Melinda Bonnie Fagan

Stem cell biology and systems biology are two prominent new approaches to studying cell development. In stem cell biology, the predominant method is experimental manipulation of concrete cells and tissues. Systems biology, in contrast, emphasizes mathematical modeling of cellular systems. For scientists and philosophers interested in development, an important question arises: how should the two approaches relate? This essay proposes an answer, using the model of Waddington’s landscape to triangulate between stem cell and systems approaches. This simple abstract model represents development as an undulating surface of hills and valleys. Originally constructed by C. H. Waddington to visually explicate an integrated theory of genetics, development and evolution, the landscape model can play an updated unificatory role. I examine this model’s structure, representational assumptions, and uses in all three contexts, and argue that explanations of cell development require both mathematical models and concrete experiments. On this view, the two approaches are interdependent, with mathematical models playing a crucial but circumscribed role in explanations of cell development

Sarah Franklin’s Biological relatives: IVF, stem cells, and the future of kinship and Charis Thompson’s Good science: the ethical choreography of stem cell research, examine recently normalized biotechnologies. Franklin’s monograph extends her previous work on in vitro fertilization , deconstructing the success of a technology that, she argues, has grown “curiouser and curiouser” while taking hold in scientific and social life. IVF in its diverse aspects becomes a lens for scrutinizing our ambivalence about new technology, which Franklin articulates by putting disparate literatures into conversation: feminist science studies, political economy, fine art, and more. Thompson’s Good science focuses more concretely on the first decade of human pluripotent stem cell research, tracing the field from the innovation of cultured human embryonic stem cells through Bush-era policy debates, to current acceptance of stem cell research as a part of the scientific and policy landscape. Th ..

Many explanations in molecular biology, neuroscience, and other fields of experimental biology describe mechanisms underlying phenomena of interest. These mechanistic explanations account for higher-level phenomena in terms of causally active parts and their spatiotemporal organization. What makes such a mechanistic description explanatory? The best-developed answer, Craver's causal-mechanical account, has several weaknesses. It does not fully explicate the target of explanation, interlevel relation, or interactive nonmodular character of many biological mechanisms as we understand them. An alternative account of MEx, emphasizing interdependence among a mechanism's components, remedies these difficulties.

Immunology is a notoriously complex field with distinct concepts and terminology. Yet immunologists regularly and effectively collaborate with other researchers, notably clinicians and experts in population health. How does such ‘collaboration without convergence’ work? This paper offers an answer. Immunology exhibits three features that support collaboration in the absence of major consensus on theories, methods, or concepts. These are: a multifaceted target of inquiry, therapeutic aspirations, and a clear interdisciplinary pathway. Building on these features, I sketch a general account of “low-effort interdisciplinarity” and connect this result to recent work on population health.

Examining stem cell biology from a philosophy of science perspective, this book clarifies the field's central concept, the stem cell, as well as its aims, methods, models, explanations and evidential challenges. The first chapters discuss what stem cells are, how experiments identify them, and why these two issues cannot be completely separated. The basic concepts, methods and structure of the field are set out, as well as key limitations and challenges. The second part of the book shows how rigorous explanations emerge from stem cell experiments, and compares these to other kinds of scientific explanation. Model organisms, the role of genes, and the significance of collaboration are also discussed. The last part of the book considers relations to systems biology and clinical medicine, arguing that both the mathematical models of the former, and ethical principles of the latter, are necessary for stem cell biology to deliver on its promises.

What is a stem cell? The answer is seemingly obvious: a cell that is also a stem, or point of origin, for something else. Upon closer examination, however, this combination of ideas leads directly to fundamental questions about biological development. A cell is a basic category of living thing; a fundamental 'unit of life.' A stem is a site of growth; an active source that supports or gives rise to something else. Both concepts are deeply rooted in biological thought, with rich and complex histories. The idea of a stem cell unites them, but the union is neither simple nor straightforward. This book traces the origins of the stem cell concept, its use in stem cell research today, and implications of the idea for stem cell experiments, their concrete results, and hoped-for clinical advances.

I have previously argued that stem cell experiments cannot demonstrate that a single cell is a stem cell. Laplane and others dispute this claim, citing experiments that identify stem cells at the single-cell level. This paper rebuts the counterexample, arguing that the alleged ‘crucial stem cell experiments’ do not measure self-renewal for a single cell, do not establish a single cell’s differentiation potential, and, if interpreted as providing results about single cells, fall into epistemic circularity. I then discuss the source of the dispute, locating it in differences between philosophical and experimental perspectives.

