Cellular decision-making mediated by active sensing of the extra-cellular world

Living cells feature remarkable abilities to make fate decisions, most notably “to be or not to be”, i.e., to proliferate or undergo apoptosis (self-killing). These fate decision-making capabilities are of fundamental scientific interest as they reveal the active and purposive nature of living systems. Moreover, at the physiological level, such cellular fate decision-making has profound implications for embryonic development, aging and various diseases, and hence for clinical/biomedical applications. Currently, there is no basic understanding of how cells reach fate decisions and what the biophysical and biochemical principles that govern them are. The proposed research is based on the hypothesis that decision-making emerges from a fine interplay between the physical properties of the environment to which cells adhere and the internal state of cells, mediated by their unique active sensing capabilities. The latter refer to the ability of cells to anchor themselves to their environment, to actively apply forces to it, and by so doing to probe – `sense’ – its physical properties, e.g., mechanical rigidity and geometry. 

Developing a new paradigm for understanding cellular decision-making will allow us to address questions such as:  What are the early-time precursors, in space and time, for cellular decision-making under various external mechanical and geometrical conditions?  How does the sensing machinery affect decision-making? Can one unify cellular proliferation and death decisions within a single mechano-chemical framework? How do such decisions emerge from information integration over many sensing sites? Can one offer guidelines for fate decision reversal? How is decision-making altered in aging cells and fibrosis?

The project will involve the training of young researchers in the multi-disciplinary, emerging field of mechanobiology and the physics of living systems, focusing on cellular fate decision-making. Our science will be exposed to broader societal circles through various outreach activities. Our findings will be disseminated through presentations in leading international conferences and peer-review publications in high-profile international journals. Overall, our project is expected to transform our understanding of cellular fate decision-making, and potentially lead to various new avenues of research, both in basic science – e.g., considering other purposive behaviors such as stem cell differentiation and multicellular decision-making – and in clinical applications – e.g., related to biological aging and pulmonary fibrosis.