Synthetic mammalian signaling circuits for robust cell population control

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Synthetic signaling circuits could allow engineered cells to sense and control their own population density. The ideal circuit would operate independently of endogenous pathways and be robust to selection pressure for mutations that allow cells to evade population size limits. Here, we show that the plant hormone auxin can be repurposed as an orthogonal communication channel and linked to pathways that control cell survival and death to create synthetic mammalian population control circuits. We identified enzymes, transporters, and other components that allow sending and receiving of two auxin variants. Using these components, we constructed a synthetic quorum sensing system and coupled it to regulation of antibiotic resistance to limit cell population size. Because this population control circuit was susceptible to mutations in signal sensing, we then designed a paradoxical population control circuit, in which auxin both stimulates and inhibits net cell growth at different concentrations. This design provides evolutionarily robust control in a 43 day continuous culture experiment. These results demonstrate robust synthetic population control in mammalian cells and establish a foundation for future cell therapies that can respond to and control their own population sizes within multicellular organisms.

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