Autologous chemotaxis at high cell density.

Autologous chemotaxis, in which cells secrete and detect molecules to determine the direction of fluid flow, is thwarted at high cell density because molecules from other cells interfere with a given cell's signal. Using a minimal model of autologous chemotaxis, we determine the cell density at which sensing fails, and we find that it agrees with experimental observations of metastatic cancer cells. To understand this agreement, we derive a physical limit to autologous chemotaxis in terms of the cell density, the Péclet number, and the lengthscales of the cell and its environment. Surprisingly, in an environment that is uniformly oversaturated in the signaling molecule, we find that not only can sensing fail, but it can be reversed, causing backwards cell motion. Our results get to the heart of the competition between chemical and mechanical cellular sensing, and they shed light on a sensory strategy employed by cancer cells in dense tumor environments.

Precision of Protein Thermometry.

Temperature sensing is a ubiquitous cell behavior, but the fundamental limits to the precision of temperature sensing are poorly understood. Unlike in chemical concentration sensing, the precision of temperature sensing is not limited by extrinsic fluctuations in the temperature field itself. Instead, we find that precision is limited by the intrinsic copy number, turnover, and binding kinetics of temperature-sensitive proteins. Developing a model based on the canonical TlpA protein, we find that a cell can estimate temperature to within 2%. We compare this prediction with in vivo data on temperature sensing in bacteria.

Multicellular sensing at a feedback-induced critical point.

Feedback in sensory biochemical networks can give rise to bifurcations in cells' behavioral response. These bifurcations share many properties with thermodynamic critical points. Evidence suggests that biological systems may operate near these critical points, but the functional benefit of doing so remains poorly understood. Here we investigate a simple biochemical model with nonlinear feedback and multicellular communication to determine if criticality provides a functional benefit in terms of the ability to gain information about a stochastic chemical signal. We find that when signal fluctuations are slow, the mutual information between the signal and the intracellular readout is maximized at criticality, because the benefit of high signal susceptibility outweighs the detriment of high readout noise. When cells communicate, criticality gives rise to long-range correlations in readout molecule number among cells. Consequently, we find that communication increases the mutual information between a given cell's readout and the spatial average of the signal across the population. Finally, we find that both with and without communication, the sensory benefits of criticality compete with critical slowing down, such that the information rate, as opposed to the information itself, is minimized at the critical point. Our results reveal the costs and benefits of feedback-induced criticality for multicellular sensing.

Cell-to-Cell Information at a Feedback-Induced Bifurcation Point.

A ubiquitous way that cells share information is by exchanging molecules. Yet, the fundamental ways that this information exchange is influenced by intracellular dynamics remain unclear. Here we use information theory to investigate a simple model of two interacting cells with internal feedback. We show that cell-to-cell molecule exchange induces a collective two-cell critical point and that the mutual information between the cells peaks at this critical point. Information can remain large far from the critical point on a manifold of cellular states but scales logarithmically with the correlation time of the system, resulting in an information-correlation time trade-off. This trade-off is strictly imposed, suggesting the correlation time as a proxy for the mutual information.

Precision of Flow Sensing by Self-Communicating Cells.

Metastatic cancer cells detect the direction of lymphatic flow by self-communication: they secrete and detect a chemical which, due to the flow, returns to the cell surface anisotropically. The secretion rate is low, meaning detection noise may play an important role, but the sensory precision of this mechanism has not been explored. Here we derive the precision of flow sensing for two ubiquitous detection methods: absorption vs reversible binding to surface receptors. We find that binding is more precise due to the fact that absorption distorts the signal that the cell aims to detect. Comparing to experiments, our results suggest that the cancer cells operate remarkably close to the physical detection limit. Our prediction that cells should bind the chemical reversibly, not absorb it, is supported by endocytosis data for this ligand-receptor pair.

Critical slowing down in biochemical networks with feedback.

Near a bifurcation point, the response time of a system is expected to diverge due to the phenomenon of critical slowing down. We investigate critical slowing down in well-mixed stochastic models of biochemical feedback by exploiting a mapping to the mean-field Ising universality class. We analyze the responses to a sudden quench and to continuous driving in the model parameters. In the latter case, we demonstrate that our class of models exhibits the Kibble-Zurek collapse, which predicts the scaling of hysteresis in cellular responses to gradual perturbations. We discuss the implications of our results in terms of the tradeoff between a precise and a fast response. Finally, we use our mapping to quantify critical slowing down in T cells, where the addition of a drug is equivalent to a sudden quench in parameter space.