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)

It has become customary to conceptualize the living cell as an intricate piece of machinery, different to a man-made machine only in terms of its superior complexity. This familiar understanding grounds the conviction that a cell's organization can be explained reductionistically, as well as the idea that its molecular pathways can be construed as deterministic circuits. The machine conception of the cell owes a great deal of its success to the methods traditionally used in molecular biology. However, the recent introduction (...) of novel experimental techniques capable of tracking individual molecules within cells in real time is leading to the rapid accumulation of data that are inconsistent with an engineering view of the cell. This paper examines four major domains of current research in which the challenges to the machine conception of the cell are particularly pronounced: cellular architecture, protein complexes, intracellular transport, and cellular behaviour. It argues that a new theoretical understanding of the cell is emerging from the study of these phenomena which emphasizes the dynamic, self-organizing nature of its constitution, the fluidity and plasticity of its components, and the stochasticity and non-linearity of its underlying processes. (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)

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)

In his late years, Thomas Kuhn became interested in the process of scientific specialization, which does not seem to possess the destructive element that is characteristic of scientific revolutions. It therefore makes sense to investigate whether and how Kuhn’s insights about specialization are consistent with, and actually fit, his model of scientific progress through revolutions. In this paper, I argue that the transition toward a new specialty corresponds to a revolutionary change for the group of scientists involved in such a (...) transition. I will clarify the role of the scientific community in revolutionary changes and characterize the incommensurability across specialties as possessing both semantic and methodological aspects. The discussion of the discovery of the structure of DNA will serve both as an illustration of my main argument and as reply to one criticism raised against Kuhn—namely, that his model cannot capture cases of revolutionary yet non-disruptive episodes of scientific progress. Revisiting Kuhn’s ideas on specialization will shed new light on some often overlooked features of scientific change. (shrink)

An important strategy in the discovery of biological mechanisms involves the piecing together of experimental results from interventions. However, if mechanisms are investigated by means of ideal interventions, as defined by James Woodward and others, then the kind of information revealed is insufficient to discriminate between modular and non-modular causal contributions. Ideal interventions suffice for constructing webs of causal dependencies that can be used to make some predictions about experimental outcomes, but tell us little about how causally relevant factors are (...) organized together and how they interact with each other in order to produce a phenomenon. I argue that lab research relies on more elaborated types of interventions targeting in a controlled fashion multiple variables at the same time in order to probe the temporal organization of causally-relevant factors along distinct causal pathways and to test for non-modular interaction effects, thus providing crucial spatial-temporal constraints guiding the formulation of more detailed mechanistic explanations. (shrink)

Causal complexities involved in biological phenomena often generate ambiguous experimental results that may create epistemic niches for new approaches and interpretations. The exploration for new approaches may foment momentum of larger epistemological shifts, and thereby introduce the possibilities of adopting new technologies. This paper describes British molecular biologist Robin Holliday’s cell aging research from 1963 to the 1980s that transformed from simple hypothesis testing to working on various alternative and integrative approaches designed to deal with complex data. In the 1960s, (...) hoping to use biochemical investigations of cells to settle a debate about whether DNA mutations or protein errors caused aging, Holliday carried out a series of experiments with fruit flies, fungi, and human fibroblast cells. The results seemed to demonstrate that cytoplasmic protein errors caused cell aging. However, other scientists obtained contradictory results and raised issues about potential flaws in Holliday’s experiments. In the 1970s, working as the director of the Genetics Division of the National Institute for Medical Research in Mill Hill, United Kingdom, Holliday relied on available talents of his associates, including computational expertise, to explore alternative hypotheses and approaches. By the early 1980s, they had worked out an epigenetic explanation and had established integrative, evolutionary models of cell aging that incorporated both DNA mutations and protein errors as critical factors. By delineating Holliday’s research path from simply testing hypotheses to integrating multiple factors involved in aging, this paper offers an account of the difficulties in targeting molecular cause in cell aging around the 1970s, whose failures nevertheless opened up an epistemic niche for integration. (shrink)

