Michaëlle N. Mayalu
Analysis and Design of Engineered Cell Population Control Circuit via Paradoxical Feedback
Abstract: Research surrounding programmed control of cell population density could lead to treatment of disease by moving beyond traditional approaches and allowing the development of “smart” cell therapies, where engineered cells can make decisions based on intercommunication between adjacent cells and the environment. One key issue in the development of previous 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 feedback control mechanism. Population control via paradoxical signaling is executed through quorum sensing (where cells produce and release a chemical signal as a function of cell density). Precisely, the same quorum sensing signal provides both positive (proliferation) and negative (death) feedback in different signal concentration regimes. Presented is a mathematical framework for analysis and design of the biomolecular and cellular circuitry of a synthetic population control circuit that regulates cell density through a feedback mechanism based on paradoxical signaling. We use control theory to improve system performance and meet pre-specified design objectives of the synthetic circuit. Furthermore, we develop conditions for robustness to certain cell mutational overgrowths using tunable and accessible experimental parameters.
Biosketch: Dr. Michaëlle N. Mayalu is an Assistant Professor of Mechanical Engineering at Stanford University. She received her Ph.D., M.S., and B.S., degrees in Mechanical Engineering at the Massachusetts Institute of Technology. She was a postdoctoral scholar at the California Institute of Technology in the Computing and Mathematical Sciences Department. She was a 2017 California Alliance Postdoctoral Fellowship Program recipient and a 2019 Burroughs Wellcome Fund Postdoctoral Enrichment Program award recipient. She is currently a Gabilan Faculty fellow and Terman Faculty fellow.
Dr. Michaëlle N. Mayalu’s area of expertise is in mathematical modeling and control theory of synthetic biological and biomedical systems. She is interested in the development of control theoretic tools for understanding, controlling, and predicting biological function at the molecular, cellular, and organismal levels to optimize therapeutic intervention.
She is the director of the Mayalu Lab whose research objective is to investigate how to optimize biomedical therapeutic designs using theoretical and computational approaches coupled with experiments. Initial project concepts include: i) theoretical and experimental design of bacterial “microrobots” for preemptive and targeted therapeutic intervention, ii) system-level multi-scale modeling of gut associated skin disorders for virtual evaluation and optimization of therapy, iii) theoretical and experimental design of “microrobotic” swarms of engineered bacteria with sophisticated centralized and decentralized control schemes to explore possible mechanisms of pattern formation. The experimental projects in the Mayalu Lab utilize established techniques borrowed from the field of synthetic biology to develop synthetic genetic circuits in E. coli to make bacterial “microrobots”. Ultimately the Mayalu Lab aims to develop accurate and efficient modeling frameworks that incorporate computation, dynamical systems, and control theory that will become more widespread and impactful in the design of electro-mechanical and biological therapeutic machines.