Section: Application Domains

Optimal control of microbial cells

Participants : Jean-Baptiste Caillau, Walid Djema [BIOCORE project-team] , Laetitia Giraldi, Jean-Luc Gouzé [BIOCORE project-team] , Sofya Maslovskaya, Jean-Baptiste Pomet, Agustín Yabo.

The growth of microorganisms is fundamentally an optimization problem which consists in dynamically allocating resources to cellular functions so as to maximize growth rate or another fitness criterion. Simple ordinary differential equation models, called self-replicators, have been used to formulate this problem in the framework of optimal and feedback control theory, allowing observations in microbial physiology to be explained. The resulting control problems are very challenging due to the nonlinearity of the models, parameter uncertainty, the coexistence of different time-scales, a dynamically changing environment, and various other physical and chemical constraints. In the framework of the ANR Maximic (PI Hidde de Jong, Inria Grenoble Rhône-Alpes) we aim at developing novel theoretical approaches for addressing these challenges in order to (i) study natural resource allocation strategies in microorganisms and (ii) propose new synthetic control strategies for biotechnological applications. In order to address (i), we develop extended self-replicator models accounting for the cost of regulation and energy metabolism in bacterial cells. We study these models by a combination of analytical and numerical approaches to derive optimal control solutions and a control synthesis, dealing with the bang-bang-singular structure of the solutions. Moreover, we define quasi-optimal feedback control strategies inspired by known regulatory mechanisms in the cell. To test whether bacteria follow the predicted optimal strategies, we quantify dynamic resource allocation in the bacterium Escherichia coli by monitoring, by means of time-lapse fluorescent microscopy, the expression of selected genes in single cells growing in a microfluidics device. In order to address (ii), we build self-replicator models that include a pathway for the production of a metabolite of interest. We also add a mechanism to turn off microbial growth by means of an external input signal, at the profit of the production of the metabolite. We formulate the maximization of the amount of metabolite produced as an optimal control problem, and derive optimal solutions and a control synthesis, as well as quasi-optimal feedback strategies satisfying chemical and physical design constraints. The proposed synthetic control strategies are being tested experimentally by growing E. coli strains capable of producing glycerol from glucose in a mini-bioreactor system. We aim at quantifying the amount of glucose consumed and glycerol produced, in the case of a predefined input signal (open-loop control) and the adaptive regulation of the input signal based on on-line measurements of the growth rate and the expression of fluorescent reporters of selected genes (closed-loop control). Currently, one PhD (A. Yabo) and one postdoc (S. Maslovskaya) are involved in these tasks and jointly supervised by colleagues from McTAO and Biocore teams at Sophia. Preliminary results concern the definition on extended (higher dimensional) models for the bacteria dynamics, check of second order optimality conditions on the resulting optimal control problem, and study of the turnpike phenomenon for these optimization problems.