Frederick Griffith was an English bacteriologist at the Pathological Laboratory of the Ministry of Health in London who believed that progress in the epidemiology and control of infectious diseases would come only with more precise knowledge of the identity of the causative microorganisms. Over the years, Griffith developed and expanded a serological technique for identifying pathogenic microorganisms, which allowed the tracing of the sources of infectious disease outbreaks: slide agglutination. Yet Griffith is not remembered for his contributions to the biology (...) and epidemiology of infectious diseases so much as for discovering the phenomenon known as ‘transformation’. Griffith’s discovery, for many, was a pure case of serendipity whose biological relevance had also largely escaped him. In this paper, I argue that the key to understanding the significance of bacterial transformation – and the scientific legacy of Fred Griffith – rests not only on it initiating a cascade of events leading to molecular genetics but also on its implications for epidemiology based on the biology of host–parasite interactions. Looking at Griffith’s entire career, instead of focusing only on the transformation study, we can better appreciate the place of the latter within Griffith’s overall contributions. Presented in this way, Griffith’s experiment on bacterial transformation also ceases to appear as an anomaly, which in turn leads us to rethink some of the most prevalent historical conceptions about his work. (shrink)

The experimental practice in contemporary molecular biology oscillates between the creativity of the researcher in tinkering with the experimental system, and the necessity of standardization of methods of inquiry. Experimental procedures, when standardized in lab protocols, might definitely be seen as actual recipes. Considering these protocols as recipes can help us understand some epistemological characteristics of current practice in molecular biology. On the one hand, protocols represent a common ground, i.e. the possibility of reproducibility, which constitutes one of the essential (...) properties for contemporary science to define an actual discovery. At the same time, however, protocols are flexible enough to be adapted by the individual researcher (within a space of maneuver given by the experimental system and by the practices that each individual discipline gives to itself) to his/her specific needs. These variations, just like the recipes, remind us that the legitimacy of an experimental practice, involves both objective and subjective constraints and it is articulated on a fuzzy background rather than a rigid and clear context. Moreover, looking at experiments according to this perspective can provide a key to understanding how different forms of science (which adopt different methodologies but which investigate the same phenomena), such as computational biology, are precisely different in the use of a different “cookbook”.Indeed, given the procedural/operational realism of biologists towards phenomena, the clash of different procedures has opened a discussion also about the nature and the meaning of the obtained results. Thus, according to the recipe-perspective that, the methodological struggle over the nature of biological phenomena (and their ways of discovery) among scientists, might be seen as a not always explicit, epistemological debate, however coming from the practice of science itself. (shrink)

Philosophers of science turned to historical case studies in part in response to Thomas Kuhn's insistence that such studies can transform the philosophy of science. In this issue Joseph Pitt argues that the power of case studies to instruct us about scientific methodology and epistemology depends on prior philosophical commitments, without which case studies are not philosophically useful. Here I reply to Pitt, demonstrating that case studies, properly deployed, illustrate styles of scientific work and modes of argumentation that are not (...) well handled by currently standard philosophical analyses. I illustrate these claims with exemplary findings from case studies dealing with exploratory experimentation and with interdisciplinary cooperation across sciences to yield multiple independent means of access to theoretical entities. The latter cases provide examples of ways that scientists support claims about theoretical entities that are not available in work performed within a single discipline. They also illustrate means of correcting systematic biases that stem from the commitments of each discipline taken separately. These findings illustrate the transformative power of case study methods, allow us to escape from the horns of Pitt's "dilemma of case studies," and vindicate some of the post-Kuhn uses to which case studies have been put. (shrink)

What is now familiarly referred to as the ‘embryonic stem (ES) cell’ is a recent biological category whose origins lie in research into benign and malignant teratomas carried out in the 1950s, 60s and 70s. In these studies, the question of the normal or pathological character of the ES cell was a matter of considerable debate and indeed the term ES cell was often used interchangeably with that of the embryonal carcinoma (EC) cell. This article argues that the indecisiveness of (...) the entity known as the ES cell—its refusal to commit to established demarcations between the normal and the pathological—continues to haunt the field of stem cell science. Exploring the prehistory of research into ES cells, early theories of cancer (in particular the embryonal theory expounded by Julius Cohnheim) and recent theoretical critiques of the somatic mutation theory, the article not only points to a shift in understandings of the normal and the pathological but asks under what conditions such shifts are able to take place. (shrink)

