We investigate the context of discovery of two significant achievements of twentieth century biochemistry: the chemiosmotic mechanism of oxidative phosphorylation and the dark reaction of photosynthesis. 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: even basic strategies can illuminate “hard cases” of scientific discovery that go far (...) beyond simple extrapolation or analogy; 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; the existing literature on mechanism discovery underemphasizes the role of combinatorial approaches in defining and exploring search spaces of possible problem solutions; 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. (shrink)

In the 1950s and 1960s, the search for the mechanism of oxidative phosphorylation by biochemists paralleled the description of mitochondrial form by George Palade and Fritiof Sjöstrand using electron microscopy. This paper explores the extent to which biochemists studying oxidative phosphorylation took mitochondrial form into account in the formulation of hypotheses, design of experiments, and interpretation of results. By examining experimental approaches employed by the biochemists studying oxidative phosphorylation, and their interactions with Palade, I suggest that use of mitochondrial form (...) as a guide to experimentation and interpretation varied considerably among investigators. Most notably, Peter Mitchell, whose chemiosmotic hypothesis was ultimately the basis of the correct mechanism of oxidative phosphorylation, incorporated crucial aspects of mitochondrial form into his model that others failed to recognize. I discuss these historical observations in terms of the background and training of the biochemists, as well as a proposed heuristic of form, whose use may increase the possibility that biologically meaningful molecular mechanisms will be discovered. (shrink)

In 1971, Günter Blobel and David Sabatini proposed a novel and quite speculative schematic model to describe how proteins might reach the proper cellular location. According to their proposal, proteins destined to be secreted from the cell contain a “signal” to direct their release. Despite the fact that Blobel and Sabatini presented their signal hypothesis as a “beautiful idea” not grounded in experimental evidence, they received criticism from other scientists who opposed such speculation. Following the publication of the 1971 model, (...) Blobel persisted in conducting experiments and revising the model to incorporate new data. In fact, over the period of 1975–1984, Blobel and colleagues published five subsequent schematic models of the signal hypothesis, each revised based on new laboratory evidence. I propose that the original 1971 model can be viewed as an epistemic creation. Additionally, analysis of the subsequent schematic diagrams over the period of 1975–1984 allows one to track Blobel’s changing conception of an epistemic object over time. Furthermore, the entire series of schematic diagrams presented by Blobel from 1971 to 1984 allow one to visualize the initial conception and subsequent reworking of a scientific theory. In 1999, Blobel was awarded the Nobel Prize in Physiology or Medicine for his work on the signal hypothesis, which was ultimately supported by experimental evidence gathered after the speculative model was published. (shrink)