CONCEPTUAL RECONSTRUCTION AND EPISTEMIC IMPORT: ALLOSTERIC MECHANISTIC EXPLANATIONS AS A UNIFIED THEORY-NET.
| Autor | Alleva, Karina |
| Cargo | Ensayo |
This paper aims to show, through a detailed case study, that formal analysis and reconstructions may be useful to discuss and shed light on substantive meta-theoretical issues with regard to explanation, mechanisms, lawfulness and theoryhood. We proceed by exemplification, analysing and reconstructing as a case study a paradigmatic biochemical theory, the Monod-Wyman-Changeux (MWC) theory of allosterism, and applying the reconstruction to the discussion of some issues raised by prominent representatives of the new mechanist philosophy. In section 1 we summarize the main elements of MWC so as to provide sufficient background for the non-specialized reader. In section 2 we present the meta-theoretical tools that we use in our reconstruction, mainly the structuralist notion of theory-net. In section 3 we start the analysis with the definition of MWC potential and partial models, and their components. In section 4 we conclude the reconstruction with the definition of MWC actual models and the network of nomological constraints and the associated hierarchical theory-net. In section 5 we apply the reconstruction to the discussion of the usefulness, questioned by some mechanists, of the notions of theory and law for a proper understanding of the explanatory practice in biochemistry and related fields where the use of mechanisms is widespread. We defend (a) that the unified aspects of allosteric explanations, which are essential for a correct understanding of such practice, cannot be accounted for merely in mechanistic terms and are well explicated by the notion of theory-net; and (b) that the notion of law, in the weak sense of non-accidental--and possibly domain-specific--generalization, as they appear in the allosteric theory-net, is essential for allosteric explanations. We conclude that our case study shows that at least in this case mechanicism and (some version of) more traditional accounts are not rivals but complementary approaches; we also claim that this result plausibly generalizes in other cases in molecular biology, biochemistry and neuroscience--although this hypothesis should be tested by future work.
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The Monod-Wyman-Changeux Theory
The Monod, Wyman and Changeux theory (MWC) focuses on a particular regulation of biochemical activity, allosteric regulation or, as they themselves call it, the "allosteric mechanism" (Monod, Wyman and Changeux 1965, p. 103). The theory was first published more than fifty years ago, but remains "the basis for nearly all attempts to analyze the mechanistic basis of regulation not only for enzymes such as aspartate transcarbamoylase, but also for similar but different systems, such as ion channels" (Cornish-Bowden 2014). Indeed, allostery has remained as a key theory in biology and biochemistry since the quantitative explanation this theory allows regarding the biological activity of oligomeric proteins is fundamental for understanding a variety of cellular processes such as hormone action, gene repression and enzyme kinetics, among others. For this reason, allostery has been referred to by Jacques Monod as the "second secret of life" (Ullman 2004, p. 201). Although to the best of our knowledge we offer the first detailed meta-theoretical analysis and reconstruction, the theory has already been a subject of interest to meta-theorists, some of whom are mechanists (Darden and Maull 1977).
Jacques Monod and Francois Jacob coined the term "allosteric" in a summary article for the Cold Spring Harbor Symposium on Cellular Regulatory Mechanisms (Monod and Jacob 1961). They first used the term "allosteric" for naming the inhibitory mechanism triggered by the binding of a ligand to a site in an enzyme distinct from the binding site for the substrates; however, the concept of allosterism was substantially modified in a later paper (Monod, Wyman and Changeux 1965); the application of the new version of allosterism presented in 1965 has grown continuously and today applies to a whole variety of protein behaviors not involving enzymes, such as trans-membrane receptors, membrane channels and transporters. The theory is still considered a fruitful proposal and continues to show its resilience in the light of new experimental results (Cui and Karplus 2008; Viappiani et al. 2014).
