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 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)

By their own account, physicalists are committed to the claim that physics is causally complete, or closed. The claim is presented as an empirical one. However, detailed and explicit empirical arguments for the claim are rare. I argue that molecular models are a key source of evidence but that, on closer inspection, they do not support the completeness claim.

We present a molecular model of eukaryotic gene transcription. For the β‐globin locus, we hypothesise that a transcription machine composed of multiple RNA polymerase II (PolII) assembles using the locus control region as a foundation. Transcription and locus remodelling can be achieved by pulling DNA through this multi‐PolII ‘reading head’. Once a transcription complex is formed, it may engage an active gene in several rounds of transcription. Observed intergenic sense and antisense transcripts may be the result of PolII pulling (...) the DNA through the reading head whilst searching for the promoter of a gene. Support for this hypothesis is provided using various data from the literature. In the model, DNA is packed in a 30‐nm chromatin fibre, thus gene regulatory regions separated by kilobases are close in space. This, and the need to store transcription‐induced supercoiling, may explain why functionally interacting regions are often separated by many kilobases. (shrink)

The practice of theoretical research in chemistry largely consists in the construction of models without which experimentation would be impossible. The best-known theoretical models in chemistry are those of the molecular structures of chemical compounds. What is the correspondence between these models and the unobservable entities that they are meant to explain? What is the ontological status of molecular models? The anti-realists question the basis of the realists’ belief in these entities and the truth (...) claims regarding them. Ultimately, the realist/anti-realist debate points to the question of the scope of scientific knowledge. In this paper, I shall show that the description of natural entities offered by the contemporary scientific worldview reveals that molecular modeling presupposes a realistic epistemology that recognizes the limits of scientific objectification. (shrink)

One important aspect of biological explanation is detailed causal modeling of particular phenomena in limited experimental background conditions. Recognising this allows one to appreciate that a sufficient condition for a reduction in biology is a molecular model of (1) only the demonstrated causal parameters of a biological model and (2) only within a replicable experimental background. These identities—which are ubiquitous in biology and form the basis of ruthless reductions (Bickle, Philosophy and neuroscience: a ruthlessly reductive account, 2003)—are criticised as (...) merely “local” (Sullivan, Synthese 167:511–539, 2009) or “fragmentary” (Schaffner, Synthese, 151(3):377–402, 2006). However, in an instructive case, a biological model is preserved in molecular terms, demonstrating a complex phenomenon that has been successfully reduced. (shrink)

This paper approaches the scientific realism question from a naturalistic perspective. On the basis of a historical case study of the work of James Clerk Maxwell and Ludwig Boltzmann on the kinetic theory of gases, it shows that scientists’ views about the epistemological status of theories and models typically interact with their scientific results. Subsequently, the implications of this result for the current realism debate are analysed. The case study supports Giere’s moderately realist view of scientific models and (...) theories, based on the notion of similarity, and it highlights the crucial role of model users. The paper concludes with a discussion of Boltzmann’s Bildtheorie, the sophisticated form of realism that he developed in response to the scientific problems of kinetic theory. (shrink)

This paper approaches the scientific realism question from a naturalistic perspective. On the basis of a historical case study of the work of James Clerk Maxwell and Ludwig Boltzmann on the kinetic theory of gases, it shows that scientists’ views about the epistemological status of theories and models typically interact with their scientific results. Subsequently, the implications of this result for the current realism debate are analysed. The case study supports Giere’s moderately realist view of scientific models and (...) theories, based on the notion of similarity, and it highlights the crucial role of model users. The paper concludes with a discussion of Boltzmann’s Bildtheorie, the sophisticated form of realism that he developed in response to the scientific problems of kinetic theory. (shrink)