The concept of mechanism is analyzed in terms of entities and activities, organized such that they are productive of regular changes. Examples show how mechanisms work in neurobiology and molecular biology. Thinking in terms of mechanisms provides a new framework for addressing many traditional philosophical issues: causality, laws, explanation, reduction, and scientific change.

Evolutionary systems biology (ESB) is a rapidly growing integrative approach that has the core aim of generating mechanistic and evolutionary understanding of genotype‐phenotype relationships at multiple levels. ESB's more specific objectives include extending knowledge gained from model organisms to non‐model organisms, predicting the effects of mutations, and defining the core network structures and dynamics that have evolved to cause particular intracellular and intercellular responses. By combining mathematical, molecular, and cellular approaches to evolution, ESB adds new insights and methods to the (...) modern evolutionary synthesis, and offers ways in which to enhance its explanatory and predictive capacities. This combination of prediction and explanation marks ESB out as a research manifesto that goes further than its two contributing fields. Here, we summarize ESB via an analysis of characteristic research examples and exploratory questions, while also making a case for why these integrative efforts are worth pursuing. (shrink)

This chapter provides an introduction to the study of the philosophical notions of mechanisms and causality in biology and economics. This chapter sets the stage for this volume, Mechanism and Causality in Biology and Economics, in three ways. First, it gives a broad review of the recent changes and current state of the study of mechanisms and causality in the philosophy of science. Second, consistent with a recent trend in the philosophy of science to focus on scientific practices, it in (...) turn implies the importance of studying the scientific methods employed by researchers. Finally, by way of providing an overview of each chapter in the volume, this chapter demonstrates that biology and economics are two fertile fields for the philosophy of science and shows how biological and economic mechanisms and causality can be synthesized. (shrink)

This paper argues that besides mechanistic explanations, there is a kind of explanation that relies upon “topological” properties of systems in order to derive the explanandum as a consequence, and which does not consider mechanisms or causal processes. I first investigate topological explanations in the case of ecological research on the stability of ecosystems. Then I contrast them with mechanistic explanations, thereby distinguishing the kind of realization they involve from the realization relations entailed by mechanistic explanations, and explain how both (...) kinds of explanations may be articulated in practice. The second section, expanding on the case of ecological stability, considers the phenomenon of robustness at all levels of the biological hierarchy in order to show that topological explanations are indeed pervasive there. Reasons are suggested for this, in which “neutral network” explanations are singled out as a form of topological explanation that spans across many levels. Finally, I appeal to the distinction of explanatory regimes to cast light on a controversy in philosophy of biology, the issue of contingence in evolution, which is shown to essentially involve issues about realization. (shrink)

This paper examines the “biotechnology problem” in the history of molecular biology, namely the alleged reinvention of a basic academic discipline looking for the logic of life, into a typical technoscientific enterprise, closely related to agriculture, medicine, and the construction of markets. The dominant STS model sees the roots of this shift in a radical change of the regime of knowledge production. The paper argues that this scheme needs to be historicized to take into account the past in our biotech (...) present. Looking at the development of breast cancer genetic testing and GMOs as examples of mounting issues of intellectual property, risk and regulation, the paper also argues that historians of biology should pay closer attention to the political, the economical and the legal changes of the last thirty years. Solving the biotech problem requires new categories. The notion of “way of regulating” is given as an example of such notions linking the local and the global. (shrink)

