Dissertation

Optimality and Plasticity in Metabolism

Wintermute, Edwin H

2011

Overview

Microbial metabolism is well characterized, conserved in evolution, and complex. Thus it is an excellent model for the systems approach to biology, which connects adaptive biological functions to the networks from which they emerge. This thesis will explore the complementary principles of optimality and plasticity in microbial metabolism, taking investigative strategies from systems and synthetic biology. Chapter 2 reviews metabolic interactions in mixed microbial communities. Basic cellular metabolism extends into cross-feeding, quorum-sensing, and communication with neighboring strains. Such interactions emerge from the metabolic network, yet represent a unique set of highly refined dynamic behaviors. Systems biology is the natural discipline for investigations in this field. Chapter 3 reports and characterizes widespread metabolic cooperation between auxotrophic strains of E. coli. We examine a library of laboratory-engineered deletion strains with no coevolutionary history and no selective pressure favoring cooperation. Yet we show they are often able to grow cooperatively in conditions where neither could grow alone. A quantitative model is developed to show how this behavior emerges from the inherrent flexibility of the metabolic network. Chapters 4 and 5 bring the tools of synthetic biology to the problem of metabolic engineering. We present the design and optimization of a system for the biological production of molecular hydrogen. Our efforts employ a range of techniques in synthetic biology: gene synthesis, standardization, protein fusion, scaffolding, and directed evolution. The flexibility of biological function is found to play an essential role in this work, as biological components are mixed and matched far from their native contexts. Chapter 6 revisits endogenous cellular metabolism with a new method for predicting the behavior of metabolic mutants. This method extends flux-balancing stoichiometric models by explicity representing ambiguity in our ability to predict fluxes. Counterintuitively, accounting for inherrent uncertainty in metabolism allows more accurate and precise predictions of metabolic behavior. The success of this method suggests a highly plastic model of metabolic fluxes that may be adaptive in the face of intracellular and environmental perturbation.

• Publisher: ProQuest Dissertations & Theses
• Subject: Systematic / Systematic biology
• ISBN: 9781267095893, 126709589X