By comparing chemistry to art, chemists have recently made claims to the aesthetic value, even beauty, of some of their products. This paper takes these claims seriously and turns them into a systematic investigation of the aesthetics of chemical products. I distinguish three types of chemical products - materials, molecules, and molecular models - and use a wide variety of aesthetic theories suitable for an investigation of the corresponding sorts of objects. These include aesthetics of materials, idealistic aesthetics (...) from Plato to Kant and Schopenhauer, psychological approaches of Ernst Gombrich and Rudolf Arnheim, and semiotic aesthetics of Nelson Goodman and Umberto Eco. Although the investigation does not support recent claims, I point out where aesthetics does and can play an import role in chemistry. Particularly, Eco's approach helps us understand that and how aesthetic experience can be a driving force in chemical research. (shrink)

The first models for an electromagnetic theory of dispersion are presented and an attempt is made to demonstrate the important role played by study of this phenomenon at the end of the nineteenth century. As well as indicating the need to have a better understanding of the microscopic properties of matter, dispersion also contributed to the discussion over the nature of X-rays and was fundamental for introduction of Lorentz's electron theory.

This paper approaches the scientific realism question from a naturalistic perspective. On the basis of a historical case study of the work of James Clerk Maxwell and Ludwig Boltzmann on the kinetic theory of gases, it shows that scientists’ views about the epistemological status of theories and models typically interact with their scientific results. Subsequently, the implications of this result for the current realism debate are analysed. The case study supports Giere’s moderately realist view of scientific models and (...) theories, based on the notion of similarity, and it highlights the crucial role of model users. The paper concludes with a discussion of Boltzmann’s Bildtheorie, the sophisticated form of realism that he developed in response to the scientific problems of kinetic theory. (shrink)

In Molecular Models: Philosophical Papers on Molecular Biology, Sahotra Sarkar presents a historical and philosophical analysis of four important themes in philosophy of science that have been influenced by discoveries in molecular biology. These are: reduction, function, information and directed mutation. I argue that there is an important difference between the cases of function and information and the more complex case of scientific reduction. In the former cases it makes sense to taxonomise important variations in scientific (...) and philosophical usage of the terms function and information . However, the variety of usage of reduction across scientific disciplines (and across philosophy of science) makes such taxonomy inappropriate. Sarkar presents reduction as a set of facts about the world that science has discovered, but the facts in question are remarkably disparate; variously semantic, epistemic and ontological. I argue that the more natural conclusion of Sarkar’s analysis is eliminativism about reduction as a scientific concept. (shrink)

The use of physical models of molecular structures as research tools has been central to the development of biochemistry and molecular biology. Intriguingly, it has received little attention from scholars of science. In this paper, I argue that these physical models are not mere three-dimensional representations but that they are in fact very special research tools: they are cognitive augmentations. Despite the fact that they are external props, these models serve as cognitive tools that augment (...) and extend the modeler’s cognitive capacities and performance in molecular modeling tasks. This cognitive enhancement is obtained because of the way the modeler interacts with these models, the models’ materiality contributing to the solving of the molecule’s structure. Furthermore, I argue that these material models and their component parts were designed, built and used specifically to serve as cognitive facilitators and cognitive augmentations. (shrink)

In the first decades of the nineteenth century the French mechanicians—Cauchy and Poisson amongst them—developed a theory of linear elasticity according to which matter is composed of material points. They believed that these points interact by means of opposite central forces, whose magnitude depends on the length of the segment joining the particles. This theory suggested that homogeneous isotropic materials were characterized by a unique elastic constant. Later experiments, however, showed that two elastic constants were necessary. These results undermined the (...) corpuscular model of matter as well as the interpretation of elasticity in terms of central intermolecular actions. The continuous theory of Green, based on the postulate that a potential function exists, gained fresh consensus in light of these experiments. These opposite views continued throughout the nineteenth century until Woldemar Voigt proposed a molecular model confirmed by experiments. This article presents the theories of each of these scientists and describes the contrasting views of nineteenth-century mechanicians. (shrink)

