Prof. Pulin Li

Professor Li studies how circuits of interacting genes in individual cells enable multicellular functions, such as self-organizing into complex tissues. She combines approaches from synthetic biology, developmental/stem cell biology, biophysics, and bioengineering to build and quantitatively analyze these multicellular behaviors. The aim is to provide both fundamental understanding of tissue development and new ways for tissue engineering.

How genes, operating in individual cells, generate coordinated multicellular behavior is a fundamental question in biology. In every cell, a set of genes interact with one another (creating “genetic circuits”) to control specific cellular functions, such as sending and receiving signals, controlling cell division, instructing cell migration, and switching cell fates. Combinations of these functional modules at the right time and place create emergent behaviors at the population level.

Embryo development is a fascinating example of such emergent behaviors, during which complex tissue structures form from a single fertilized egg. In the past few decades, a lot has been learned about the function of individual genes in embryo development, but much less about how the circuits of these interacting genes determine key features of development, such as its speed, size, precision, and evolution. Circuit-level understanding is not only necessary for obtaining a dynamic picture of embryo development, but also essential for constructing a predictive framework to enable rationally programming tissue formation from stem cells.

Li’s postdoc work focused on a key developmental mechanism: morphogen gradients. Morphogens set up the blueprint for tissue patterning by establishing spatio-temporal gradients. Understanding how genetic circuits determine the gradients in time and space requires systematically rewiring the circuits and quantitatively analyzing the resulting gradient dynamics, which is challenging in vivo. Li has discovered that morphogens could travel in confluent layers of cultured cells and form gradients. Using this simple system, in combination with extensive genetic engineering, parameter tuning, quantitative time-lapse imaging, and mathematical modeling, Li revealed design principles of negative feedback circuits in controlling the speed and precision of gradient formation. This cell-based reconstitution in a Petri dish 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 tissue patterning. Specifically, she is interested in understanding how cells interpret quantitative signals at the single-cell level, what are the general principles for creating complex patterns by spatially and temporally combining multiple signals (as those occur in the nervous system), and how key parameters in the circuits control patterning speed, size, and evolution.

These questions will be studied in two types of experimental systems that are complementary to each other. One type is cells that inherently have self-organizing capabilities, such as cultured stem cells and developing embryos of model organisms. In these systems, natural circuits can be inferred and quantitatively analyzed using genetic and single-cell analysis tools. The other type of systems is cells without self-organizing capabilities, such as fibroblasts. By engineering synthetic circuits in these cells and reconstituting multicellular behaviors, the sufficiency and tradeoffs of different circuit designs can be systematically studied. The intersection between the two systems could yield potential applications, such as programming stem cells to form tissues and designing prosthetic cells for regenerative medicine.

In 2019, Li became a Whitehead Institute Member and an assistant professor of Biology at Massachusetts Institute of Technology, after completing a postdoctoral fellowship with Michael B. Elowitz at California Institute of Technology. She 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.