Steroid hormone receptors are ligand‐inducible transcription factors that exhibit potent effects on gene expression in living cells. Precise dissection of their mode of action at the molecular level can best be carried out in functional cell‐free systems. This article will describe the benefits of such systems and review their development up to the recent establishment of steroid receptor‐dependent in vitro transcription. Subsequent advances in our knowledge of receptor function arising from the exploitation of this powerful experimental tool will be described. (...) Particular emphasis will be placed upon two key problems: the role of steroid hormone in receptor action and the mechanisms by which steroid receptors activate gene transcription. (shrink)

Human microbiome research makes causal connections between entire microbial communities and a wide array of traits that range from physiological diseases to psychological states. To evaluate these causal claims, we first examine a well-known single-microbe causal explanation: of Helicobacter pylori causing ulcers. This apparently straightforward causal explanation is not so simple, however. It does not achieve a key explanatory standard in microbiology, of Koch’s postulates, which rely on manipulations of single-microorganism cultures to infer causal relationships to disease. When Koch’s postulates (...) are framed by an interventionist causal framework, it is clearer what the H. pylori explanation achieves and where its explanatory strengths lie. After assessing this ‘simple’, single-microbe case, we apply the interventionist framework to two key areas of microbiome research, in which obesity and mental health states are purportedly explained by microbiomes. Despite the experimental data available, interventionist criteria for explanation show that many of the causal claims generated by microbiome research are weak or misleading. We focus on the stability, specificity and proportionality of proposed microbiome causal explanations, and evaluate how effectively these dimensions of causal explanation are achieved in some promising avenues of research. We suggest some conceptual and explanatory strategies to improve how causal claims about microbiomes are made. (shrink)

Human microbiome research makes causal connections between entire microbial communities and a wide array of traits that range from physiological diseases to psychological states. To evaluate these causal claims, we first examine a well-known single-microbe causal explanation: of Helicobacter pylori causing ulcers. This apparently straightforward causal explanation is not so simple, however. It does not achieve a key explanatory standard in microbiology, of Koch’s postulates, which rely on manipulations of single-microorganism cultures to infer causal relationships to disease. When Koch’s postulates (...) are framed by an interventionist causal framework, it is clearer what the H. pylori explanation achieves and where its explanatory strengths lie. After assessing this ‘simple’, single-microbe case, we apply the interventionist framework to two key areas of microbiome research, in which obesity and mental health states are purportedly explained by microbiomes. Despite the experimental data available, interventionist criteria for explanation show that many of the causal claims generated by microbiome research are weak or misleading. We focus on the stability, specificity and proportionality of proposed microbiome causal explanations, and evaluate how effectively these dimensions of causal explanation are achieved in some promising avenues of research. We suggest some conceptual and explanatory strategies to improve how causal claims about microbiomes are made. (shrink)

Este estudio revisa el desarrollo del análisis propuesto por Michel Foucault sobre el poder político en términos de gubernamentalidad, y esboza sus características principales. Se examina el despliegue de esta perspectiva, centrándose particularmente en cómo este enfoque genealógico del análisis de la conducta de todos y cada uno ha sido acogido y desarrollado en el mundo angloparlante. Se evalúan algunas de las críticas fundamentales que han sido planteadas a la analítica de la gubernamentalidad, y se arguye en favor de la (...) productividad continua y la creatividad de estas maneras de analizar la emergencia, naturaleza y consecuencias de las artes de gobierno. (shrink)

This commentary focuses on the authors’ treatment of Koch’s postulates. It argues in favour of a modification of Koch’s postulates and their analysis in terms of necessary and sufficient conditions. This leads to a criticism of the authors’ treatment of the C. difficile case, and to query the need for the criteria of specificity and proportionality.

The model of major transitions in evolution devised by Maynard Smith and Szathmáry has exerted tremendous influence over evolutionary theorists. Although MTE has been criticized for inconsistently combining different types of event, its ongoing appeal lies in depicting hierarchical increases in complexity by means of evolutionary transitions in individuality. In this paper, we consider the implications of major evolutionary events overlooked by MTE and its ETI-oriented successors, specifically the biological oxygenation of Earth, and the acquisitions of mitochondria and plastids. By (...) reflecting on these missed events, we reveal a central philosophical disagreement over the explanatory goals of major transitions theory that has yet to be made explicit in the literature. We go on to argue that this philosophical disagreement is only reinforced by Szathmáry’s recent revisions of MTE in the form of MTE 2.0. This finding motivates us to propose an alternative explanatory strategy: specifically, an interactionist metabolic perspective on major transitions. A metabolic framework not only avoids many of the criticisms that beset classic and revised MTE models, but also accommodates missing events and provides crucial explanatory components for standard major transitions. Although we do not provide a full-blown alternative theory and do not claim to achieve unity, we explain why foregrounding metabolism is crucial for any attempt to capture the major turning points in evolution, and why it does not lead to unmanageable pluralism. (shrink)

