Methodology is philosophy

Robert Shulman

Systems Biology is one approach that shares the increasing interest in explaining functions of the whole organism in terms of the component molecules, cells or structures. Given the varied disciplines that participate in this goal e.g. genomics, proteomics, and cognitive neuroscience, it is timely to consider if their common strategies can be identified and addressed most generally at their philosophical level. The scope of this symposium proposes that scientists should respond to the novel questions raised by Systems Biology with new experimental and theoretical methods. In my opinion any methodology both determines and reflects a philosophy so that Methodology is Philosophy.

More specifically I propose that Systems Biology can be studied by a methodology that my laboratory has been developing for more than 30 years, which will be exemplified by one set of experiments. The philosophical basis of this study will be presented and contrasted with alternatives.

Magnetic Resonance Spectroscopic (MRS) measurements of fluxes and metabolites have been conducted non-invasively in humans, animals, perfused organs and microorganisms. These experiments measure the parameters that Metabolic Control Analysis (MCA) needs to related higher level functions to the physical properties of the constituent molecules.

The studies to be discussed started by 13CMRS measurements of the flux from labeled glucose into muscle glycogen in humans and were subsequently supplemented by in vivo concentrations of key metabolites. An MCA analysis of these results showed that the flux was under supply control by plasma glucose concentration and glucose transporters, mediated by insulin. The allosteric, phosphorylated enzyme Glycogen Synthase did not control flux but maintained metabolite homeostasis. Hence these results jumped two levels, relating the constitutive biomolecules to homeostasis and control at the metabolic and physiological levels. These results were connected to the level of Systems Biology by explaining the metabolic nature of Non Insulin Dependent Diabetes (NIDD), a disease with both genetic and life style contributions. Similar MRS experiments comparing rates of glycogen synthesis in NIDD patients with controls showed the genetic deficit to lie in a reduced recruitment of glucose transporters to the muscle plasma membrane. Effects of exercise and obesity upon this recruitment and its mechanism are all being fruitfully studied

Philosophically these studies are driven by a search for mechanism- where the systemic function is defined in chemical or physical terms. In the alternative philosophies the systemic function is defined by”clear and distinct” intuitions, such as the explanatory nature of concepts like Mind, Gene or Structure-Functions connections, rather than by scientific hypotheses. These methods look for physical correlates of function, which begs the question of mechanism, rather than answering it. I see no need to abandon the hypothetic-deductive methods and philosophies of physical science.