Section: Research Program
External Control of Cell Processes
External control has been employed since many years to regulate culture growth and other physiological properties. Recently, taking inspiration from developments in synthetic biology, closed loop control has been applied to the regulation of intracellular processes. Such approaches offer unprecedented opportunities to investigate how a cell process dynamical information by maintaining it around specific operating points or driving it out of its standard operating conditions. They can also be used to complement and help the development of synthetic biology through the creation of hybrid systems resulting from the interconnection of in vivo and in silico computing devices.
In collaboration with Pascal Hersen (CNRS MSC lab), we developed a platform for gene expression control that enables to control protein concentrations in yeast cells. This platform integrates microfluidic devices enabling long-term observation and rapid change of the cells environment, microscopy for single cell measurements, and software for real-time signal quantification and model based control. We demonstrated in 2012 that this platform enables controlling the level of a fluorescent protein in cells with unprecedented accuracy and for many cell generations (Jannis Uhlendorf, Agnés Miermont, Thierry Delaveau, Gilles Charvin, François Fages, Samuel Bottani, Grégory Batt, Pascal Hersen. Long-term model predictive control of gene expression at the population and single-cell levels. Proceedings of the National Academy of Sciences USA, 109(35):14271–14276, 2012.).
More recently, motivated by an analogy with a benchmark control problem, the stabilization of an inverted pendulum, we investigated the possibility to balance a genetic toggle switch in the vicinity of its unstable equilibrium configuration. We searched for solutions to balance an individual cell and even an entire population of heterogeneous cells, each harboring a toggle switch (Jean-Baptiste Lugagne, Sebastian Sosa Carrillo and Melanie Kirch, Agnes Köhler, Gregory Batt and Pascal Hersen. Balancing a genetic toggle switch by real-time feedback control and periodic forcing. Nature Communications, 8(1):1671, 2017.).
Independently, in collaboration with colleagues from IST Austria, we investigated the problem of controlling cells, one at a time, by constructing an integrated optogenetic-enabled microscopy platform. It enables experiments that bridge individual and population behaviors. We demonstrated: (i) population structuring by independent closed-loop control of gene expression in many individual cells, (ii) cell–cell variation control during antibiotic perturbation, (iii) hybrid bio-digital circuits in single cells, and freely specifiable digital communication between individual bacteria (Remy Chait, Jakob Ruess, Tobias Bergmiller and Gavsper Tkavcik, Cvalin Guet. Shaping bacterial population behavior through computer-interfaced control of individual cells. Nature Communications, 8(1):1535, 2017.).