Abstract: The theoretical study of multicellular feedback control is a challenging emerging field with the potential for developing and modifying new avenues in control theory. In a multicellular coordination problem, control action takes place on 2 levels: 1) individual cells can activate or repress relevant genes 2) cells can access the ensemble state of the entire population as obtained through diffusible signaling molecules. From a control theoretic perspective, a large population of agents (cells) are interconnected through (cell-cell) communication, and each agent contributes to the collective behavior of the population.

There are many synthetic biology applications for cooperative feedback control systems that can maintain the density of a cell population at a desired level.  Furthermore, research surrounding synthetic population control circuits could lead to treatment of disease by moving beyond traditional approaches and allowing the development of smart therapies, where the therapeutic agent can make decisions based on intercommunication between adjacent cells and the environment. One key issue in the development of the previously developed synthetic population circuits is their sensitivity to sensing mutations which can cause overgrowth of the cell population.

These concerns can be addressed using a paradoxical signaling-based population control mechanism. Paradoxical signaling occurs when the same quorum sensing molecule can affect antagonistic cell behaviors. For example, in natural systems, T-Cells secret cytokine IL-2 which promotes T-Cell proliferation and also affects cell death. It has been shown that cells with this signaling capability have bi-stable population dynamics and can achieve identical levels of population homeostasis independent of the intracellular paradoxical components and to develop accurate models to provide insight into optimal design characteristics.

Presented is a study on internal mechanisms necessary for paradoxical signaling in T-Cells. Through analysis of intracellular mechanisms, we draw general design principles that can give insight into the optimal design of engineering cells with paradoxical components. Using these principles, we further model the population dynamic, internal-cell, and cell-cell biochemical signaling of a synthetic population and robustness properties of the synthetic circuit. Future research includes experimental implementation of theoretical results to further validate robustness, stability and performance of these systems in-vitro.

Biosketch: Dr. Michaëlle N. Mayalu is currently a Postdoctoral Scholar in the Computing and Mathematical Science Department at the California Institute of Technology, Pasadena, CA. Her Postdoctoral mentor is Richard Murray. Her research focuses on mathematical modeling and control theory of synthetic biological systems. She received her B.S., M.S., and Ph.D. degrees in Mechanical Engineering in 2010, 2012, and 2017 from Massachusetts Institute of Technology. Her thesis supervisor was Professor H. Harry Asada in the Department of Mechanical Engineering at MIT.