Cells communicate with each other to produce tissue-level phenomena, such as forming spatial patterns, recruiting immune cells to fight infections, and repairing damage. In every cell, a set of genes interact with one another, creating “genetic circuits” to control when to send a signal, how far the signal travels, what information the signal carries, and how to respond to a given signal or set of signals. Importantly, all steps are choreographed in space and time to ensure the accuracy of the communication. We combine approaches from synthetic biology, developmental biology, biophysics and systems biology to build and quantitatively understand the genetic circuits underlying cell-cell communication that creates tissue-level behaviors. We aim to provide both fundamental insights into tissue biology and new methods for tissue engineering.

Biophysical control of positional information

Within a tissue, a cell’s position is critically linked to its fate. How does a cell determine its position relative to other cells? In developing tissues, this problem is partly solved by a group of secreted signaling molecules called morphogens. Morphogens move through the extracellular space and establish concentration gradients, acting like a GPS system. However, the capability to provide positional information is not a unique privilege of morphogens. Cells constantly secrete a wide range of metabolites, small peptides, proteins, and vesicles into the extracellular space. Circulating drugs, antibodies and hormones also constantly enter solid tissues. Their distribution is critical for the spatial organization of cell types and states in healthy and diseased tissues, and affects the therapeutic efficacy. We previously discovered that confluently cultured fibroblast cells can communicate over long distances by establishing morphogen gradients in a petri dish (Li et al., 2018; Kim et al., 2020). Taking advantage of this observation, we are reconstituting diverse cell-cell communication systems that are amenable to high-resolution imaging and high-throughput genetic perturbation, to quantitatively understand how cells modulate and decode positional information. We are also asking how the natural diversity of extracellular environments in different organs and tumors modulates cell-cell communication.

Feedback circuits in cell communication

Productive conversation – among cells as among people – requires bi-directional communication and timely feedback. To understand the design principles of feedback circuits in tissue biology, we build communication circuits from the bottom up using synthetic biology tools. For example, we systematically rewired the feedback architecture of Sonic Hedgehog pathway in fibroblast cells, and revealed how an evolutionarily conserved feedback circuit improves the speed and precision of tissue patterning (Li et al., 2018). We are applying this framework to understand how feedback circuits control tissue patterns, in a broad sense, during development and viral infection. In addition, we are developing computational approaches that predict communication circuits in natural tissues, and platforms that model genetic circuits and multicellular dynamics to provide testable hypotheses. This bottom-up reconstitution approach provides a new methodology for revealing general design principles of communication circuits (Schlissel & Li, 2020).

Evolution of cell communication

A major surprising discovery about cell communication is that a relatively small number of signaling pathways are responsible for the diverse cell-cell communication across different species and different tissues within the same species (Li & Elowitz, 2019). Throughout evolution, components in the signaling pathways have duplicated and diverged, and the genetic circuits that enable their precise signaling have also adapted to achieve the correct spatio-temporal dynamics for each signaling context. How did signaling pathways emerge and change during the course of evolution to create the diversity of life? How do different tissues utilize the common set of signaling pathways to create variations of communication circuits?  We are currently exploring the protein sequence space to identify how changes have occurred, and using animal models to understand the functional implications of these changes, with a focus on developmental and cytokine signaling pathways. We are also developing high-throughput platforms to quantitatively map the sequence-function relationship. Both the technical platform and knowledge gained from this project will assist the design of synthetic proteins for therapeutic applications.