Strong Inference for Systems Biology

Platts essay on strong inference Platt, J.R., 1964. Science 146, 347-353 illuminates a rational approach to scientific inquiry that integrates seamlessly with current investigations on the operation of complex biological systems. Yet in reexamining the 1964 essay in light of current trends, it is apparent that the groundbreaking approach has failed to become universal. Here it is argued that both the opportunity and the need to follow Platts advice are now greater than ever. A revised method of strong inference for sys-tems biology is presented and applied to analyze longstanding questions in cardiac energy metabolism. It is shown how this logical framework combined with computational-based hypothesis testing illumi-nates unresolved questions regarding how the energetic state of the heart is maintained in response to changes in the rate of ATP hydrolysis. Part 1. Philosophical Framework Platt’s Strong Inference A half century ago Platt proposed a formal schema for scientific inquiry based, in part, on his assess-ment of the rapid progress made in molecular biology and theoretical physics in the middle part of the twentieth century. Building on the “simple old-fashioned method of inductive inference that goes back to Francis Bacon ” 1, Platt proposed a method of strong inference, applied through the following logi-cal sequence: “1. Devising alternative hypotheses; 2. Devising a crucial experiment (or several of them), with alternative possible outcomes, each of which will, as nearly as possible, exclude one or more of the hypotheses; 3. Carrying out the experiment so as to get a clean result; 1’. Recycling the procedure, making subhypotheses or sequential hypotheses to refine the possibilities that remain; and so on.”1 Current use of the scientific method ideally applies this logic, but all too often work stagnates at a par-ticular step without completing the cycle. In adopting and effectively applying Platt’s steps, hypotheses are systematically disproved and refined, successively moving toward a more complete understanding of 1 Where unattributed, all quotations are from Platt 1.