Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyze the ability of temporal signal modulation, that is dynamics, to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca2+), and nuclear factor kappa-B (NFκB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to non-dynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.

The pervasive view of bacteria as strictly pathogenic has given way to an appreciation of the widespread prevalence of beneficial microbes within the human body1–3. Given this milieu, it is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies4–6. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ7–10. Here, we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We use microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we track the bacterial population dynamics in ectopic syngeneic colorectal tumors in mice. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies11, we orally administer the lysis strain, alone or in combination with a clinical chemotherapeutic, to a syngeneic transplantation model of hepatic colorectal metastases. We find that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumor activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.

Biological clocks are self-sustained oscillators that adjust their phase to the daily environmental cycles in a process known as entrainment. Molecular dissection and mathematical modeling of biological oscillators have progressed quite far, but quantitative insights on the entrainment of clocks are relatively sparse. We simultaneously tracked the phases of hundreds of synthetic genetic oscillators relative to a common external stimulus to map the entrainment regions predicted by a detailed model of the clock. Synthetic oscillators were frequency-locked in wide intervals of the external period and showed higher-order resonance. Computational simulations indicated that natural oscillators may contain a positive-feedback loop to robustly adapt to environmental cycles.