What things count as individuals, and how do we individuate them? It is a classic philosophical question often tackled from the perspective of analytic metaphysics. This volume proposes that there is another channel by which to approach individuation -- from that of scientific practices. From this perspective, the question then becomes: How do scientists individuate things and, therefore, count them as individuals? This volume collects the work of philosophers of science to engage with this central philosophical conundrum from a new angle, highlighting the crucial topic of experimental individuation and building upon recent, pioneering work in the philosophy of science. An introductory chapter foregrounds the problem of individuation, arguing it should be considered prior to the topic of individuality. The following chapters address individuation and individuality from a variety of perspectives, with prominent themes being the importance of experimentation, individuation as a process, and pluralism in individuation's criteria. Contributions examine individuation in a wide range of sciences, including stem cell biology, particle physics, and community ecology. Other chapters examine the metaphysics of individuation, its bearing on realism/antirealism debates, and interrogate epistemic aspects of individuation in scientific practice. In exploring individuation from the philosophy of biology, physics, and other scientific subjects, this volume ultimately argues for the possibility of several criteria of individuation, upending the tenets of traditional metaphysics. It provides insights for philosophers of science, but also for scientists interested in the conceptual foundations of their work.

Ontologies of living things are increasingly grounded on the concepts and practices of current life science. Biological development is a process, undergone by living things, which begins with a single cell and (in an important class of cases) ends with formation of a multicellular organism. The process of development is thus prima facie central for ideas about biological individuality and organismality. However, recent accounts of these concepts do not engage developmental biology. This paper aims to fill the gap, proposing the lineage view of stem cells as an ontological framework for conceptualizing organismal development. This account is grounded on experimental practices of stem cell research, with emphasis on new techniques for generating biological organization in vitro. On the lineage view, a stem cell is the starting point of a cell lineage with a specific organismal source, time-interval of existence, and ‘tree topology’ of branch-points linking the stem to developmental termini. The concept of ‘enkapsis’ accommodates the cell-organism relation within the lineage view; this hierarchical notion is further explicated by considering the methods and results of stem cell experiments. Results of this examination include a (partial) characterization of stem cells’ developmental versatility, and the context-dependence of developmental processes involving stem cells.

Science is increasingly interdisciplinary, as evidenced by empirical measures, funding initiatives, and the rise of integrative fields such as systems biology and cognitive neuroscience. In this paper, I motivate and outline an account of explanation for interdisciplinary contexts, building on recent debates about scientific perspectivism. Insights from these debates yield an inclusive list of relations between models constructed from different perspectives, which I then refine and generalize into a simple taxonomy. Within this taxonomy of relations among models, I identify the set of relations applicable to interdisciplinary contexts, discuss concepts of unification associated with each, and introduce three further constraints which furnish norms for this variety of explanation. Finally, I discuss implications of this account for a recent debate about understanding and explanation. One important consequence of my view is that explanation in interdisciplinary contexts and understanding of individual agents in those contexts are not equivalent.