Summary In 1874, the Dutch chemist and Nobel prizewinner Jacobus Henricus van 't Hoff (1852?1911) laid the foundations for stereochemistry with a publication in which he openly suggested that molecules were real physical entities with a three-dimensional structure. He visualized this new spatial concept with illustrations, but also with the help of small cardboard molecular models, which he made himself. Some of these models have survived the ravages of time and are among the oldest molecular (...) class='Hi'>models in the world still in existence. What is more, they are the first material models of a three-dimensional molecular structure ever made. This article describes the surviving Van 't Hoff models, kept in Museum Boerhaave in Leiden and in the Deutsches Museum in Munich. Special attention is paid to the use of these models and the specific purposes they served. A closer examination of the models and their context reveals that they had an essential part to play in the early development and spread of Van 't Hoff's stereochemistry theory: he put his molecular models not only to versatile use as didactic tools, scientific instruments, and precursors to experimental proof, but also as devices to persuade other scientists of the usefulness of his theory. (shrink)

As supposed in the last Editorial (HYLE, 5-1, p. 78), our special topic ‘Models in Chemistry’ has attracted new attention to the philosophy of chemistry. Only during the past couple of month, the number of visitors of the HYLE website has nearly doubled to some 1,600 per month. There is nothing comparable in the whole field of philosophy of science, as there is no other science having such a lot to catch up on philosophical work. At the same time, (...) this means a great challenge to meet the expectation of such a large and heterogeneous readership. (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)

This paper explores the epistemology of extrapolation from model organisms to humans in molecular medicine. We take into account two common views on the issue, the homology view and the disanalogy view. In response to both interpretations, we argue that the foundational basis of extrapolations cannot simply be provided by homology and that relevant disanalogies can, thanks to the techniques of molecular biology, be experimentally controlled and exploited to allow useful and reliable extrapolations. The case of "humanised mice" (...) in the context of cancer stem cell research provides evidence of how animal models can be construed to approximate bona fide causal analogue models of human diseases. To supplement this view we show how the epistemology of model organisms needs to take into account the engineering side of molecular medicine. Model organisms are often manipulated to create analogies or remove disanalogies with the target system. We maintain that highlighting this feature is fundamental to explain what warrants extrapolation in the search for the molecular causes of disease. (shrink)

We apply molecular code theory to a rule-based model of the human inner kinetochore and study how complex formation in general can give rise to molecular codes. We analyze 105 reaction networks generated from the rule-based inner kinetochore model in two variants: with and without dissociation of complexes. Interestingly, we found codes only when some but not all complexes are allowed to dissociate. We show that this is due to the fact that in the kinetochore model proteins can (...) only bind at kinetochores by attaching to already attached proteins and cannot form complexes in free solution. Using a generalized linear mixed model we study which centromere protein can take which role in a molecular code . By this, associations between CENPs and code roles are found. We observed that CenpA is a major risk factor while CenpQ is a major protection factor . Finally we show, using an abstract model of copolymer formation, that molecular codes can also be realized solely by the formation of stable complexes, which do not dissociate. For example, with particular dimers as context a molecular code mapping from two different monomers to two particular trimers can be realized just by non-selective complex formation. We conclude that the formation of protein complexes can be utilized by the cell to implement molecular codes. Living cells thus facilitate a subsystem allowing for an enormous flexibility in the realization of mappings, which can be used for specific regulatory processes, e.g. via the context of a mapping. (shrink)

Many lymphokine genes have now been cloned from activated T cells and their products have been expressed in mammalian cells. Use of these recombinant lymphokines has provided the opportunity to evaluate both the spectrum of their biological activities and the mechanisms of their action in promoting proliferation and differentiation of hemopoietic and lymphoid cells. Characterization of the structure of lymphokine genes will provide information about their regulated expression in T‐cell activation.

