Understanding the Combinatorial Fragility of Life

Abstract

The goal of the modern biologist is not just to learn how biological components work, but to understand entire, complex biological systems.? With so many genes, gene products and metabolites to keep track of, there is a great need for methods that identify the contributions of individual elements to specific processes. Current methods are mostly based on the assumption that important elements contribute more or less additively to biological function. Yet our ordinary experiences with technology, economics, psychology and medicine all suggest that critical functions are often almost completely immune to disturbances unless enough of them happen in combination, a phenomenon we term “combinatorial fragility”, and which is quite the opposite of additivity. Increasingly, data suggest that combinatorial fragility may explain much of the contribution of genetic variation to human disease. I will present arguments, rooted both in engineering concepts and evolutionary theory, together with results of simulations, which support the idea that we should generally expect combinatorial fragility for important biological functions, yet not for biological observations in general. I will discuss the implications of these ideas for how we collect and analyze biological “big data”.