The core general idea of MWC is to explain a particular pattern of biological activity showed by certain enzymes. Most enzymes show a biological activity with a hyperbolic dose-response profile ("dose" being the amount of substrate, and "response" the activity measured): the activity increases with the amount of substrate up to a certain value, and then remains constant (grey curve in Fig. 1). However, not all enzymes present this activity profile; others show sigmoidal behavior (black curve in Fig. 1). The variety of sigmoidal behaviors is what MWC aims to explain, introducing two main ideas: the occurrence of a relevant oligomeric structure for signal-transducing proteins, and a pre-existing equilibrium between two different conformations of oligomers depending on different affinities for different ligands (Changeux 2012). Roughly: the theory postulates that proteins have "parts" that may be in different "conformational states" which modify their "affinity" for different substances, obeying certain nomological connections that imply the observed patterns of activity.
The theory applies to proteins, named oligomers, having several sub-units, named protomers. Protomers have sites for the binding of ligands, which can be either substrates or modulators (i.e., activators that increase protein activity or inhibitors that decrease it). According to MWC, there are two possible spatial structures or conformational states for each oligomeric protein, each one with a different biological activity: a tense state ([tau]), with low affinity for substrate and low biological activity, and a relaxed state (r), with high affinity for substrate and high biological activity.
A symmetry condition is central to the theory and implies that all protomers of an oligomer are always in the same conformational state. The theory also claims that a change in conformational states is possible only in the absence of ligands (thus an oligomer that has bound a ligand no longer participates in allosteric transition), and that oligomers in r and [tau] conformational states co-exist in equilibrium when no ligand is present. This equilibrium, called allosteric transition, implies that: (i) oligomers are continuously changing from [tau] to r state and vice versa, but (ii) the ratio between oligomers in [tau] state and oligomers in r state is constant. The value of this ratio, a chemical equilibrium constant, receives the name of allosteric constant ([[iota].sub.0]) and characterizes each group of oligomers in certain conditions. Oligomers may behave differently with different ligands, reaching different equilibria, which are conceptualized as the specific "affinities" that the oligomer has for the specific ligands, and are formally represented by microscopic dissociation constants.
This is the general theoretical framework of the theory that allows it to explain different types of activity curves by different types of binding situations. The theory then explains different correlations between changes in ligand binding and changes in activity by, roughly, attributing to oligomers two different "conformational states" in which they may have more or less "affinity" with respect to ligands, and postulating some nomological connections between conformational states, affinities, binding states and activity.
It must be stressed that, initially, when MWC theory explained the biological activity of certain proteins it did so by referring to two parameters, the saturation function (the proportion of bound sites for all conformational states) and the r state function (the proportion of proteins in the relaxed state r, see below), linked to protein biological activity. The MWC model assumes that the biological activity can qualitatively be analogous to the saturation function. According to our point of view, shared by other authors (e.g., Bindslev 2008), in order to represent the biological activity of the oligomers the r state function is more appropriate, since it expresses the fraction of relaxed states that are responsible for the activity in the oligomer. On the other hand, the r state function is able to capture the spontaneous biological activity that some oligomers, such as channel proteins, might have. This function, however, was not considered by the authors of the model to account for the biological activity of the systems. We believe that this could be due to the fact that the allosteric systems to which the model was intended to be applied when the theory was created, comprised only enzymes and hemoglobin, proteins that do not have any spontaneous activity. The use of the saturation function for representing biological activity has been the object of controversy (Bindslev 2008). This controversy notwithstanding, in the original presentation of the theory, the authors themselves accept that using the saturation function depends on "assumptions about the mechanism of the reaction itself" and that "the saturation function cannot be determined directly but inferred form kinetics results" (Bindsley 2008, p. 94)--for enzymes. In this regard, our reconstruction helps to clarify that the corresponding concept here is biological activity.
This brief summary suffices for showing that the MWC explanatory set-up has the characteristic structure of other unified explanatory theories and can then be reconstructed as a unified theory-net in the precise sense announced above and that we are now going to specify.
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Theory-Nets
The structuralist notion of theory-net originates in the Kuhnian concept of paradigm/disciplinary matrix. When Kuhn introduces the two first components of disciplinary matrices, namely symbolic generalizations (i.e., laws)...
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