‘‘Adaptive radiation’’ is an evocative metaphor for explosive evolutionary divergence, which for over 100 years has given a powerful heuristic to countless scientists working on all types of organisms at all phylogenetic levels. However, success has come at the price of making ‘‘adaptive radiation’’ so vague that it can no longer reflect the detailed results yielded by powerful new phylogeny-based techniques that quantify continuous adaptive radiation variables such as speciation rate, phylogenetic tree shape, and morphological diversity. Attempts to shoehorn the (...) results of these techniques into categorical ‘‘adaptive radiation: yes/no’’ schemes lead to reification, in which arbitrary quantitative thresholds are regarded as real. Our account of the life cycle of metaphors in science suggests that it is time to exchange the spent metaphor for new concepts that better represent the full range of diversity, disparity, and speciation rate across all of life. (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’ 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)

The use of multiple means of determination to “triangulate” on the existence and character of a common phenomenon, object, or result has had a long tradition in science but has seldom been a matter of primary focus. As with many traditions, it is traceable to Aristotle, who valued having multiple explanations of a phenomenon, and it may also be involved in his distinction between special objects of sense and common sensibles. It is implicit though not emphasized in the distinction between (...) primary and secondary qualities from Galileo onward. It is arguably one of several conceptions involved in Whewell’s method of the “consilience of inductions” (Laudan 1971) and is to be found in several places in Peirce. (From M. Brewer and B. Collins, eds., (1981); Scientific Inquiry in the Social Sciences (a festschrift for Donald T. Campbell), San Francisco: Jossey-Bass, pp. 123–162.). (shrink)

In the last few years, biologists and computer scientists have claimed that the introduction of data science techniques in molecular biology has changed the characteristics and the aims of typical outputs (i.e. models) of such a discipline. In this paper we will critically examine this claim. First, we identify the received view on models and their aims in molecular biology. Models in molecular biology are mechanistic and explanatory. Next, we identify the scope and aims of data science (machine learning in (...) particular). These lie mainly in the creation of predictive models which performances increase as data set increases. Next, we will identify a tradeoff between predictive and explanatory performances by comparing the features of mechanistic and predictive models. Finally, we show how this a priori analysis of machine learning and mechanistic research applies to actual biological practice. This will be done by analyzing the publications of a consortium—The Cancer Genome Atlas—which stands at the forefront in integrating data science and molecular biology. The result will be that biologists have to deal with the tradeoff between explaining and predicting that we have identified, and hence the explanatory force of the ‘new’ biology is substantially diminished if compared to the ‘old’ biology. However, this aspect also emphasizes the existence of other research goals which make predictive force independent from explanation. (shrink)

We present two case studies from contemporary biology in which we observe conflicts between established and emerging approaches. The first case study discusses the relation between molecular biology and systems biology regarding the explanation of cellular processes, while the second deals with phylogenetic systematics and the challenge posed by recent network approaches to established ideas of evolutionary processes. We show that the emergence of new fields is in both cases driven by the development of high-throughput data generation technologies and the (...) transfer of modeling techniques from other fields. New and emerging views are characterized by different philosophies of nature, i.e. by different ontological and methodological assumptions and epistemic values and virtues. This results in a kind of conflict we call “epistemic competition” that manifests in two ways: On the one hand, opponents engage in mutual critique and defense of their fundamental assumptions. On the other hand, they compete for the acceptance and integration of the knowledge they provide by a broader scientific community. Despite an initial rhetoric of replacement, the views as well as the respective audiences come to be seen as more clearly distinct during the course of the debate. Hence, we observe—contrary to many other accounts of scientific change—that conflict results in the formation of new niches of research, leading to co-existence and perceived complementarity of approaches. Our model thus contributes to the understanding of the pluralization of the scientific landscape. (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)

Causal selection has to do with the distinction we make between background conditions and “the” true cause or causes of some outcome of interest. A longstanding consensus in philosophy views causal selection as lacking any objective rationale and as guided, instead, by arbitrary, pragmatic, and non-scientific considerations. I argue against this position in the context of causal selection for disease traits. In this domain, causes are selected on the basis of the type of causal control they exhibit over a disease (...) of interest. My analysis clarifies the principled rationale that guides this selection and how it involves both pragmatic and objective considerations, which have been overlooked in the extant literature. (shrink)

