Systems biology of robustness and homeostatic mechanisms

Abstract

All organisms are subject to large amounts of genetic and environmental variation and have evolved mechanisms that allow them to function well in spite of these challenges. This property is generally referred to as robustness. We start with the premise that phenotypes arise from dynamical systems and are therefore system properties. Phenotypes occur at all levels of the biological organizational hierarchy, from gene products, to biochemical pathways, to cells, tissues, organs, appendages, and whole bodies. Phenotypes at all these levels are subject to environmental and genetic challenges against which their form and function need to be protected. The mechanisms that can produce robustness are diverse and several different kinds often operate simultaneously. We focus, in particular, on homeostatic mechanisms that dynamically maintain form and function against varying environmental and genetic factors. Understanding how homeostatic mechanisms operate, how they reach their set point, and the nature of the set point pose difficult challenges. In developmental systems, homeostatic mechanisms make the progression of morphogenesis relatively insensitive to genetic and environmental variation so that the outcomes vary little, even in the presence of severe mutational and environmental stress. Accordingly, developmental systems give the appearance of being goal-oriented, but how the target phenotype is encoded is not known. We discuss why and how individual variation poses challenges for mathematical modeling of biological systems, and conclude with an explanation of how system population models are a useful method for incorporating individual variation into deterministic ordinary differential equation (ODE) models. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Physiology > Mammalian Physiology in Health and Disease Physiology > Organismal Responses to Environment Biological Mechanisms > Regulatory Biology.

Keywords: Allosteric regulation; cryptic genetic variation; homeostasis; metabolism; robustness.