Session X55: Principles of Cell to Cell Communication

Optimal census by quorum sensing

Bacteria regulate their gene expression in response to changes in local cell density in a process called quorum sensing. To synchronize their gene-expression programs, these bacteria need to glean as much information as possible about local density. Our study is the first to physically model the flow of information in a quorum-sensing microbial community, wherein the internal regulator of the individual’s response tracks the external cell density via an endogenously generated shared signal. Combining information theory and Lagrangian optimization, we find that quorum-sensing systems can improve their information capabilities by tuning circuit feedbacks. At the population level, external feedback adjusts the dynamic range of the shared input to individuals’ detection channels. At the individual level, internal feedback adjusts the regulator’s response time to dynamically balance output noise reduction and signal tracking ability. Our analysis suggests that achieving information benefit via feedback requires dedicated systems to control gene expression noise, such as sRNA-based regulation.   

Using memory to enforce stereotyped behavior in a bacterial community

Bacteria communicate with each other by the exchange of chemical cues. I will describe a simple system in which bacteria form a one-dimensional community in which behavior in the community is enforced by trans-generational memory inherited from a founder cell rather than by intercellular signaling. The bacterium B. subtlis held under constant conditions of exponential phase growth switches between a unicellular, motile state and a sessile state in which individual cells are held together in a chain. I will show that cells enter the chaining state spontaneously by a stochastic competition mechanism involving tight binding between two proteins and remain in that state for a stereotyped number of generations due to the action of a third protein that is responsible for memory. The motile state, in contrast, is memoryless. Reconstruction of the principal features of the two states in an unrelated bacterium, E. coli, provides evidence that the three proteins are necessary and sufficient to account for the alternative behaviors. Thus, B. subtilis is capable of cell-cell communication by an epigenetic information is transmitted to progeny cells for a characteristic number of cell divisions.   

Design principles of paradoxical signaling in the immune system

A widespread feature of cell-cell signaling systems is paradoxical pleiotropy: the same secreted signaling molecule can induce opposite effects in the responding cells. For example, the cytokine IL-2 can promote proliferation and death of T-cells. The role of such paradoxical signaling remains unclear. We suggest that this mechanism provides homeostatic concentration of cells, independent of initial conditions. The crux of the paradoxical mechanism is the combination of a positive and a negative feedback loops creating two stable states - an OFF state and an ON state. Experimentally, we found that CD4$+$ cells grown in culture with a 30-fold difference in initial concentrations reached a homeostatic concentration nearly independent of initial cell levels (ON-state). Below an initial threshold, cell density decayed to extinction (OFF-state). Mathematical modeling explained the observed cell and cytokine dynamics and predicted conditions that shifted cell fate from homeostasis to the OFF-state. We suggest that paradoxical signaling provides cell circuits with specific dynamical features that are robust to environmental perturbations.   

The BMP Pathway is a Programmable Multi-Ligand Signal Processing System

The BMP signaling pathway comprises multiple ligands and receptors that interact promiscuously and appear in combinations. This feature is often understood in the context of redundancy and tissue specificity, but it has remained unclear whether it enables specific signal processing capabilities. Here, we show that the BMP pathway performs a specific set of computations, including sums, ratios, and balance and imbalance detection, across the multi-dimensional space of ligand concentrations. These computations can arise directly from receptor-ligand interactions without requiring transcriptional regulation. Furthermore, cells can re-program the type of computation performed on specific ligands through changes in receptor expression, allowing different cell types to perceive distinct signals in the same ligand environment. Together, these results may help explain the prevalence of promiscuous ligand-receptor architectures across pathways and enable predictive understanding and control of BMP signaling.   

A positional code and anisotropic forces control tissue remodeling in Drosophila

A major challenge in developmental biology is to understand how tissue-scale changes in organism structure arise from events that occur on a cellular and molecular level. We are using cell biological, biophysical, and quantitative live-embryo imaging approaches to understand how genes encode the forces that shape tissues, and to identify the mechanisms that modulate cell behavior in response to local forces. In many animals, the elongated head-to-tail body axis is achieved by rapid and coordinated movements of hundreds of cells. We found that in the fruit fly, these cell movements are regulated by subcellular asymmetries in the localization of proteins that generate contractile and adhesive forces between cells. Asymmetries in the force-generating machinery are in turn controlled by a positional code of spatial information provided by an ancient family of Toll-related receptors that are widely used for pathogen recognition by the innate immune system. I will describe how this spatial system systematically orients local cell movements and collective rosette-like clusters in the Drosophila embryo. Rosettes have now also been shown to shape the body axis in chicks, frogs, and mice, demonstrating that rosette behaviors are a general mechanism linking cellular asymmetry to tissue reorganization.