Cells and their lineages are the critical interpreter that transform the genetic information into living organisms. Cell fate decisions lie in the heart of the developmental processes that build the organisms, and the homeostatic processes that facilitate their adaptation to changing environments. We seek to understand how these decisions are regulated in the temporal and spatial domain. To do so, we leverage high-throughput live-cell microscopy and genetic lineage tracing to track cells and their state transitions, combining with temporally controlled perturbations to probe the causal organization, and modelling to understand non-intuitive principles of the underlying systems.
Our research efforts fall into two broad categories:
Cell fate decision regulated by dynamical environmental signals and internal cell states
Cells live in ever-changing environments – waves of chemical messengers, fluctuations of temperature, push and pull from neighbours, and up and down of food levels. The inside of cells is even more of a crowded mess – constant fission and fusion of organelles, breakdown and synthesis of large molecules, growing and shrinking of cytoskeleton, and transport of cargos – and all these, happens in a Brownian blizzard. How do all these contribute to the decisions a cell make as a basic unit of life? Decades of work in genetics and biochemical has provide us a list of critical molecular elements influencing each major cell decision. To understand how they work in time and space, we are building live-cell tools to watch and to quantify these decision-making processes under the microscope. We are leveraging this dynamical information to build quantitative models to help us understand how cells work.
Using live-cell image, we found that, in contrast to textbook models that cells sense growth signal only in G1 phase, cells in fact continuously sense and integrate signals throughout the entire cell cycle. See Min et al., Science, 2020.
Cell plasticity under stress
A fundamental question in biology is how novelty arises. The evolution theory provides a plausible answer – via variation, selection, and heredity. The discovery of DNA as the molecular nature of heredity leads to the assumption that the evolutionary-meaningful variation occurs in DNA. However, while DNA mutations are rare, random and often deleterious, new traits can be generated rapidly and adaptively, particularly in suboptimal (stressful) environments. It has been proposed that the remarkable evolvability of biological systems can be attributed to physiological plasticity that not only promotes survival in stressful conditions, but also generates phenotypic variations as raw material for selection, and may accelerate more heritable adaptation. How stress conditions unleash the phenotypic plasticity – flipping cells into fundamentally different operational states without genetic changes, and how the physiological adaptation is relayed from short to longer time-scales, are still missing jigsaws in the picture.
Traditional evolution experiments focus on sequence-based end-point readouts. Whilst the stable mutants are examined, the trajectories of which these mutants evolve under selection pressure cannot be interrogated. We monitor the dynamical cellular response to stress using live-cell imaging and sequence-base lineage tracing to span the timescale from minutes to months. These lines of research will enable approaches to the outstanding evolution question on how physiological plasticity promotes evolution, and to shed light on the emergence of resistance to cancer therapy and antibiotic treatment. For example: what kind of dynamical features in stress response promotes survival in stressful conditions in short timescales? Do cells reinforce the short-term adaptation to longer-term molecular memories? Are these physiological processes stochastic, as shown for genetic variation? Or the molecular landscape underlying adaptation is deterministic?