Unwarranted assumptions: Claude Bernard and the growth of the vera causa standard.

The physiologist Claude Bernard was an important nineteenth-century methodologist of the life sciences. Here I place his thought in the context of the history of the vera causa standard, arguably the dominant epistemology of science in the eighteenth and early nineteenth centuries. Its proponents held that in order for a cause to be legitimately invoked in a scientific explanation, the cause must be shown by direct evidence to exist and to be competent to produce the effects ascribed to it. Historians of scientific method have argued that in the course of the nineteenth century the vera causa standard was superseded by a more powerful consequentialist epistemology, which also admitted indirect evidence for the existence and competence of causes. The prime example of this is the luminiferous ether, which was widely accepted, in the absence of direct evidence, because it entailed verified observational consequences and, in particular, successful novel predictions. According to the received view, the vera causa standard's demand for direct evidence of existence and competence came to be seen as an impracticable and needless restriction on the scope of legitimate inquiry into the fine structure of nature. The Mill-Whewell debate has been taken to exemplify this shift in scientific epistemology, with Whewell's consequentialism prevailing over Mill's defense of the older standard. However, Bernard's reflections on biological practice challenge the received view. His methodology marked a significant extension of the vera causa standard that made it both powerful and practicable. In particular, Bernard emphasized the importance of detection procedures in establishing the existence of unobservable entities. Moreover, his sophisticated notion of controlled experimentation permitted inferences about competence even in complex biological systems. In the life sciences, the vera causa standard began to flourish precisely around the time of its alleged abandonment.

Spot the difference: Causal contrasts in scientific diagrams.

An important function of scientific diagrams is to identify causal relationships. This commonly relies on contrasts that highlight the effects of specific difference-makers. However, causal contrast diagrams are not an obvious and easy to recognize category because they appear in many guises. In this paper, four case studies are presented to examine how causal contrast diagrams appear in a wide range of scientific reports, from experimental to observational and even purely theoretical studies. It is shown that causal contrasts can be expressed in starkly different formats, including photographs of complexly visualized macromolecules as well as line graphs, bar graphs, or plots of state spaces. Despite surface differences, however, there is a measure of conceptual unity among such diagrams. In empirical studies they often serve not only to infer and communicate specific causal claims, but also as evidence for them. The key data of some studies is given nowhere except in the diagrams. Many diagrams show multiple causal contrasts in order to demonstrate both that an effect exists and that the effect is specific - that is, to narrowly circumscribe the phenomenon to be explained. In a large range of scientific reports, causal contrast diagrams reflect the core epistemic claims of the researchers.

[Peptic ulcer disease and helicobacter pylori: How we know what we know]. / Peptische Ulzera und Helicobacter pylori: Wie wir wissen, was wir wissen.

The bacterium Helicobacter pylori is one of the main causes of peptic ulcers. But how was this causal relationship demonstrated? A historical and philosophical analysis of a series of studies conducted during the 1980s can elucidate the question. In the beginning, a mere correlation between the newly discovered bacterium and peptic ulcers was found in gastric biopsies. It remained an open question whether the bacterium caused the disease, or whether it constituted merely an opportunistic infection. Yet determining the direction of causality was difficult in the absence of an animal model: Even though gastritis was observed in a courageous self-experiment involving a swallowed bacterial culture, tf!e significance of the individual case was small. The failings of the self-experiment could only be rectified by a randomised, placebo-controlled trial which met the requirements of Koch's third postulate. Moreover, it was necessary to gain an initial understanding of the mechanism by which the causal relationship between H. pylori and peptic ulcers is mediated: How, forexample, does the bacterium survive in the acid environment of the stomach? The study of the case from the perspective of the history and philosophy of science illustrates how medical knowledge is established incrementally.

Discovery of causal mechanisms: Oxidative phosphorylation and the Calvin-Benson cycle.

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.

Spinal muscular atrophy: position and functional importance of the branch site preceding SMN exon 7.

In spinal muscular atrophy, the SMN1 gene is deleted or destroyed by mutation, while the neigboring, nearly identical SMN2 gene acts as a partial functional substitute. However, due to a single nucleotide exchange, the seventh exon of SMN2 is mostly excluded from the mature mRNA, and the resulting shorter protein is non-functional. Here, we map the previously uncharacterized intron 6 branch point by RT-PCR. Moreover we show that exon 7 inclusion can be either abolished or improved by mutations in this branch site region.