Controller Motifs for Homeostatic Regulation and Their Applications in Biological Systems

Abstract

Living organisms have over billions of years evolved into highly specific and complex entities. Although the range of organisms that inhabit our planet is strikingly diverse, they are all in some extent able to protect their inner environment by keeping important variables within relatively narrow limits. This is called homeostasis and is achieved through elaborate regulatory networks with nonlinear interactions between genes, proteins and metabolites. These regulatory networks incorporate a combination of mechanisms, such as negative feedback, feedforward, integral control and proportional control. It is clear that concepts from control theory, most often applied in systems engineered by humans, can also be applied to further the understanding of regulatory networks in biology. The complexity and nonlinearity of biological network does, however, make this not as straight forward and easy as one might think. Man-made systems are contrary to biological systems most often engineered from a set of separable components or subsystems, and specifically designed to keep interactions between different subsystems as simple as possible. This thesis aims to explore how chemical species in a biological system can interact to form simple structures with homeostatic properties. A set of building blocks for regulation, consisting of two-component reaction kinetic schemes called controller motifs, is presented and formalized. The controller motifs have a structure that combines negative feedback with integral control, consequently giving the motifs homeostatic properties. The controller motifs are useful in modeling and understanding of cellular homeostasis. They are herein employed to explore transepithelial glucose transport and ionic homeostasis in enterocytes. A mathematical enterocyte model is developed, and controller motifs are used in this model to explain how enterocytes can maintain a near constant internal concentration of sodium while dealing with sodium coupled nutrient transport. Furthermore, this thesis demonstrates how controller motifs can be applied in synthetic biology as guidelines on how to design novel regulatory networks. A copper controller in the form of a copper transporting Cu-ATPase, under control of a copper dependent promoter, is added to yeast (Saccharomyces cerevisiae) by genomic integration. This controller extends the yeast’s ability to regulate its internal concentration of copper, and moreover the controller is shown to increase the yeast’s survivability in environments with high concentrations of copper. Finally, the controller motifs and the classical concept of homeostasis are extended and applied on oscillatory systems. A wide range of biological processes are, in fact, oscillatory. Examples include signaling by cytosolic calcium and circadian rhythms. This part of the thesis shows how even oscillatory systems can have properties, such as average level and frequency, that are maintained in a homeostatic fashion.