Griffiths and Stotz’s Genetics and Philosophy: An Introduction offers a very good overview of scientific and philosophical issues raised by present-day genetics. Examining, in particular, the questions of how a “gene” should be defined and what a gene does from a causal point of view, the authors explore the different domains of the life sciences in which genetics has come to play a decisive role, from Mendelian genetics to molecular genetics, behavioural genetics, and evolution. In this review, I highlight what (...) I consider as the two main theses of the book, namely: genes are better conceived as tools; genes become causes only in a context. I situate these two theses in the wider perspective of developmental systems theory. This leads me to emphasize that Griffiths and Stotz reflect very well an on going process in genetics, which I call the “epigenetization” of genetics, i.e., the growing interest in the complex processes by which gene activation is regulated. I then make a factual objection, which is that Griffiths and Stotz have almost entirely neglected the perspective of ecological developmental biology, and more precisely recent work on developmental symbioses, and I suggest that this omission is unfortunate in so far as an examination of developmental symbioses would have considerably strengthened Griffiths and Stotz’s own conclusions. (shrink)

ABSTRACT. This paper contemplates Organicism and its relation with molecular and evolutionary biology. We explore whether twentieth-first century biology is returning to positions held at the beginning of the twentieth century and then abandoned. The guiding line is a history of theoretical biology in which we distinguish three periods: 1. The 20s-30s, and the Theoretical Biology Club (Needham, Woodger, and Waddington, among others); 2. An intermediate period in the 60s-70s, in which, in spite of the eclosion of the molecular and (...) evolutionary biologies, there is some recovery of organicist positions, and 3. The present post-genomic situation, which is demanding a systemic approach. (shrink)

I describe two traditions of philosophical accounts of evidence: one characterizes the notion in terms of signs of success, the other characterizes the notion in terms of conditions of success. The best examples of the former rely on the probability calculus, and have the virtues of generality and theoretical simplicity. The best examples of the latter describe the features of evidence which scientists appeal to in practice, which include general features of methods, such as quality and relevance, and general features (...) of evidence, such as patterns in data, concordance with other evidence, and believability of the evidence. Two infamous episodes from biomedical research help to illustrate these features. Philosophical characterization of these latter features—conditions of success—has the virtue of potential relevance to, and descriptive accuracy of, practices of experimental scientists. (shrink)

Philosophers have traditionally conceived of discovery in terms of internal cognitive acts. Close consideration of Rosalind Franklin's role in the discovery of the DNA double helix, however, reveals some problems with this traditional conception. This article argues that defining discovery in terms of mental operations entails problematic conclusions and excludes acts that should fall within the domain of discovery. It proposes that discovery be expanded to include external acts of making visible. Doing so allows for a reevaluation of Franklin's role (...) in the discovery of the structure of DNA. (shrink)

The chemical characterization of the substance responsible for the phenomenon of “transformation” of pneumococci was presented in the now famous 1944 paper by Avery, MacLeod, and McCarty. Reception of this work was mixed. Although interpreting their results as evidence that deoxyribonucleic acid (DNA) is the molecule responsible for genetic changes was, at the time, controversial, this paper has been retrospectively celebrated as providing such evidence. The mixed and changing assessment of the evidence presented in the paper was due to the (...) work’s interpretive flexibility – the evidence was interpreted in various ways, and such interpretations were justified given the neophytic state of molecular biology and methodological limitations of Avery’s transformation studies. I argue that the changing context in which the evidence presented by Avery’s group was interpreted partly explains the vicissitudes of the assessments of the evidence. Two less compelling explanations of the reception are a myth-making account and an appeal to the wartime historical context of its publication. (shrink)

The inapplicability of variations on theory reduction in the context of genetics and their irrelevance to ongoing research has led to an anti-reductionist consensus in philosophy of biology. One response to this situation is to focus on forms of reductive explanation that better correspond to actual scientific reasoning (e.g. part–whole relations). Working from this perspective, we explore three different aspects (intrinsicality, fundamentality, and temporality) that arise from distinct facets of reductive explanation: composition and causation. Concentrating on these aspects generates new (...) forms of reductive explanation and conditions for their success or failure in biology and other sciences. This analysis is illustrated using the case of protein folding in molecular biology, which demonstrates its applicability and relevance, as well as illuminating the complexity of reductive reasoning in a specific biological context. (shrink)

