Microbial strains used in biotechnological industry need to produce their biotechnological products at high yield and at the same time they are desired to be robust to the intrinsic nutrient dynamics of large-scale bioreactors, most noticeably to transient limitations of carbon sources and oxygen. The engineering principles for robustness of metabolism to nutrient dynamics are however not yet well understood. The ROBUSTYEAST project aims to reveal these principles for microbial strain improvement in biotechnological applications using a systems biology approach. This will contribute to establishing evolutionary optimization protocols for making microbial production strains robust against dynamic nutrient conditions.
The consortium will study the robustness of Saccharomyces cerevisiae in experiments during the dynamics associated with two cyclic nutrient transitions that are each of major relevance to industry: repeated cycles of glucose and ethanol growth and of aerobic and anaerobic growth. We shall monitor the physiological changes during the evolutionary adaptation of yeast to those transitions, using laboratory-evolution in lab-scale bioreactors (chemostat mode). By combining this data with computational modelling we shall identify the metabolic features that make yeast robust to these industrially relevant condition cycles. The theoretical and computational approaches that the consortium will develop involve optimisation methods applicable to metabolism transiting from one steady state to the next via dynamic regulation.
We shall iterate experiments and modelling to improve our models given experimental data, to identify new measurements critical to improve our understanding, and to finally identify key regulatory mechanisms for a robust metabolism of S. cerevisiae, given changes in glucose, ethanol and oxygen concentrations. The robustness of metabolic regulation under dynamic conditions will be evaluated from the kinetic models, and the regulatory interactions that confer such robustness will be determined