Design principles underlying nearly-homeostatic biological networks

Abstract

A nearly-homeostatic system like body temperature maintenance keeps the steady state system output like internal body temperature within a narrow range, regardless of different persistent levels of environmental perturbations like external temperatures. Nearly-homeostatic systems can be implemented to guarantee performance of a therapeutic device in different patient contexts. Exploration of different near-homeostasis-supporting architectures to satisfy different design requirements is necessary, but methods for doing so in a fast and comprehensive manner remain elusive. We have identified two constrained optimization approaches to find near-homeostasis supporting architectures 10 to 100 times faster than brute-force search. Once such architectures are found, characterizing the underlying mechanisms of near-homeostasis is hindered by the very cumbersome and limited nature of traditional statistical analysis approaches. We have developed two levels of "inverse homeostasis plots", and used them to identify two novel near-homeostasis mechanisms that tolerate much higher undesired basal expression and much higher undesired first order degradation rates than previously characterized near-homeostasis mechanisms. TeaserA comprehensive toolset was developed for much faster discovery and much more comprehensive analysis of near-homeostasis-supporting architectures.