Theoretical Design of Paradoxical Signaling-Based Synthetic Population Control Circuit inE. coli

Abstract

We have developed a mathematical framework to analyze the cooperative control of cell population homeostasis via paradoxical signaling in synthetic contexts. Paradoxical signaling functions 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. As a consequence, the relationship between intercellular quorum sensing signal concentration and net growth rate (cell proliferation minus death rates) can be non-monotonic. This relationship is a condition for robustness to certain cell mutational overgrowths and allows for increased stability in the presence of environmental perturbations. Here, we explore stability and robustness of a conceptualized synthetic circuit. Furthermore, we asses possible design principles that could exist among a subset of paradoxical circuit implementations. This analysis sparks the development a bio-molecular control theory to identify ideal underlying characteristics for paradoxical signaling control systems. Paradoxical Signaling | Coordinated Population Control | Homeostasis | Mathematical Modeling | Stability Analysis

Robust differentiation in a synthetic stem-cell circuit

“…1A). Biphasic control has been studied in oncogenic mutants 33 and population control circuits with no differentiation 34,35 . In the realm of stem cell differentiation, the concept of biphasic control has yet to be tested experimentally.…”