The term ‘cell’, in addition to designating fundamental units of life, has also been applied since the nineteenth century to technical apparatuses such as fuel and galvanic cells. This paper shows that such technologies, based on the electrical effects of chemical reactions taking place in containers, had a far-reaching impact on the concept of the biological cell. My argument revolves around the controversy over oxidative phosphorylation in bioenergetics between 1961 and 1977. In this scientific conflict, a two-level mingling of technological (...) culture, physical chemistry and biological research can be observed. First, Peter Mitchell explained the chemiosmotic hypothesis of energy generation by representing cellular membrane processes via an analogy to fuel cells. Second, in the associated experimental scrutiny of membranes, material cell models were devised that reassembled spatialized molecular processes in vitro. Cells were thus modelled both on paper and in the test tube not as morphological structures but as compartments able to perform physicochemical work. The story of cells and membranes in bioenergetics points out the role that theories and practices in physical chemistry had in the molecularization of life. These approaches model the cell as a ‘topology of molecular action’, as I will call it, and it involves concepts of spaces, surfaces and movements. They epitomize an engineer’s vision of the organism that has influenced diverse fields in today’s life sciences. (shrink)

In this paper, I discuss the discovery of the DNA structure by Francis Crick and James Watson, which has provoked a large historical literature but has yet not found entry into philosophical debates. I want to redress this imbalance. In contrast to the available historical literature, a strong emphasis will be placed upon analysing the roles played by theory, model, and evidence and the relationship between them. In particular, I am going to discuss not only Crick and Watson's well-known model (...) and Franklin's x-ray diffraction pictures (the evidence) but also the less well known theory of helical diffraction, which was absolutely crucial to Crick and Watson's discovery. The insights into this groundbreaking historical episode will have consequences for the ‘new’ received view of scientific models and their function and relationship to theory and world. The received view, dominated by works by Cartwright and Morgan and Morrison ([1999]), rather than trying to put forth a ‘theory of models’, is interested in questions to do with (i) the function of models in scientific practice and (ii) the construction of models. In regard to (i), the received view locates the model (as an idealized, simplified version of the real system under investigation) between theory and the world and sees the model as allowing the application of the former to the latter. As to (ii) Cartwright has argued for a phenomenologically driven view and Morgan and Morrison ([1999]) for the ‘autonomy’ of models in the construction process: models are determined neither by theory nor by the world. The present case study of the discovery of the DNA structure strongly challenges both (i) and (ii). In contrast to claim (i) of the received view, it was not Crick and Watson's model but rather the helical diffraction theory which served a mediating purpose between the model and the x-ray diffraction pictures. In particular, Cartwright's take on (ii) is refuted by a comparison of Franklin's bottom-up approach with Crick and Watson's top-down approach in constructing the model. The former led to difficulties, which only a strong confidence in the structure incorporated in the model could circumvent. How to Get to the Structure 1.1 X-ray diffraction and its synthesis 1.2 Model building and Pauling's panache 1.3 The structure of proteins 1.3.1 A failed inference to the best explanation 1.3.2 The misleading 5.1 Å spot in proteins and how to get rid of it 1.3.3 Derived predictions from Pauling's alpha-helix of protein molecules The CCV Theory of Helical X-Ray Diffraction 2.1 The role of the CCV theory in the discovery of the DNA structure Killing the Helix 3.1 Appreciating all evidence—in vain Conclusion Epilogue: Chargaff's Ratios CiteULike Connotea Del.icio.us What's this? (shrink)

We outline three very different concepts of the gene—instrumental, nominal, and postgenomic. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide (...) range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype. (shrink)