Philosophical understanding of experimental scientific practice is impeded by disciplinary differences, notably that between philosophy and sociology of science. Severing the two limits the stock of philosophical case studies to narrowly circumscribed experimental episodes, centered on individual scientists or technologies. The complex relations between scientists and society that permeate experimental research are left unexamined. In consequence, experimental fields rich in social interactions have received only patchy attention from philosophers of science. This paper sketches a remedy for both the symptom and its root cause. An empirical study of social interactions in an established field of biomedicine grounds a robust account of success in experimental practice. The core idea is the concept of collaboration, of participants working together on a common project toward a shared goal. The interactive social integument of experimental research is both examined and enacted in a study integrating socio-historical research and philosophical investigation. The two approaches are used in concert to explicate the concept of scientific objectivity. Their joint explication of this contested epistemic ideal demonstrates that philosophical and sociological approaches can work together toward a social epistemology of scientific practice. The explication is in three stages. First, a minimal framework for investigating collaborative activities is established. Social action is understood and evaluated in terms of the connection between shared goals that participants hope to accomplish together, and the coordinated means by which they try to do so. This connection is explicated as participation, a relation mediating between a group and its members, which includes minimal constraints of instrumental rationality. Second, this framework is fleshed out via empirical study of scientific practices. The focal case examines the intersection of immunology and stem cell research in mid-20th century biomedicine, tracing the key social interactions within and among laboratory groups, as the field of blood stem cell research emerged in the 1960s and advanced throughout the next four decades. The study yields a robust empirical result. Participants consistently recognize two aspects of scientific success: construction of improved models of blood cell development, and formation of new boundaries among scientific groups. In the third and final stage, this result is generalized to other experimental episodes and shown to fit with recent accounts of models in scientific practice. The generalized result approximates a familiar normative view of scientific knowledge. An epistemic ideal of scientific objectivity in practice is then derived from this robust general result, using the minimal constraints on rational participation. The derivation is analogous to specification of ends in moral philosophy; given the means taken and assuming some hope of success, what must the goal of scientific inquiry be like? The aim of science so conceived corresponds to a classic conception of scientific objectivity: knowledge independent of epistemic criteria specific to particular persons or groups. This result weaves together sociological and philosophical accounts of science, explicating the epistemic ideal of objectivity in relation to social aspects of scientific practice. This undercuts the entrenched dualism between normative, vs. descriptive approaches to scientific knowledge. Socio-historical study of science does not deflate, but vindicates, scientific objectivity. Philosophy and sociology are recast as collaborating participants in articulating social epistemology of science

Epistemology of science is currently polarized. Descriptive accounts of the social aspects of science coexist uneasily with normative accounts of scientific knowledge. This tension leads students of science to privilege one of these important aspects over the other. I use an episode of recent immunology research to develop an integrative account of scientific inquiry that resolves the tension between sociality and epistemic success. The search for the hematopoietic stem cell by members of Irving Weissman’s laboratory at Stanford University Medical Center exhibits both the goal-oriented character of contemporary immunology and the importance of social interactions in successful achievement of those goals. This episode includes three kinds of epistemic success: characterization of HSC, formation of new interdisciplinary interfaces, and reconciliation of apparently incompatible models. All three depend on coordinating the work of diverse participants via social interactions. Together, they reveal the crucial role of social interactions within and between research groups in producing epistemic success. These features of the search for the HSC generalize to immunology as a whole, and plausibly to other disciplines. This account thus resolves the polarizing tension in epistemology of science, and complements individualistic accounts of scientific knowledge and rationality

This essay examines the role of social interactions in the search for blood stem cells, in a recent episode of biomedical research. Linked to mid-20th century cell biology, genetics and radiation research, the search for blood stem cells coalesced in the 1960s and took a developmental turn in the late 1980s, with significant ramifications for immunology, stem cell and cancer biology. Like much contemporary biomedical research, this line of inquiry exhibits a complex social structure and includes several prominent scientific successes, recognized as such by participating researchers. I use personal interviews and the published record to trace the social interactions crucial for scientific success in this episode. All recognized successes in this episode have two aspects: improved models of blood cell development, and new interfaces with other lines of research. The narrative of the search for blood stem cells thus yields a robust account of scientific success in practice, which generalizes to other scientific episodes and lends itself to expansion to include wider social contexts

In this paper, I propose a new way to integrate historical accounts of social interaction in scientific practice with philosophical examination of scientific knowledge. The relation between descriptive accounts of scientific practice, on the one hand, and normative accounts of scientific knowledge, on the other, is a vexed one. This vexatiousness is one instance of the gap between normative and descriptive domains. The general problem of the normative/descriptive divide takes striking and problematic form in the case of social aspects of scientific knowledge. With respect to this issue, history and philosophy of science appear starkly incompatible. I show how this dualism can be overcome, drawing on social action theory and the recent history of cellular immunology.