Synthetic biology is an increasingly high‐profile area of research that can be understood as encompassing three broad approaches towards the synthesis of living systems: DNA‐based device construction, genome‐driven cell engineering and protocell creation. Each approach is characterized by different aims, methods and constructs, in addition to a range of positions on intellectual property and regulatory regimes. We identify subtle but important differences between the schools in relation to their treatments of genetic determinism, cellular context and complexity. These distinctions tie into (...) two broader issues that define synthetic biology: the relationships between biology and engineering, and between synthesis and analysis. These themes also illuminate synthetic biology's connections to genetic and other forms of biological engineering, as well as to systems biology. We suggest that all these knowledge‐making distinctions in synthetic biology raise fundamental questions about the nature of biological investigation and its relationship to the construction of biological components and systems. BioEssays 30:57–65, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

The papers published here were given at the second biennial conference of the Hegel Society of America, held at the University of Notre Dame, November 9-11, 1972. They appear in an order which reflects roughly two headings: (1) Hegel's conception of the history of philosophy in general, and (2) his relation to individual thinkers both before and after him. Given the importance of the history of philosophy for Hegel, and the far-reaching impact of his thought upon subsequent philosophy, it becomes (...) immediately apparent that we have here only a beginning. At the conference, cries went up "Why not Hegel and Aristotle, Aquinas, HusserI and Hart mann?" Indeed, why not? The answer, of course, might be given by Hegel himself : if we wish to accomplish anything, we have to limit ourselves. We trust that future conferences and scholarship will bring to light these relationships and the many more which testify to Hegel's profound presence in the mainstream of past and present thought. It is furthermore no accident that the renaissance of Hegelian studies has brought with it a rebirth of the history of philosophy as something relevant to our own problems. For Hegel, the object of philosophy is alone the truth, the history of philosophy is philosophy itself, and this truth which it gives us cannot be what has passed away. (shrink)

Obesity is the focus of multiple lines of inquiry that have -- together and separately -- produced many deep insights into the physiology of weight gain and maintenance. We examine three such streams of research and show how they are oriented to obesity intervention through multilevel integrated approaches. The first research programme is concerned with the genetics and biochemistry of fat production, and it links metabolism, physiology, endocrinology and neurochemistry. The second account of obesity is developmental and draws together epigenetic (...) and environmental explanations that can be embedded in an evolutionary framework. The third line of research focuses on the role of gut microbes in the production of obesity, and how microbial activities interact with host genetics, development and metabolism. These interwoven explanatory strategies are driven by an orientation to intervention, both for experimental and therapeutic outcomes. We connect the integrative and intervention-oriented aspects of obesity research through a discussion of translation, broadening the concept to capture the dynamic, iterative processes of scientific practice and therapy development. This system-oriented analysis of obesity research expands the philosophical scrutiny of contemporary developments in the biosciences and biomedicine, and has the potential to enrich philosophy of science and medicine. (shrink)

The discovery and ongoing investigation of microRNAs suggest important conceptual and methodological lessons for philosophers and historians of biology. This paper provides an account of miRNA research and the shift from viewing these tiny regulatory entities as minor curiosities to seeing them as major players in the post-transcriptional regulation of genes. Conceptually, the study of miRNAs is part of a broader change in understandings of genetic regulation, in which simple switch-like mechanisms were reinterpreted as aspects of complex cellular and genome-wide (...) processes. Among them are the activities of small RNAs, previously regarded as non-functional. Methodologically, the miRNA story suggests new ways of characterizing biological research that should prove helpful to philosophers of science who seek to develop more pluralistic, pragmatic models of scientific inquiry. miRNA research displays iterative movements between multiple modes of investigation that include not only the proposal and testing of hypotheses but also exploratory, technology-oriented and question-driven modes of research. As an exemplary story of scientific discovery and development, the miRNA case illustrates transitions from genetics to genomics and systems biology, and it shows how diverse configurations of research practice are related to major scientific advances. (shrink)

