Control circuits for dynamic metabolic engineering - Dr. Diego Oyarzún (Imperial College London)

Advances in metabolic engineering have led to the synthesis of a wide variety of chemicals with microorganisms. Traditional approaches use “push-pull-block” strategies to re-route metabolic flux, where some enzymes are overexpressed to push flux toward cofactors and precursors, others are overexpressed to pull flux through a pathway of interest, and some genes are knocked out to block flux through competing pathways. However, strains are often optimised for specific laboratory setups and are sensitive to environmental fluctuations. Exposure to sub-optimal growth conditions during large-scale fermentation often reduces their production capacity. Moreover, engineered pathways may cause cofactor imbalances or accumulation of toxic intermediates, which imposes burden on the host and results in decreased production. 

To overcome these challenges, the last decade has witnessed the birth of a new technology that uses genetic circuits to dynamically control pathway activity, in ways akin to regulatory networks found in nature. In this talk I will outline some of our theoretical and experimental work on precision engineering of control circuits for metabolic pathways. Our approach combines ideas from dynamical systems, stochastic analysis and computational optimisation to gain a predictive understanding of the relation between circuit architecture and pathway performance. We will discuss the current challenges on the design of metabolite biosensors, the assembly of parts into functional circuits, and the control of non-genetic heterogeneity across a microbial population.