This review surveys three central issues in philosophy of stem cell biology: the nature of stem cells, stem cell experiments, and explanations of stem cell capacities. First, I argue that the fundamental question ‘what is a stem cell?’ has no single substantive answer. Instead, the core idea is explicated via an abstract model, which accounts for many features of stem cell experiments. The second part of this essay examines several of these features: uncertainty, model organisms, and manipulability. The results shed light on the form of our emerging knowledge of stem cells: mechanistic explanations. The third part of the essay sketches some key features of these explanations, which are constructed by a collaborative experimenting community

Epistemology of science is currently polarized. Descriptive accounts of the social aspects of science coexist uneasily with normative accounts of scientific knowledge. This tension leads students of science to privilege one of these important aspects over the other. I use an episode of recent immunology research to develop an integrative account of scientific inquiry that resolves the tension between sociality and epistemic success. The search for the hematopoietic stem cell (HSC) by members of Irving Weissman’s laboratory at Stanford University Medical Center exhibits both the goal-oriented character of contemporary immunology and the importance of social interactions in successful achievement of those goals. This episode includes three kinds of epistemic success: characterization of HSC, formation of new interdisciplinary interfaces, and reconciliation of apparently incompatible models. All three depend on coordinating the work of diverse participants via social interactions. Together, they reveal the crucial role of social interactions within and between research groups in producing epistemic success. These features of the search for the HSC generalize to immunology as a whole, and plausibly to other disciplines. This account thus resolves the polarizing tension in epistemology of science, and complements individualistic accounts of scientific knowledge and rationality.

This paper examines a case of failed interdisciplinary collaboration, between experimental stem cell research and theoretical systems biology. Recently, two groups of theoretical biologists have proposed dynamical systems models as a basis for understanding stem cells and their distinctive capacities. Experimental stem cell biologists, whose work focuses on manipulation of concrete cells, tissues and organisms, have largely ignored these proposals. I argue that ‘failure to communicate’ in this case is rooted in divergent views of explanation: the theoretically-inclined modelers are committed to a version of the covering-law view, while experimental stem cell biologists aim at mechanistic explanations. I propose a way to reconcile these two explanatory approaches to cell development, and discuss the significance of this result for interdisciplinary collaboration in systems biology and beyond

I have previously argued that stem cell experiments cannot demonstrate that a single cell is a stem cell (Fagan 2013a, b). Laplane and others dispute this claim, citing experiments that identify stem cells at the singlecell level. This paper rebuts the counterexample, arguing that the alleged ‘crucial stem cell experiments’ do not measure self-renewal for a single cell, do not establish a single cell’s differentiation potential, and, if interpreted as providing results about single cells, fall into epistemic circularity. I then discuss the source of the dispute, locating it in differences between philosophical and experimental perspectives.

This paper aims to bring the epistemic dimensions of stem cell experiments out of the background, and show that they can be critically evaluated. After introducing some basic concepts of stem cell biology, I set out the current “gold standard” for experimental success in that field (§2). I then trace the origin of this standard to a 1988 controversy over blood stem cells (§3). Understanding the outcome of this controversy requires attention to the details of experimental techniques, the organization of epistemic communities, and relations between the two (§4). With its resolution, a standard for experimental success was established for HSC research, which in turn serves as an exemplar for studies of other stem cells. This historical case study reveals a robust standard for experimental success in stem cell biology: to trace processes of development at the single-cell level, in the form of cell lineage hierarchies. Experiments conforming to this standard can be further critically assessed as means to the therapeutic end of stem cell research: use of stem cells to repair human organs and tissues.

There is a pervasive contrast in the early natural history writings of the co-discoverers of natural selection, Alfred Russel Wallace and Charles Darwin. In his writings from South America and the Malay Archipelago (1848-1852, 1854-1862). Wallace consistently emphasized species and genera, and separated these descriptions from his rarer and briefer discussions of individual organisms. In contrast, Darwin's writings during the Beagle voyage (1831-1836) emphasized individual organisms, and mingled descriptions of individuals and groups. The contrast is explained by the different practices of the two naturalists in the field. Wallace and Darwin went to the field with different educational experiences and social connections, constrained by different responsibilities and theoretical interests. These in turn resulted in different natural history practices; i.e., different habits and working routines in the field. Wallace's intense collecting activities aimed at a complete inventory of different species and their distributions at many localities. Darwin's less intense collecting practice focused on detailed observations of individual organisms. These different practices resulted in different material, textual and conceptual products. Placing natural history practices at the center of analysis reveals connections among these diverse products, and throws light on Wallace and Darwin's respective treatment of individuals and groups in natural history. In particular, this approach clarifies the relation between individuals and groups in Wallace's theory of natural selection, and provides an integrative starting point for further investigations of the broader social factors that shaped Victorian natural history practices and their scientific products.