Microbial cell factories containing engineered metabolisms can be very effective biocatalysts for sustainable production of fuels, chemicals, and natural products. However, achieving commercially viable titers, yields, and productivities remains a major challenge. Temporal and spatial control over engineered metabolic pathways has emerged as a promising strategy to significantly enhance the efficiency of these systems.
In the first part of my talk, I will present our pioneering work on the use of optogenetics – the application of light-responsive proteins to control biological processes – to achieve unprecedented dynamic regulation of metabolism in microbial cell factories. Light offers several distinct advantages: it is orthogonal to native cellular processes, tunable, reversible, and readily programmable via computer interfaces. These properties make it ideal for real-time and automated metabolic control during fermentation. I will highlight several optogenetic circuits we have developed to regulate microbial growth and metabolic flux, including recent demonstrations showing how these systems improve chemical production. This includes innovations to overcome limited light penetration in dense cultures, thereby enabling the application of optogenetics in bioreactor-scale fermentations.
In the second part of my talk, I will discuss our recent advances in the compartmentalization of biosynthetic pathways in liquid protein condensates. We have successfully used these membraneless synthetic organelles to direct and enhance metabolic flux. I will describe recent progress in their rational design and functionalization using theoretical frameworks, molecular dynamics simulations, and experimental validation. Finally, I will discuss how the integration of dynamic and spatial control strategies is establishing a new paradigm in metabolic engineering—one that promises to significantly expand the capabilities of microbial cell factories.