. Focusing on the intellectual and institutional context that Schmitt was situated in, this article unveils the way that the brain was conceptualized as a distinct object, requiring the launch of a new research community in (...) the US. In doing so, this article moves beyond the dominant narratives on the triumph of molecularization of the brain at the beginning of neuroscience. Instead, it argues that what brought researchers together in the name of neuroscience was not just a molecule but an aspiration to develop biological theories of the brain/mind, which resonated with biologists in a postwar context and was materialized through support for basic research. The article highlights the tension over the computerization and molecularization of the brain, which shaped the interdisciplinary gathering of neuroscientists in the context of growing interest in basic research. Thereby, this article reveals the rise of theoretical concerns in brain science that reflect the distinct desires and concerns of biologists in the US at an intellectual and institutional level. By revisiting the launch of the NRP with a focus on Schmitt, the article sheds light on the historical contingencies in launching the new community as neuroscience in the US and their meaning for the locality and transiency of (inter)disciplinarity in brain science. (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 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: (1) A theoretical framework is present in molecular biology, exerting its influence in hypothesis formation and evaluation; (2) 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; (3) 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 (4) 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, as outlined by both Francis Crick and James Watson, will be given. The developments in scrapie research from 1965 to 1972 will then be traced. This section will summarize many of the puzzling, non-viral-like properties of the scrapie agent. Alternative hypotheses to the viral explanation will also be 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 balanced 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)

This essay considers how scholarly approaches to the development of molecular biology have too often narrowed the historical aperture to genes, overlooking the ways in which other objects and processes contributed to the molecularization of life. From structural and dynamic studies of biomolecules to cellular membranes and organelles to metabolism and nutrition, new work by historians, philosophers, and STS scholars of the life sciences has revitalized older issues, such as the relationship of life to matter, or of (...) physicochemical inquiries to biology. This scholarship points to a novel molecular vista that opens up a pluralist view of molecularizations in the twentieth century and considers their relevance to current science. (shrink)

ArgumentThis paper examines the role of metaphors in science on the basis of a historical case study. The study explores how metaphors of “genetic information,” “genetic code,” and scripture representations of heredity entered molecular biology and reshaped experimentation during the 1950s and 1960s. Following the approach of the philosopher Hans Blumenberg, I will argue that metaphors are not merely a means of popularization or a specific kind of modeling but rather are representations that can unfold an operational force (...) of their own.While the influence of cybernetics and information theory on molecular biology is well documented in historical analysis throughout recent years, this paper offers new insights into the metaphysical and religious resonances of textual metaphors in the life sciences. The main focus will be on developments in Germany, in particular on the work of the German biochemist Gerhard Schramm. In this historical case study the interaction between metaphors and experimental practices will be discussed. The paper analyzes different phases in the use of metaphors during the 1950s and 1960s: it will explore how the metaphors of a “genetic alphabet” or of “genetic code” developed into a new research program and eventually attained ontological status in the early 1960s. At that time Schramm's use of textual metaphors was reminiscent of nineteenth-century German natural philosophy. In this case, the metaphorical shift shows how the metaphor of a “genetic text” or a “genetic code,” which were central for the emerging molecular biology, drew on older cultural traditions with all of their metaphysical and religious preoccupations. (shrink)

This article shows how Lamarckism was essential in the birth of the French school of molecular biology. We argue that the concept of inheritance of acquired characters positively shaped debates surrounding bacteriophagy and lysogeny in the Pasteurian tradition during the interwar period. During this period the typical Lamarckian account of heredity treated it as the continuation of protoplasmic physiology in daughter cells. Félix d’Hérelle applied this conception to argue that there was only one species of bacteriophage and Jules (...) Bordet applied it to develop an account of bacteriophagy as a transmissible form of autolysis and to analyze the new phenomenon of lysogeny. In a long-standing controversy with Bordet, Eugène Wollman deployed a more morphological understanding of the inheritance of acquired characters, yielding a particulate, but still Lamarckian, account of lysogeny. We then turn to André Lwoff who, with several colleagues, completed Wollman’s research program from 1949 to 1953. We examine how he gradually set aside the Lamarckian background, finally removing inheritance of acquired characters from the resulting account of bacteriophagy and lysogeny. In the conclusion, we emphasize the complex dual role of Lamarckism as it moved from an assumed explanatory framework to a challenge that the nascent molecular biology had to overcome. (shrink)

Preparative and analytical methods developed by separation scientists have played an important role in the history of molecular biology. One such early method is gel electrophoresis, a technique that uses various types of gel as its supporting medium to separate charged molecules based on size and other properties. Historians of science, however, have only recently begun to pay closer attention to this material epistemological dimension of biomolecular science. This paper substantiates the historiographical thread that explores the relationship between (...) modern laboratory practice and the production of scientific knowledge. It traces the historical development of gel electrophoresis from the mid-1940s to the mid-1960s, with careful attention to the interplay between technical developments and disciplinary shifts, especially the rise of molecular biology in this time-frame. Claiming that the early 1950s marked a decisive shift in the evolution of electrophoretic methods from moving boundary to zone electrophoresis, I reconstruct various trajectories in which scientists such as Oliver Smithies sought out the most desirable solid supporting medium for electrophoretic instrumentation. Biomolecular knowledge, I argue, emerged in part from this process of seeking the most appropriate supporting medium that allowed for discrete molecular separation and visualization. The early 1950s, therefore, marked not only an important turning point in the history of separation science, but also a transformative moment in the history of the life sciences as the growth of molecular biology depended in part on the epistemological access to the molecular realm available through these evolving technologies. (shrink)

Cell lines and cell samples from patients provide opportunities for studying the mechanisms of leukemic cellular differentiation and proliferation. Phorbol esters and 1,25 dihydroxy vitamin D3 can induce differentiation of myeloid leukemic cells to macrophages. Differentiation to granulocytes can be induced by several different compounds. Myeloid differentiation is associated closely with the alteration in expression of several oncogenes. These regulatory events may be associated with the extent of methylation, unfolding or association of chromatin to the nuclear matrix. Oncogene amplification, mutation, (...) or deletion can occur with malignant transformation. Future studies point to the development of specific pharmacological agents which can modify the neoplastic transformation. (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 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, as outlined by both Francis Crick and James Watson, will be given. The developments in scrapie research from 1965 to 1972 will then be traced. This section will summarize many of the puzzling, non-viral-like properties of the scrapie agent. Alternative hypotheses to the viral explanation will also be 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 balanced 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)