According to Kuhn's speciation analogy, scientific specialisation is fundamentally analogous to biological speciation. In this paper, we extend Kuhn's original language-centred formulation of the speciation analogy, to account for episodes of scientific specialisation centred around methodological differences. Building upon recent views in evolutionary biology about the process of speciation by genetic divergence, we will show how these methodology-centred episodes of scientific specialisation can be understood as cases of specialisation driven by value divergence. We will apply our model of specialisation by (...) value divergence to an episode of methodology-centred scientific specialisation: the emergence of molecular biology. (shrink)

Historically, hypotheses failed in most cases to correctly forecast the workings of complex biological systems. Francis Crick’s adaptor hypothesis, however, stands out as an exceptional case of a confirmed abstract prediction. This hypothesis presciently anticipated the existence of RNA adaptors that function as bridges between amino acids and the chemically different nucleic acid template for proteins. Crick conjectured that the adaptors are enzymatically charged with cognate amino acids, they bind to complementary protein-coding nucleic acid, and their liberated amino acids are (...) incorporated into growing protein chains. Independently from and concomitantly with Crick’s hypothesis, Mahlon Hoagland and Paul Zamecnik conducted experiments with no guiding theory that culminated in discoveries of the actual adaptors, transfer RNA (tRNA) molecules, and their amino acids charging enzymes. This paper traces the parallel histories of Crick’s adaptor hypothesis and of the experimental discovery of tRNA and compares their relative impacts on the scientific community. Remarkably, despite the brilliance of Crick’s confirmed prognostication, it had marginal impact on practicing scientists. Conversely, Hoagland and Zamecnik’s experimental discoveries and their evidence-based model of protein synthesis had immediate and enduring impact. I discuss possible explanations for the different impacts of the theoretical prediction and experimental identifications of the same entities. (shrink)

The issue of the conservatism of scientific research questions the nature and the role of the internal and external forces controlling the emergence of new research questions or problems, the exploration of risky directions of research, or the use of risky research methods. This issue has recently gained a new framing in connection with the growing importance of the peer-review process and of the social and economic pressures weighing on the funding of scientific research. Current literature then interrogates the external (...) and internal features that promote what are described as conservative tendencies in scientific research. In this paper, I propose to contribute to this debate by clarifying what might be internal sources of conservatism in science; that is, that are inherent to the research process itself. I distinguish two possible understandings of the sources and manifestations of this internal conservatism. I first present a representational description of the nature and origin of conservatism in science, which brings to the fore the difficulties researchers find in setting aside their conceptual framework. I then offer for consideration a larger perspective on conservatism by arguing for the existence of a practical conservatism generated by all the dimensions of scientific activities. In this framework, conservatism in science can be explained by the tendency of all practices to close in on their own local objectives. I illustrate this view by reference to an historical episode: the discovery of the chemical nature of genes by Avery. (shrink)

Knowing how introns originated should greatly enhance our understanding of the information we carry in our DNA. Gilbert’s suggestion that introns initially arose to facilitate recombination still stands, though not for the reason he gave. Reanney’s alternative, that evolution, from the early “RNA world” to today’s DNA-based world, would require the ability to detect and correct errors by recombination, now seems more likely. Consistent with this, introns are richer than exons in the potential to extrude the stem-loop structures needed for (...) the homology search that can lead to heteroduplex formation and the recognition of base mismatches. In nucleic acid sequences that were unable concomitantly to encode sufficient stem-loop potential, protein-encoding potential was constrained to arise as segments (exons) interrupted by segments rich in stem-loop potential (introns). Thus, sequences with properties that we now deem intronic are likely to have preceded the emergence of exons. (shrink)

