Thesis Defense: Ania Baetica

Title: Design, analysis, and computational methods for engineering synthetic biological networks

Abstract

This thesis has contributed to three aspects of engineering biological systems: analysis, design, and computational methods. First, we considered stochastic biological circuits and discussed the design of their stationary and transient behaviors. Noise is often indispensable to key cellular activities such as gene expression, necessitating the use of stochastic models to capture their dynamics. We designed the distributional response of these stochastic systems by formulating and solving it as a constrained optimization problem. Secondly, we analyzed a biological controller implemented by a sequestration feedback motif. We derived an analytical criterion for the stability of sequestration feedback networks and we determined their performance properties to provide guidelines for their implementation. Lastly, we developed a model reduction method to efficiently perform parameter identification for stochastic biological systems. The model reduction step decreased the computational time of parameter identification by an order of magnitude at a small cost in parameter accuracy. 

In this talk, we will focus on this thesis's contribution to the analysis of a sequestration feedback motif for biological control. Negative feedback is a ubiquitous motif in endogenous biological systems. Synthetic biological controllers have also typically relied on a negative feedback implementation to achieve homeostasis. However, negative feedback cannot guarantee adaptation to stimuli and it confers limited disturbance rejection properties. Sequestration feedback is an alternative implementation of biological control with potentially better performance properties of perfect adaptation through integral control.
Sequestration controllers can be built using a variety of biological parts for the two sequestering controller species (e.g. transcriptional parts such a mRNA and antisense RNA pair, protein parts such a sigma and anti-sigma pair). Depending on the choice of parts, the sequestration controllers have different properties; we derived an analytical criterion for their stability and we determined their performance. Additionally, we used these performance specifications to provide guidelines for the implementation of sequestration feedback.