Homeostasis in input-output networks: Structure, Classification and Applications

Homeostasis is concerned with regulatory mechanisms, present in biological systems, where some specific variable is kept close to a set value as some external disturbance affects the system. Many biological systems, from gene networks to signaling pathways to whole tissue/organism physiology, exhibit homeostatic mechanisms. In all these cases there are homeostatic regions where the variable is relatively to insensitive external stimulus, flanked by regions where it is sensitive. Mathematically, the notion of homeostasis can be formalized in terms of an input-output function that maps the parameter representing the external disturbance to the output variable that must be kept within a fairly narrow range. This observation inspired the introduction of the notion of infinitesimal homeostasis, namely, the derivative of the input-output function is zero at an isolated point. This point of view allows for the application of methods from singularity theory to characterize infinitesimal homeostasis points (i.e. critical points of the input-output function). In this paper we review the infinitesimal approach to the study of homeostasis in input-output networks. An input-output network is a network with two distinguished nodes 'input' and 'output', and the dynamics of the network determines the corresponding input-output function of the system. This class of dynamical systems provides an appropriate framework to study homeostasis and several important biological systems can be formulated in this context. Moreover, this approach, coupled to graph-theoretic ideas from combinatorial matrix theory, provides a systematic way for classifying different types of homeostasis (homeostatic mechanisms) in input-output networks, in terms of the network topology. In turn, this leads to new mathematical concepts, such as, homeostasis subnetworks, homeostasis patterns, homeostasis mode interaction. We illustrate the usefulness of this theory with several biological examples: biochemical networks, chemical reaction networks (CRN), gene regulatory networks (GRN), Intracellular metal ion regulation and so on.