Much is being written these days about integration, its desirability and even its necessity when complex research problems are to be addressed. Seldom, however, do we hear much about the failure of such efforts. Because integration is an ongoing activity rather than a final achievement, and because today’s literature about integration consists mostly of manifesto statements rather than precise descriptions, an examination of unsuccessful integration could be illuminating to understand better how it works. This paper will examine the case of (...) prokaryote phylogeny and its apparent failure to achieve integration within broader tree-of-life accounts of evolutionary history. Despite the fact that integrated databases exist of molecules pertinent to the phylogenetic reconstruction of all lineages of life, and even though the same methods can be used to construct phylogenies wherever the organisms fall on the tree of life, prokaryote phylogeny remains at best only partly integrated within tree-of-life efforts. I will examine why integration does not occur, compare it with integrative practices in animal and other eukaryote phylogeny, and reflect on whether there might be different expectations of what integration should achieve. Finally, I will draw some general conclusions about integration and its function as a ‘meta-heuristic’ in the normative commitments guiding scientific practice. (shrink)

Reproduction is central to biology and evolution. Standard concepts of reproduction are drawn from animals. Nonstandard examples of reproduction can be found in unicellular eukaryotes that distribute their reproductive strategies across multiple generations, and in mutualistic systems that combine different modes of reproduction across multiple lineages. Examining multigenerational and multilineal reproducers and how they align fitness has implications for conceptualizing units of evolution.

Synthetic biology is an umbrella term that covers a range of aims, approaches, and techniques. They are all brought together by common practices of analogizing, synthesizing, mechanicizing, and kludging. With a focus on kludging as the connection point between biology, engineering, and evolution, I show how synthetic biology’s successes depend on custom-built kludges and a creative, “make-it-work” attitude to the construction of biological systems. Such practices do not fit neatly, however, into synthetic biology’s celebration of rational design. Nor do they (...) straightforwardly embody Richard Feynman’s “last blackboard” statement that without creating something it cannot be understood. Reflecting further on the relationship between synthetic construction and knowledge making gives philosophy of science new avenues of insight into scientific practice. (shrink)

Metagenomics is an emerging microbial systems science that is based on the large-scale analysis of the DNA of microbial communities in their natural environments. Studies of metagenomes are revealing the vast scope of biodiversity in a wide range of environments, as well as new functional capacities of individual cells and communities, and the complex evolutionary relationships between them. Our examination of this science focuses on the ontological implications of these studies of metagenomes and metaorganisms, and what they mean for common (...) sense and philosophical understandings of multicellularity, individuality and organism. We show how metagenomics requires us to think in different ways about what human beings are and what their relation to the microbial world is. Metagenomics could also transform the way in which evolutionary processes are understood, with the most basic relationship between cells from both similar and different organisms being far more cooperative and less antagonistic than is widely assumed. In addition to raising fundamental questions about biological ontology, metagenomics generates possibilities for powerful technologies addressed to issues of climate, health and conservation. We conclude with reflections about process-oriented versus entity-oriented analysis in light of current trends towards systems approaches. (shrink)

Microbes and microbiology are seldom encountered in philosophical accounts of the life sciences. Although microbiology is a well-established science and microbes the basis of life on this planet, neither the organisms nor the science have been seen as philosophically significant. This book will change that. It fills a major gap in the philosophy of biology by examining central philosophical issues in microbiology. Topics are drawn from evolutionary microbiology, microbial ecology, and microbial classification. These discussions are aimed at philosophers and scientists (...) who wish to gain insight into the basic philosophical issues of microbiology. (shrink)

In this first systematic reconstruction of the concept of human flourishing, Eri Mountbatten-O'Malley addresses the central problems with the treatment of the concept in psychology, education, policy and science. He develops a sophisticated methodology of conceptual analysis and makes the case for paying closer attention to complex human contexts, purposes and uses. Re-humanizing current research on the concept that is technicalized and detached from ordinary uses, this volume takes the 'human' in conceptions of human flourishing seriously.

Systems biology is the rapidly growing and heavily funded successor science to genomics. Its mission is to integrate extensive bodies of molecular data into a detailed mathematical understanding of all life processes, with an ultimate view to their prediction and control. Despite its high profile and widespread practice, there has so far been almost no bioethical attention paid to systems biology and its potential social consequences. We outline some of systems biology's most important socioethical issues by contrasting the concept of (...) systems as dynamic processes against the common static interpretation of genomes. New issues arise around systems biology's capacities for in silico testing, changing cultural understandings of life, synthetic biology, and commercialization. We advocate an interdisciplinary and interactive approach that integrates social and philosophical analysis and engages closely with the science. Overall, we argue that systems biology socioethics could stimulate new ways of thinking about socioethical studies of life sciences. (shrink)

