Abstract
Stem cells are defined as undifferentiated cells that can produce both undifferentiated and differentiated (specialized) cells. The stem cell concept is thus intimately connected to core assumptions about the process of development. Making these assumptions explicit clarifies the general explanandum-phenomenon of stem cell biology: the branching pattern of cell development, from a single initiating ‘stem,’ through intermediate stages, to one or more termini. Importantly, the whole process, not only developmental termini (specialized cells of a mature multicellular organism), is the target of explanation. Explanations of cell developmental processes are revealed by experiments. Here I focus on one important kind of experiment: direct cell reprogramming, which manipulates the development of cells in artificial culture conditions. I then examine three accounts of biological explanation in light of this case: interventionist, gene-centric, and mechanistic. Though each offers some insight into explanations based on reprogramming, none is fully satisfactory. This motivates a modified account of mechanistic explanation, emphasizing interdependence among components.
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Notes
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A complementary view is offered by Gross (2015, this volume) who defends the explanatory value of non-dependence relationships.
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Much about the process of development remains controversial, including its start- and end-points (see Pradeu 2011, and related articles).
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Examples of such general definitions can be found in the most recent edition of Essentials of Stem Cell Biology (Melton and Cowan 2009, xxiv); the first issue of Cell Stem Cell, the official journal of the International Society for Stem Cell Research (Ramelho-Santos and Willenbring 2007, 35); and information pages on the websites of the US National Institutes of Health (http://stemcells.nih.gov/info/basics/basics1.asp) and the European Stem Cell Network (http://www.eurostemcell.org/stem-cell-glossary).
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There are two modes of cell division: mitosis and meiosis. In mitosis, the genome replicates once before the cell divides. In meiosis, the genome replicates once, but two rounds of cell division follow, yielding four offspring cells with half the complement of DNA. Stem cell phenomena involve mitosis, so only that mode of cell division is discussed here.
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Demonstrating this potential experimentally is another matter (see Fagan 2013).
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Many stem cell biologists use calendar time rather than number of cell generations as a time-parameter. The two are interchangeable if an estimate of the rate of cell division for L is available (which is usually the case).
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Another aspect of differentiation is diversification: a population of cells diversifies over n cell generations if and only if variation in C-values increases with successive generations. As the notion of specialization appears to predominate in stem cell research today, I focus on this aspect of differentiation.
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The limiting case is an un-branched line. Some scientists deny that cells that initiate lineages with this pattern count as stem cells. This view imposes an additional constraint on the minimal model; the basic components and relations are the same.
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The first two are ‘cloning’ techniques of the sort that produced Dolly the sheep. They are usually conceived as effects of cytoplasm on the nucleus, while the latter two are conceived as effects of external factors on whole cells.
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Woodward’s full analysis is more elaborate. But this simplified treatment will do for present purposes.
- 17.
Waters does allow that some molecules other than DNA qualify as actual specific difference-makers, notably RNA splicing agents and micro-RNAs in eukaryotes (2007, pers. comm.). So his view is not strictly gene-centric. Nonetheless, explanatory privilege for these other molecules is premised on their being causes of the same sort as DNA, and in this sense, Waters’ view is gene-centric. Thanks to the editors for pushing me to clarify this point.
- 18.
Paraphrase of Waters (2007, 566–567). The final requirement is further explicated by several conditions pertaining to specificity, which are set aside here for simplicity.
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Woodward distinguishes two specificity concepts. As they are closely related, however, I discuss only the more rigorous here.
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This terminology follows Machamer et al. (2000). There are several other important accounts of mechanistic explanation in biology, which overlap in many but not in all respects; these include Glennan (1996, 52) and Bechtel and Abrahamsen (2005, 423). Note that this definition is actually narrower than that of Machamer and colleagues, restricted to constitutive or multilevel mechanisms (see below).
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Experimental biologists often seek underlying mechanisms, to explain an overall process in terms of its working parts. This is part of the explanatory aim shared by many stem cell biologists.
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This formulation is not Woodward’s own, though it captures what I take to be the main ideas of conception of modularity as it pertains to mechanistic explanation. Modularity in Woodward’s own theory (2003) has a somewhat different significance.
- 24.
This term is adapted from social action theory, where it describes actions of two or more agents (e.g., walking together, building a cathedral) and associated intentions.
- 25.
For simplicity, only the two-component case is presented. This makes condition (ii) redundant though it is necessary for complexes with three or more components.
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Acknowledgements
Many thanks to Pierre-Alain Braillard and Christophe Malaterre for the opportunity to contribute to this volume as well as helpful comments on the manuscript. Earlier versions of material in this paper were presented at workshops on Epistemology of Modeling and Simulation (Pittsburgh, PA, April 2011), Interdisciplinarity and Systems Biology (Aarhus University, Denmark, August 2011), and Individuals Across the Sciences (Sorbonne, Paris, May 2012), and at meetings of the Society for the Philosophy of Science in Practice (Exeter, UK, June 2011) and the American Philosophical Association, Pacific Division (Seattle, WA, April 2012). This essay has benefited from questions and comments of participants at all these events. Particular thanks are due to Hanne Andersen, Richard Grandy, Oleg Igoshin, Kirstin Matthews, Sean Morrison, Maureen O’Malley, Joe Ulatowski, Irv Weissman, and participants in the Fall 2010 graduate seminar in Philosophy of Science (Rice University). Support for this research was provided by the Humanities Research Center at Rice University’s Collaborative Research Fellowship (2009–2010), and Faculty Innovation Fund (2010–2012).
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Fagan, M.B. (2015). Explanatory Interdependence: The Case of Stem Cell Reprogramming. In: Explanation in Biology. History, Philosophy and Theory of the Life Sciences, vol 11. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9822-8_17
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