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)

We desperately need to know more of the biological details of the onset and progression of breast cancer. The disease is of startlingly high incidence (approaching 1 in 9 women), our current therapies for the disease are inadequate once it has metastasized, and the disease is characterized by excessive morbidity and mortality.Most of the growth and differentiation of the mammary gland occurs relatively late in life: during sexual maturation, and then cyclically during pregnancy and lactation. Normal as well as malignant (...) growth is regulated by endocrine hormones as well as by local tissue factors, such as polypeptide growth factors, Cancer seems to progress as hyperplastic ductal or lobular epithelial growth, acquiring progressive genetic changes (including those of oncogenes and tumor suppressor genes) leading to clonal outgrowths of progressively more malignant cells. The nature of proliferative controls and the relevant genetic changes are the subjects of the current review. (shrink)

This book explains the role of simple biological model systems in the growth of molecular biology. Essentially the whole history of molecular biology is presented here, tracing the work in bacteriophages in E. coli, the role of other prokaryotic systems, and also the protozoan and algal models—Paramecium and Chlamydomonas, primarily—and the move into eukaryotes with the fungal systems Neurospora, Aspergillus and yeast. Each model was selected for its appropriateness for asking a given class of questions, and each (...) spawned its own community of investigators. Some individuals made the transition to a new model over time, and remnant communities of investigators continue to pursue questions in all these models, as the cutting edge of molecular biological research flowed onward from model to model, and onward into higher organisms and, ultimately, mouse and man. (shrink)

During the past few decades, philosophers of biology have debated the issue of reductionism versus anti-reductionism, with both sides often claiming a ‘pluralist’ position. However, both sides also tend to focus on a single research paradigm, which analyzes living things in terms of certain macromolecular components. I offer a case study where biologists pursue other analytic pathways, in a tradition of quantitative genetics that originates with the initially purely mathematical theories of R. A. Fisher, J. B. S. Haldane, and Sewall (...) Wright in the 1930s. Aster Models offers a class of statistical models designed for studying the fitness of plant and animal populations, by integrating the measurements of separate, sequential, non-normally distributed fitness components in novel ways. Their work generates important theoretical and practical results that do not require elaboration by molecular biology, and thus serves as a counterexample to the claims of philosophers whose ‘pluralism’ still harbors reductionist assumptions. (shrink)

During the 1930s and 1940s, American physical organic chemists employed electronic theories of reaction mechanisms to construct models offering explanations of organic reactions. But two molecular rearrangements presented enormous challenges to model construction. The Claisen and Cope rearrangements were predominantly inaccessible to experimental investigation and they confounded explanation in theoretical terms. Drawing on the idea that models can be autonomous agents in the production of scientific knowledge, I argue that one group of models in particular were (...) functionally autonomous from the Hughes–Ingold theory. Cope and Hardy’s models of the Claisen and Cope rearrangements were resources for the exploration of the Hughes–Ingold theory that otherwise lacked explanatory power. By generating ‘how-possibly’ explanations, these models explained how these rearrangements could happen rather than why they did happen. Furthermore, although these models were apparently closely connected to theory in terms of their construction, I argue that partial autonomy issued in extra-logical factors concerning the attitudes of American chemists to the Hughes–Ingold theory. And in the absence of a complete theoretical hegemony, a degree of consensus was reached concerning modelling the Claisen rearrangement mechanism.Keywords: Models; Explanation; Physical organic chemistry; Rearrangements. (shrink)

In the 1960s molecular population geneticists used Monte Carlo experiments to evaluate particular diffusion equation models. In this paper I examine the nature of this comparative evaluation and argue for three claims: first, Monte Carlo experiments are genuine experiments: second, Monte Carlo experiments can provide an important meansfor evaluating the adequacy of highly idealized theoretical models; and, third, the evaluation of the computational adequacy of a diffusion model with Monte Carlo experiments is significantlydifferent from the evaluation of (...) the emperical adequacy of the same diffusion model. (shrink)

This paper examines processes of translation through which molecular genetic technologies and practices are incorporated into environmental health research and regulation. Specifically, it considers how scientists, risk assessors, and regulators have used genetically modified mouse models to translate across scientific disciplines, articulate emergent molecular forms, standards, and practices with the extant? gold standard,? and establish roles for molecular knowledge in risk assessment and regulation. Noting variation both within and between regulatory agencies in responses to data from (...) these models, the article describes also the role of public-private networks and their effects on professional and institutional imperatives which shape regulators? responses to the potential applications of these models. The conclusions address the importance of translation for understanding the wider implications of the molecularization of environmental health science. (shrink)