The theory of concepts advanced in the dissertation aims at accounting for a) how a concept makes successful practice possible, and b) how a scientific concept can be subject to rational change in the course of history. Traditional accounts in the philosophy of science have usually studied concepts in terms only of their reference; their concern is to establish a stability of reference in order to address the incommensurability problem. My discussion, in contrast, suggests that each scientific concept consists of (...) three components of content: 1) reference, 2) inferential role, and 3) the epistemic goal pursued with the concept's use. I argue that in the course of history a concept can change in any of these three components, and that change in one component—including change of reference—can be accounted for as being rational relative to other components, in particular a concept's epistemic goal.This semantic framework is applied to two cases from the history of biology: the homology concept as used in 19th and 20th century biology, and the gene concept as used in different parts of the 20th century. The homology case study argues that the advent of Darwinian evolutionary theory, despite introducing a new definition of homology, did not bring about a new homology concept (distinct from the pre-Darwinian concept) in the 19th century. Nowadays, however, distinct homology concepts are used in systematics/evolutionary biology, in evolutionary developmental biology, and in molecular biology. The emergence of these different homology concepts is explained as occurring in a rational fashion. The gene case study argues that conceptual progress occurred with the transition from the classical to the molecular gene concept, despite a change in reference. In the last two decades, change occurred internal to the molecular gene concept, so that nowadays this concept's usage and reference varies from context to context. I argue that this situation emerged rationally and that the current variation in usage and reference is conducive to biological practice.The dissertation uses ideas and methodological tools from the philosophy of mind and language, the philosophy of science, the history of science, and the psychology of concepts. (shrink)

This paper investigates continuities and changes in the definition of sickle cell disease in 1950s Brazil, taking into account that diseases have a history and are recognized as such according to the knowledge and perceptions available in a certain historical period and specific location. In the post-war era, new diagnostic tools, inheritance theories and, in particular, discussions on the concepts of race and racial relations, both nationally and internationally, were changing previous racialist and racist views. Nonetheless, the Brazilian medical interpretations (...) of sickle cell disease continued to racialize it and even use deep-rooted racist formulations to explain its symptoms or the existence of the disease. It is argued that the celebration of racial mixture and racial democracy might have concealed racist presumptions biasing the study of sickle cell disease. Although race as a biological concept gradually gave way to other genetic expressions, in Brazilian medical papers on sickle cell disease, race continued to influence the interpretation of the disease, along with the persistence of concepts of heredity through blood mixture. (shrink)

According to the hypothesis-generator account, valid extrapolations from a source to a target system are circular, since they rely on knowledge of relevant similarities and differences that can onl...

Biomedical ontologies are considered a serious innovation for biomedical research and clinical practice. They promise to integrate information coming from different biological databases thus creating a common ground for the representation of knowledge in all the life sciences. Such a tool has potentially many implications for both basic biomedical research and clinical practice. Here I discuss how this tool has been generated and thought. Due to the analysis of some empirical cases I try to elaborate how biomedical ontologies constitute a (...) novelty also from an epistemological point of view. (shrink)

A notion of experimental series is developed, in which experiments or experimental sets are connected through experimental suggestions arising from previous experimental outcomes. To that end, the justification of Howard Temin's DNA provirus hypothesis is examined. The hypothesis originated with evidence from two exploratory experimental sets on an oncogenic virus and was substantiated by including evidence from three additional experimental sets. Collectively these sets comprise an experimental series and the accumulative evidence from the series was adequate to justify the hypothesis (...) by persuading the virology community of its veracity. The notion of crucial experiment is also discussed in terms of experimental series. (shrink)

Collecting, comparing, and computing molecular sequences are among the most prevalent practices in contemporary biological research. They represent a specific way of producing knowledge. This paper explores the historical development of these practices, focusing on the work of Margaret O. Dayhoff, Richard V. Eck, and Robert S. Ledley, who produced the first computer-based collection of protein sequences, published in book format in 1965 as the Atlas of Protein Sequence and Structure. While these practices are generally associated with the rise of (...) molecular evolution in the 1960s, this paper shows that they grew out of research agendas from the previous decade, including the biochemical investigation of the relations between the structures and function of proteins and the theoretical attempt to decipher the genetic code. It also shows how computers became essential for the handling and analysis of sequence data. Finally, this paper reflects on the relationships between experimenting and collecting as two distinct “ways of knowing” that were essential for the transformation of the life sciences in the twentieth century. (shrink)