Biological information is exploding, thanks to increasingly sophisticated experimental tools and approaches. Dr. Liu’s laboratory uses the tools of statistical physics to cohere this expanding data set into quantitative models that capture fundamental insights and make concrete predictions about multiple cellular processes, including membrane trafficking, cell motility, and cell division.
Cells ingest materials from outside their membrane boundaries through a highly regulated process of endocytosis, this is one aspect of membrane trafficking. A number of well-studied proteins are dynamically integrated into the steps of membrane invagination and pinching off to form intracellular vesicles. The process itself has been observed in a variety of cells through time-lapse microscopy. In a 2009 PLoS Biology paper, Dr. Liu brought together the known functional properties of membrane proteins in yeast into a mechanochemical model of endocytosis. From the central principle that membrane curvature is bi-directionally coupled to accompanying biochemical reactions, the model was able to recapitulate experimental observations as well as provide a unifying functional account of debated molecular differences between yeast and mammalian cell types. In particular, the model provided a more refined and testable view of BAR domain protein (BDP) function and that of lipid remodeling enzymes in membrane pinching.
How does a cell generate the force required to move, and how does this force feedback into intracellular and biochemical pathways? Components of the actin cytoskeleton have been studied extensively in vitro to reveal that even outside cells, actin networks can exhibit a highly adaptive response to force. Using agent-based stochastic simulation, Dr. Liu has established a mechanism for this adaptive response in which the branched actin network remodels due to branching and capping events produced in response to mechanical resistance. The remodeling accounts for both adaptive and non-adaptive mechanical responses of the network.
Cells adhere to the extracellular matrix, where they form focal adhesions that anchor the cell. For the cell to move, it needs to spatially and temporally coordinate the formation and dissolution of focal adhesions according to the direction of motion. The distribution of proteins as well as the traction force is not uniform within focal adhesions, but the reasons for these asymmetries are not understood. Dr. Liu is involved in collaborations to create a model of focal adhesion formation to capture its entire life cycle. The goal is then to combine multiple focal adhesions and study their regulation by the extracellular matrix—“durotaxis”.
When mitotic cells divide, a furrow is created where the two daughter cells will split apart. The furrow is triggered by an actomyosin contractile ring. Others have observed that the furrow does not contract symmetrically; one part of the furrow will stand still in space while the other is driven towards it. Dr. Liu has developed a mechanical model based on the impact of local membrane curvature on cytoskeletal organization that not only quantitatively recapitulates observations from time-lapse imaging, but also makes predictions for the adaptors that mediate filament attachment to the membrane.
Dr. Liu takes a distinct approach to theoretical biology, treating cellular systems as discrete functional modules comprising a set of critical players. This allows both simplification and retention of essential biological features. The larger goal of this modular approach is to allow for processes to be combined at a theoretical level to reveal the interplay among them in the cell as a whole.