Infinitesimal homeostasis in three-node input-output networks.

Homeostasis occurs in a system where an output variable is approximately constant on an interval on variation of an input variable [Formula: see text]. Homeostasis plays an important role in the regulation of biological systems, cf.  Ferrell (Cell Syst 2:62-67, 2016), Tang and McMillen (J Theor Biol 408:274-289, 2016), Nijhout et al. (BMC Biol 13:79, 2015), and Nijhout et al. (Wiley Interdiscip Rev Syst Biol Med 11:e1440, 2018). A method for finding homeostasis in mathematical models is given in the control theory literature as points where the derivative of the output variable with respect to [Formula: see text] is identically zero. Such points are called perfect homeostasis or perfect adaptation. Alternatively, Golubitsky and Stewart (J Math Biol 74:387-407, 2017) use an infinitesimal notion of homeostasis (namely, the derivative of the input-output function is zero at an isolated point) to introduce singularity theory into the study of homeostasis. Reed et al. (Bull Math Biol 79(9):1-24, 2017) give two examples of infinitesimal homeostasis in three-node chemical reaction systems: feedforward excitation and substrate inhibition. In this paper we show that there are 13 different three-node networks leading to 78 three-node input-output network configurations, under the assumption that there is one input node, one output node, and they are distinct. The different configurations are based on which node is the input node and which node is the output node. We show nonetheless that there are only three basic mechanisms for three-node input-output networks that lead to infinitesimal homeostasis and we call them structural homeostasis, Haldane homeostasis, and null-degradation homeostasis. Substantial parts of this classification are given in Ma et al. (Cell 138:760-773, 2009) and Ferrell (2016) among others. Our contributions include giving a complete classification using general admissible systems (Golubitsky and Stewart in Bull Am Math Soc 43:305-364, 2006) rather than specific biochemical models, relating the types of infinitesimal homeostasis to the graph theoretic existence of simple paths, and providing the basis to use singularity theory to study higher codimension homeostasis singularities such as the chair singularities introduced in Nijhout and Reed (Integr Comp Biol 54(2):264-275, 2014. https://doi.org/10.1093/icb/icu010) and Nijhout et al. (Math Biosci 257:104-110, 2014). See Golubitsky and Stewart (2017). The first two of these mechanisms are illustrated by feedforward excitation and substrate inhibition. Structural homeostasis occurs only when the network has a feedforward loop as a subnetwork; that is, when there are two distinct simple paths connecting the input node to the output node. Moreover, when the network is just the feedforward loop motif itself, one of the paths must be excitatory and one inhibitory to support infinitesimal homeostasis. Haldane homeostasis occurs when there is a single simple path from the input node to the output node and then only when one of the couplings along this path has strength 0. Null-degradation homeostasis is illustrated by a biochemical example from Ma et al. (2009); this kind of homeostasis can occur only when the degradation constant of the third node is 0. The paper ends with an analysis of Haldane homeostasis infinitesimal chair singularities.