Pulin Li

Question

How do genes, operating in individual cells, generate coordinated multicellular behavior?

Approach

Communication is crucial for coordinating behaviors between cells to produce tissue-level phenomena, such as forming patterns of different cell types within a tissue, maintaining physiological homeostasis across different organs, and recruiting immune cells to fight infections. In every cell, a set of genes interact with one another, creating “genetic circuits” to control when to send or terminate a signal, how far the signal travels, what information the signal carries, and how to act upon the signal. Importantly, all steps are meticulously choreographed in space and time to ensure the accuracy of the communication. The Li Lab combines approaches from synthetic biology, developmental biology, biophysics and systems biology to quantitatively understand the genetic circuits underlying cell-cell communication that creates multicellular behaviors.

Li’s postdoctoral research work focused on tissue patterning — a fascinating example of emergent behaviors in groups of cells — centering on a key developmental mechanism called morphogen gradients. Morphogens are chemicals present in developing embryos that form concentration gradients to help determine the spatial arrangements of different cell types — which groups of cells will go on to form brains, hearts, intestines, etc. Genetic circuits in morphogen-sending and receiving cells determine the gradient dynamics in time and space. Li has discovered that morphogens can form gradients in confluent layers of lab-grown cells, providing a way to model this process in a Petri dish. Using this simple system, in combination with genetic engineering, quantitative time-lapse imaging, and mathematical modeling, Li has revealed design principles of negative feedback circuits in controlling the speed and precision of gradient formation. This cell-based reconstitution for studying multicellular interactions is analogous to biochemical reconstitution in a test tube for probing molecular interactions. Such a reconstitution approach can test whether a small set of components, or a well-defined circuit, is sufficient for enabling a predicted function. It represents a new methodology for developmental biology: understanding by building from the bottom up.

At Whitehead Institute, the Li Lab continues to work on understanding and programming cell-cell communication circuits. In the past few decades, a major surprising discovery has emerged that a relatively small number of signaling pathways are responsible for the diverse cell-cell communication carried out by different cell types and across different species. How does a signaling pathway expand its encoding capability to send different information to different cells? How do cells interpret quantitative information or integrate multiple signals? How are signal-sending and receiving events choreographed in time and space to create emergent behaviors, such as patterning of tissues and temporal oscillation of hormones? How did signaling pathways emerge and change during the course of evolution to create the diversity of life? The Li lab tackles these questions in a variety of cell-cell communication systems that are amenable for synthetic circuit engineering, high-throughput screening, and time-lapse imaging at the single-cell level. They also adopt engineering techniques, such as micropatterning and microfluidics, to reconstitute cell-cell communication in a Petri dish, which provides experimentally tractable systems. In addition, computational approaches that model protein-protein interactions, genetic circuits and multicellular dynamics are being developed in the lab to provide testable hypotheses. By quantitatively analyzing and manipulating cell-cell communication, they aim to provide both fundamental insights into multicellular behaviors, as well as new methods for tissue-level engineering, such as programming stem cells to form tissues and designing prosthetic cells for regenerative medicine.

Bio

Li earned a bachelor’s degree in life sciences from Peking University and a Ph.D. in Chemical Biology at Harvard University in the lab of Leonard Zon. She became a Whitehead Institute Member and an assistant professor of biology at Massachusetts Institute of Technology in 2019, after completing a postdoctoral fellowship with Michael B. Elowitz at California Institute of Technology.