Cells are complex, autonomous genetic machines with rich information processing capabilities. Synthetic Biology builds on these properties to design novel, synthetic genetic programs in cells with the aim of benefiting humans in their everyday life. For example, researchers are imagining bacterial therapeutic cells that could, for example, be used to improve human health; More generally, synthetic biology and the “made by biology” approaches have the potential to radically improve everyday life. Yet, this will require the ability to safely and robustly controlling such synthetic cells. This is a tremendous challenge for synthetic biologists, as the robustness of any circuit is limited by their high dependence on the cellular host machinery and the fundamental stochastic nature of gene expression. Taking inspiration from physics and engineering we have imagined a computer-based feedback loop that can remotely, in real-time, control the state of a synthetic genetic program running in cells. In this project, we combined microfluidics, optogenetics, inference methods and control algorithms into a real time control device of gene expression for cells. We notably studied how cells can be controlled at different scales and with increasing levels of complexity from a simple circuit to a simple multicellular ecosystem. Specifically, we showed that simple protein expression can be controlled in yeast cells, (2) we demonstrated that complex circuits, such as bistable synthetic genetic circuit, can also be controlled robustly and designed novel strategies to control them. We also took control of key genes that are used by cells to perform complex adapative response, such as adaptation to osmotic stress in yeast. Finally, we explored the possibility to control multicellular assemblies through the control of its individual components. We demonstrated that optogenetics can be used to trigger the behaviour of cells at selected location and studied its impact on the overall population. Taken together, these actions established a solid scientific and technological foundations of a novel research area, called Cybergenetics, combining physics, engineering and synthetic biology to take control of living systems. More globally, we envision that this project will provide the first steps towards the design and study of hybrid bio-robotic systems in which machine and living systems feedback on each other to provide robust behaviors that could be applied to bioengineering and health technological and scientific challenges.
