Karl Matlin

This article draws on and extends Bechtel’s influential work on the historical and philosophical implications of mechanistic research in cell biology. Beginning in the 1940s, cell biology relied on electron microscopy (EM) and cell fractionation, exemplifying the coupled epistemic strategies of structural decomposition and localization through experimental engagement with component parts and operations (Bechtel and Richardson [1993]2010; Bechtel 2006). In the 1970s, however, fluorescence microscopy (FM) enabled visualization of proteins and macromolecular assemblies in intact cells, which transformed mechanistic studies in cell biology. Through a historical analysis of cell adhesion and migration research, we show how the development and use of FM enabled what we call exposition of mechanisms. Instead of physically decomposing cells into component parts, FM allowed researchers to visually expose these parts directly in their spatial-functional context in intact and even living cells. This epistemic strategy retained the mechanistic assumption that living systems can be meaningfully studied through localizable parts and operations. Yet, FM allowed for a more holistic approach to investigate structurally integrated components of minimally decomposable systems, such as focal contacts and the cytoskeleton, thus illustrating the importance of preserving the cellular context.

Cell biologists, including those seeking molecular mechanistic explanations of cellular phenomena, frequently rely on experimental strategies focused on identifying the cellular context relevant to their investigations. We suggest that such practices can be understood as a guided decomposition strategy, where molecular explanations of phenomena are defined in relation to natural contextual (cell) boundaries. This “top-down” strategy contrasts with “bottom-up” reductionist approaches where well-defined molecular structures and activities are orphaned by their displacement from actual biological functions. We focus on the central role of microscopic imaging in cell biology to uncover possible constraints on the system. We show how identified constraints are used heuristically to limit possible mechanistic explanations to those that are biologically meaningful. Historical examples of this process described here include discovery of the mechanism of oxidative phosphorylation in mitochondria, molecular explanation of the first steps in protein secretion, and identification of molecular motors. We suggest that these instances are examples of a form of downward causation or, more specifically, constraining relations, where higher-level structures and variables delimit and enable lower-level system states. The guided decomposition strategy in our historical cases illustrates the irreducibility of experimentally identified constraints in explaining biological activities of cells. Rather than viewing decomposition and recomposition as separate epistemic activities, we contend that they need to be iteratively integrated to account for the ontological complexity of multi-level systems.

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.