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Discovery of causal mechanisms

Oxidative phosphorylation and the Calvin–Benson cycle

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Abstract

We investigate the context of discovery of two significant achievements of twentieth century biochemistry: the chemiosmotic mechanism of oxidative phosphorylation (proposed in 1961 by Peter Mitchell) and the dark reaction of photosynthesis (elucidated from 1946 to 1954 by Melvin Calvin and Andrew A. Benson). The pursuit of these problems involved discovery strategies such as the transfer, recombination and reversal of previous causal and mechanistic knowledge in biochemistry. We study the operation and scope of these strategies by careful historical analysis, reaching a number of systematic conclusions: (1) even basic strategies can illuminate “hard cases” of scientific discovery that go far beyond simple extrapolation or analogy; (2) the causal–mechanistic approach to discovery permits a middle course between the extremes of a completely substrate-neutral and a completely domain-specific view of scientific discovery; (3) the existing literature on mechanism discovery underemphasizes the role of combinatorial approaches in defining and exploring search spaces of possible problem solutions; (4) there is a subtle interplay between a fine-grained mechanistic and a more coarse-grained causal level of analysis, and both are needed to make discovery processes intelligible.

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Notes

  1. For conceptual analysis, see particularly Simon (1973), the essays in Nickles (1980b), and Hoyningen-Huene (1987, 2006). For early historical work, see the case studies in Nickles (1980a), Darden (1991), Bechtel and Richardson (1993) and Schaffner (1994). More recently, scientific discovery was reinvigorated by the volumes by Bechtel (2005), Darden (2006), Schickore and Steinle (2006), Meheus and Nickles (2009) and Craver and Darden (2013). See also references cited therein.

  2. Our focus on causal–mechanistic reasoning strategies is not meant to be exclusionary: We believe that our approach is one of many useful points of view. First, we deal with our case studies at a much less fine-grained resolution than analyses of laboratory notebooks (see especially Holmes et al. 2003; Holmes 2004). Like Holmes, we believe that multiple scales of temporal “graininess” can each reveal important aspects of the context of discovery (2004, Chapter 2; 2009, pp. 77–78). Second, our study is not a contribution to cognitive science because we do not analyse the process of hypothesis generation in terms of the immediate mental operations performed by scientists (cf. Holmes 1991; Holyoak and Thagard 1996; Nersessian 2008, and see references therein). For the same reason, moreover, we do not hold that the strategies we describe could be implemented computationally so as to automate scientific discovery: we do not know if this will ever be possible, but at this stage of the project it certainly is not. Finally, we do not use Rheinberger’s (1997) “experimental systems” approach because we have a different focus: like Weber (2005, Chapter 5) we take a methodological analysis of hypothesis generation to be a necessary complement to the study of the capacities of experimental systems.

  3. We do not commit to any particular philosophical account of causation. We expect that our epistemological conclusions will be compatible with whatever the best metaphysical analysis of causation turns out to be—be it a probabilistic theory, a counterfactual theory, a process theory, or something else.

  4. We present a schema of the mechanism accepted today as a guide for readers who are unfamiliar with the biochemical details. Mitchell’s original proposal differed from this schema in several respects. For instance, his proposal imagined the orientation of the membrane transport systems (components 2 and 3) to be the reverse of what is actually the case. Moreover, Mitchell included a fourth component: an ion exchange system which would allow \(\hbox {H}^{+}/\hbox {K}^{+}\)-exchange, reducing the pH differential and replacing it with a potassium membrane potential (also driving \(\hbox {H}^{+}\) flow). Finally, Mitchell’s hypotheses about the mechanisms by which these components operate differed significantly from what is accepted today.

  5. For a contemporary overview of some of these hypotheses, see Danielli (1954).

  6. It is telling that Mitchell and Moyle argued for their theory of membrane transport by highlighting not its originality but its orthodoxy (Mitchell and Moyle 1958, p. 373). Although the Popperians are no longer on the scene, the prejudice still prevails that scientists generally aim to propose revolutionary hypotheses (for a discussion and critique of this position, see Chalmers 1973). But while iconoclasm is certainly a desirable long-term outcome, conservatism seems to be more highly prized in everyday hypothesis generation (trying to explain oxidative phosphorylation by analogy to glycolysis, or membrane transport in terms of enzyme reactions). We will have more such instances in our second case study in Sect. 4.

  7. Robertson distinguishes between charge separation as a process occurring in the membrane-bound cytochrome system and secretion as one result of charge separation.

  8. See Robinson (1997) for a discussion of the history of the redox pump hypothesis on pp. 113–116.

  9. See Joseph D. Robinson’s invaluable history of membrane transport, especially chapters 3–8, for an in-depth discussion of these developments (Robinson 1997).

  10. In recognition of the discovery, Skou received the Nobel Prize in Chemistry in 1997, together with Paul D. Boyer and John E. Walker.

  11. Prebble (2000) notes that Mitchell “came up with mechanisms in large numbers” and “was allergic to systems that depended on processes which at the time could not be defined precisely at the molecular level” (p. 330). He defends Mitchell’s penchant for inventing mechanisms with the suggestion that a few successes justify “so many apparently fruitless mechanisms”. We would argue that no defense is needed: scientific discovery relies on the proposal of appropriate candidate mechanisms. Moreover, we are not sure to what extent Mitchell’s insistence on molecular detail was unusual, since at least Robertson (as discussed above) also formulated hypotheses largely at the mechanistic level. Prebble mentions that many further ideas for mechanisms exist in Mitchell’s unpublished documents, and it will be worthwhile to investigate these in the light of a causal–mechanistic understanding of discovery.

  12. A pointed comment on this fact as well as on Calvin’s failure to acknowledge Benson’s contribution in public ever since is provided by Fuller (1999), pp. 9–10.

  13. This is not meant to suggest that the radiotracer techniques were unimportant. However, an appropriate treatment would double the paper’s length.

  14. The abbreviation [\(\hbox {C}_2\)] denotes that this compound contains two carbon atoms, usually as a backbone chain. Within a compound the carbons are given numbers according to their position in the chain.

  15. This compound is known today as “ribulose bisphosphate”; in order to be consistent with the historical sources, the older name has been adopted for the paper.

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Acknowledgments

We thank the Lake Geneva Biology Interest Group (LG-BIG) and the participants of a January 2014 workshop on “Causality in the Biological Sciences” in Cologne, Germany. In addition, we are particularly grateful to the following for a close reading of an earlier version of the manuscript: Bill Bechtel, Ingo Brigandt, Sara Green and Nick Jones. Raphael Scholl was supported by a Grant from the Swiss National Science Foundation (P300P1_154590).

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Scholl, R., Nickelsen, K. Discovery of causal mechanisms. HPLS 37, 180–209 (2015). https://doi.org/10.1007/s40656-015-0061-2

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