Microbiome research is changing how ecosystems, including animal bodies, are understood. In the case of humans, microbiome knowledge is transforming medical approaches and applications. However, the field is still young, and many conceptual and explanatory issues need resolving. These include how microbiome causality is understood, and how to conceptualize the role microbiomes have in the health status of their hosts and other ecosystems. A key concept that crops up in the medical microbiome literature is “balance.” A balanced microbiome is thought (...) to produce health and an imbalanced one disease. Based on a quantitative and qualitative analysis of how balance is used in the microbiome literature, this “think again” essay critically analyses each of the several subconceptions of balance. As well as identifying problems with these uses, the essay suggests some starting points for filling this conceptual gap in microbiome research. (shrink)

We address three fundamental questions: What does it mean for an entity to be living? What is the role of inter-organismic collaboration in evolution? What is a biological individual? Our central argument is that life arises when lineage-forming entities collaborate in metabolism. By conceiving of metabolism as a collaborative process performed by functional wholes, which are associations of a variety of lineage-forming entities, we avoid the standard tension between reproduction and metabolism in discussions of life – a tension particularly evident (...) in discussions of whether viruses are alive. Our perspective assumes no sharp distinction between life and non-life, and does not equate life exclusively with cellular or organismal status. We reach this conclusion through an analysis of the capabilities of a spectrum of biological entities, in which we include the pivotal case of viruses as well as prions, plasmids, organelles, intracellular and extracellular symbionts, unicellular and multicellular life-forms. The usual criterion for classifying many of the entities of our continuum as non-living is autonomy. This emphasis on autonomy is problematic, however, because even paradigmatic biological individuals, such as large animals, are dependent on symbiotic associations with many other organisms. These composite individuals constitute the metabolic wholes on which selection acts. Finally, our account treats cooperation and competition not as polar opposites but as points on a continuum of collaboration. We suggest that competitive relations are a transitional state, with multi-lineage metabolic wholes eventually outcompeting selfish competitors, and that this process sometimes leads to the emergence of new types or levels of wholes. Our view of life as a continuum of variably structured collaborative systems leaves open the possibility that a variety of forms of organized matter – from chemical systems to ecosystems – might be usefully understood as living entities. (shrink)

Ecology is usually described as the study of organisms interacting with one another and their environments. From this view of ecology, viruses – not usually considered to be organisms – would merely be part of the environment. Since the late 1980s, however, a growing stream of micrographic, experimental, molecular, and model-based (theoretical) research has been investigating how and why viruses should be understood as ecological actors of the most important sort. Viruses, especially phage, have been revealed as participants in the (...) planet's most crucial food webs, even though viruses technically consume nothing (they do not metabolize by themselves). Even more impressively, viruses have been identified as regulators of planetary biogeochemistry, in which they control cycles such as carbon, nitrogen and phosphorus – cycles on which all life depends. Although much biogeochemical research black-boxes the entities filling functional roles, it is useful to focus a little more closely to understand how viruses can be held responsible for the global processes of life. This paper will give a brief overview of the history of virus ecology and tease out the implications of large-scale ecological modelling with viruses. This analysis suggests that viruses should be conceptualized as ecological actors that are at least comparable and possibly equal to organismal actors. Ecological agency can therefore be distinguished from standard interpretations of biological agency. (shrink)

Contemporary law and government are increasingly characterized by a focus on risk. Fields such as health, psychiatry, criminal justice, vehicle safety, urban design and environmental governance all provide examples of settings in which problems are dealt with as risks. In this volume, the most influential examinations and interpretations of this major trend have been brought together, in order to make clear the range and diversity, the spread and penetration of risk in contemporary societies.

Must readers intend to process a word to activate various levels of representation, or is such processing simply triggered by the presentation of a word ? This issue was addressed via the use of Besner and Care’s Task Set paradigm. On each trial a cue, which indicated which of two tasks to perform appeared either before the target, or at the same time as the target. If subjects can process the target while preparing a task set, then the effect of (...) a manipulated psycholinguistic factor should be absorbed into the time taken to process the cue. Despite robust main effects of SOA and word frequency there was no interaction between these factors when the task was to read aloud. This result implies that target processing is delayed until the subject knows what task to perform, and therefore that intention plays an important role when reading words aloud. (shrink)

