• The Inria's Research Teams produce an annual Activity Report presenting their activities and their results of the year. These reports include the team members, the scientific program, the software developed by the team and the new results of the year. The report also describes the grants, contracts and the activities of dissemination and teaching. Finally, the report gives the list of publications of the year.

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## Section: Research Program

### Natural and engineered control of growth and gene expression

Participants : Célia Boyat, Eugenio Cinquemani, Johannes Geiselmann [Correspondent] , Hidde de Jong [Correspondent] , Stephan Lacour, Marco Mauri, Tamas Muszbek, Michel Page, Antrea Pavlou, Delphine Ropers.

The adaptation of bacterial physiology to changes in the environment, involving changes in the growth rate and a reorganization of gene expression, is fundamentally a resource allocation problem. It notably poses the question how microorganisms redistribute their protein synthesis capacity over different cellular functions when confronted with an environmental challenge. Assuming that resource allocation in microorganisms has been optimized through evolution, for example to allow maximal growth in a variety of environments, this question can be fruitfully formulated as an optimal control problem. We have developed such an optimal control perspective, focusing on the dynamical adaptation of growth and gene expression in response to envrionmental changes, in close collaboration with the BIOCORE project-team.

A complementary perspective consists in the use of control-theoretical approaches to modify the functioning of a bacterial cell towards a user-defined objective, by rewiring and selectively perturbing its regulatory networks. The question how regulatory networks in microorganisms can be externally controlled using engineering approaches has a long history in biotechnology and is receiving much attention in the emerging field of synthetic biology. Within a number of on-going projects, IBIS is focusing on two different questions. The first concerns the development of open-loop and closed-loop growth-rate controllers of bacterial cells for both fundamental research and biotechnological applications (Figure 5). Second, we are working on the development of methods for the real-time control of the expression of heterologous proteins in communities of interacting bacterial populations. The above projects involve collaborations with, among others, the Inria project-teams LIFEWARE (INBIO), BIOCORE, and McTAO as well as with a biophysics group at Univ Paris Descartes and a mathematical modeling group at INRA Jouy-en-Josas.

Figure 5. Growth arrest by external control of the gene expression machinery (Izard, Gomez Balderas et al., Molecular Systems Biology, 11:840, 2015). An E. coli strain in which an essential component of the gene expression machinery, the $\beta {\beta }^{\text{'}}$ subunits of RNA polymerase, was put under the control of an externally-supplied inducer (IPTG), was grown in a microfluidics device and phase-contrast images were acquired every 10 min. The cells were grown in minimal medium with glucose, initially in the presence of 1 mM IPTG. 6 h after removing IPTG from the medium, the growth rate slows down and cells are elongated. About 100 min after adding back 1 mM IPTG into the medium, the elongated cells divide and resume normal growth. The growth rates in the plot are the (weighted) mean of the growth rates of 100 individual cells. The error bars correspond to $±$ one standard deviation. The results of the experiment show that the growth rate of a bacterial can be switched off in a reversible manner by an external inducer, based on the reengineering of the natural control of the expression of RNA polymerase.