A strategy for multicellular feedback control in mammalian cells

While early synthetic biology circuits were implemented in unicellular organisms, new tools for genome editing allow their realization in multicellular systems and bottom-up reconstruction of multicellular phenomena. Still, context dependence and the general lack of robustness challenge the implementation of synthetic gene circuits in mammalian cells; such difficulties can be compensated using control strategies. Here, we propose the first in silico implementation of engineered multicellular control in mammalian cells, through a feedback loop distributed across two cell populations. Our design encompasses a negative feedback loop between the controller and target cell populations, and orthogonal communication devices; also, the controller cell population responds to an external input, considered as the control reference in the system. We adapted an existing Ordinary Differential Equation model for synthetic two-way communication to formalize our design; a computational proof-of-concept of the control strategy feasibility is provided, together with an indication of the possible biological parts to be used for the system experimental implementation. Our approach can be advantageous thanks to its modularity and reduced cell burden; two-way communication-based control could be later used for the implementation of complex multicellular systems with the desired functionality.