In the context of scientists' reflections on genomics, we examine some fundamental issues in the emerging postgenomic discipline of systems biology. Systems biology is best understood as consisting of two streams. One, which we shall call ‘pragmatic systems biology’, emphasises large‐scale molecular interactions; the other, which we shall refer to as ‘systems‐theoretic biology’, emphasises system principles. Both are committed to mathematical modelling, and both lack a clear account of what biological systems are. We discuss the underlying issues in identifying systems (...) and how causality operates at different levels of organisation. We suggest that resolving such basic problems is a key task for successful systems biology, and that philosophers could contribute to its realisation. We conclude with an argument for more sociologically informed collaboration between scientists and philosophers. BioEssays 27:1270–1276, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Thomas Kuhn had little to say about scientific change in biological science, and biologists are ambivalent about how applicable his framework is for their disciplines. We apply Kuhn’s account of paradigm change to evolutionary microbiology, where key Darwinian tenets are being challenged by two decades of findings from molecular phylogenetics. The chief culprit is lateral gene transfer, which undermines the role of vertical descent and the representation of evolutionary history as a tree of life. To assess Kuhn’s relevance to this (...) controversy, we add a social analysis of the scientists involved to the historical and philosophical debates. We conclude that while Kuhn’s account may capture aspects of the pattern of an episode of scientific change, he has little to say about how the process of generating new understandings is occurring in evolutionary microbiology. Once Kuhn’s application is limited to that of an initial investigative probe into how scientific problem-solving occurs, his disciplinary scope becomes broader. (shrink)

The concepts currently operating in much medical microbiome research bear a curious resemblance to an ancient tradition of Western medicine. This tradition, humoral medicine, is concerned with the four humors: yellow and black bile, phlegm, blood. Both humoral medicine and medical microbiome research use notions of imbalance and balance for broad explanations of disease and health. Both traditions also hold that the composition of humors or microbiomes determines bodily as well as mental states. Causality in each system is often conceived (...) teleologically, meaning that humors or microbiomes "function for" the maintenance of the whole. And ultimately, each framework situates the humors or microbiomes in a multilevel interactionist theory that conceptualizes individual health within a broader environmental context. As well as critically assessing the parallels between these systems, this article sketches some explanations of how they may have arisen. The authors also evaluate the implications of these similarities for the future of medical microbiome research and suggest ways in which the field might move forward. (shrink)

Microbial model systems have a long history of fruitful use in fields that include evolution and ecology. In order to develop further insight into modelling practice, we examine how the competitive exclusion and coexistence of competing species have been modelled mathematically and materially over the course of a long research history. In particular, we investigate how microbial models of these dynamics interact with mathematical or computational models of the same phenomena. Our cases illuminate the ways in which microbial systems and (...) equations work as models, and what happens when they generate inconsistent findings about shared targets. We reveal an iterative strategy of comparative modelling in different media, and suggest reasons why microbial models have a special degree of epistemic tractability in multimodel inquiry. (shrink)

Since the 1940s, microbiologists, biochemists and population geneticists have experimented with the genetic mechanisms of microorganisms in order to investigate evolutionary processes. These evolutionary studies of bacteria and other microorganisms gained some recognition from the standard-bearers of the modern synthesis of evolutionary biology, especially Theodosius Dobzhansky and Ledyard Stebbins. A further period of post-synthesis bacterial evolutionary research occurred between the 1950s and 1980s. These experimental analyses focused on the evolution of population and genetic structure, the adaptive gain of new functions, (...) and the evolutionary consequences of competition dynamics. This large body of research aimed to make evolutionary theory testable and predictive, by giving it mechanistic underpinnings. Although evolutionary microbiologists promoted bacterial experiments as methodologically advantageous and a source of general insight into evolution, they also acknowledged the biological differences of bacteria. My historical overview concludes with reflections on what bacterial evolutionary research achieved in this period, and its implications for the still-developing modern synthesis. (shrink)

Fines and monetary damages account for the majority of legal sanctions across the whole spectrum of legal governance. Money is, in key respects, the primary tool law has to achieve compliance. Yet money has largely been ignored by social analyses of law, and especially by social theory. _The Currency of Justice_ examines the differing rationalities, aims and assumptions built into money’s deployment in diverse legal fields and sanctions. This raises major questions about the extent to which money appears as an (...) abstract universal or whether it takes on more particular meanings when deployed in various areas of law. Indeed, money may be unique in that it can take on the meanings of punishment, compensation, denunciation or regulation. _The Currency of Justice_ examines the implications of the ‘monetization of justice’ as life is increasingly regulated through this single medium. Money not only links diverse domains of law; it also links legal sanctions to other monetary techniques which govern everyday life. Like these, the concern with monetary sanctions is not who pays, but that money is paid. Money is perhaps the only form of legal sanction where the burden need not be borne by the wrongdoer. In this respect, this book explores the view that contemporary governance is less concerned with disciplining individuals and more concerned with regulating distributions and flows of behaviours and the harms and costs linked with these. (shrink)