In the last decades, Systems Biology (including cancer research) has been driven by technology, statistical modelling and bioinformatics. In this paper we try to bring biological and philosophical thinking back. We thus aim at making diferent traditions of thought compatible: (a) causality in epidemiology and in philosophical theorizing—notably, the “sufcient-component-cause framework” and the “mark transmission” approach; (b) new acquisitions about disease pathogenesis, e.g. the “branched model” in cancer, and the role of biomarkers in this process; (c) the burgeoning of omics (...) research, with a large number of “signals” and of associations that need to be interpreted. In the paper we summarize frst the current views on carcinogenesis, and then explore the relevance of current philosophical interpretations of “cancer causes”. We try to ofer a unifying framework to incorporate biomarkers and omic data into causal models, referring to a position called “evidential pluralism”. According to this view, causal reasoning is based on both “evidence of diference-making” (e.g. associations) and on “evidence of underlying biological mechanisms”. We conceptualize the way scientists detect and trace signals in terms of information transmission, which is a generalization of the mark transmission theory developed by philosopher Wesley Salmon. Our approach is capable of helping us conceptualize how heterogeneous factors such as micro and macro-biological and psycho-social—are causally linked. This is important not only to understand cancer etiology, but also to design public health policies that target the right causal factors at the macro-level. (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)

In this paper I argue that dispositionalism is the metaphysical theory that can best contribute to the construction of a metaphysical model for Molecular Gastronomy. Molecular Gastronomy is better explained if physical and chemical theories, which lie at the heart of Molecular Gastronomy, and cooking phenomena in general are described in terms of dispositions. This is the reason why trying to construct a metaphysical model for Molecular Gastronomy by using a dispositional metaphysics is a challenge worth (...) taking on. I will thus explore what happens when we bring dispositions in the kitchen, and so the intersection between food, science and metaphysics. The main aim of the paper is then to pave the way toward the development of a metaphysical model for the physical and the chemical aspects behind Molecular Gastronomy. In the first section, I will briefly reconstruct the history of Molecular Gastronomy, give a definition of it and outline its program. In the second section, I will describe the version of dispositionalism that I adopt in this paper. In the third section, I will sketch a dispositional model for Molecular Gastronomy by relying on two case studies. In the fourth and final section I will draw my conclusions and raise some issues deserving further investigation. (shrink)

Although molecular systematists may use the terminology of cladism, claiming that the reconstruction of phylogenetic relationships is based on shared derived states , the latter is not the case. Rather, molecular systematics is based on the assumption, first clearly articulated by Zuckerkandl and Pauling , that degree of overall similarity reflects degree of relatedness. This assumption derives from interpreting molecular similarity between taxa in the context of a Darwinian model of continual and gradual change. Review of the (...) history of molecular systematics and its claims in the context of molecular biology reveals that there is no basis for the “molecular assumption.”. (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)

Together with microtubules and actin microfilaments, ∼11 nm wide intermediate filaments (IFs) constitute the integrated, dynamic filament network present in the cytoplasm of metazoan cells. This network is critically involved in division, motility and other cellular processes. While the structures of microtubules and microfilaments are known in atomic detail, IF architecture is presently much less understood. The elementary ‘building block’ of IFs is a highly elongated, rod‐like dimer based on an α‐helical coiled‐coil structure. Assembly of cytoplasmic IF proteins, such as (...) vimentin, begins with a lateral association of dimers into tetramers and gradually into the so‐called unit‐length filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately yielding mature IFs after a compaction step. For nuclear lamins, however, assembly starts with a head‐to‐tail association of dimers. Recently, X‐ray crystallographic data were obtained for several fragments of the vimentin dimer. Based on the dimer structure, molecular models of the tetramer and the entire filament are now a possibility. BioEssays 25:243–251, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This chapter contains section titled: The Neutral Theory of Molecular Evolution The Molecular Clock The Neutral Null Model Controversy in Molecular Evolution Acknowledgment References Further Reading.