Active mechanochemical description of the cell cytoskeleton

Each cell in our bodies must generate forces, in order to perform their tasks, such as transporting proteins, dividing to produce new cells or changing shape to sculpt organs during embryo development. To do so, each cell contains molecular motors, with these motors able to convert chemical energy into physical motion. This physical motion is then transmitted within the cell by networks of filaments (the cytoskeleton), and across different cells by cell-cell adhesion molecules. However, this raises a number of outstanding theoretical questions: how do individual motors coordinate to produce coherent forces within an entire cell? How do different cells coordinate their force generation to allow for robust biological function? The tools of theoretical physics are well-suited to help answer these questions, as they offer systematic ways to describe this emergence, i.e. how large-scale patterns emerge from many interactions of molecular processes. Here, we wish in particular to understand how force generation and the mechanics of the cytoskeleton are integrated with the tight genetic and biochemical regulation that cells exert on all their components. Indeed, many existing models treat these two aspects (mechanics and biochemistry) separately, and we believe that developing integrated theoretical models of the two is likely to help us understand a number of key biological processes. Moreover, we hypothesize that mechano-chemical theories can help understand not only how cells regulate the forces that they exert, but also how they can feel and respond to forces exerted by other cells. This is essential to understand not only how molecular motors are coordinated within cells, but how, at the larger scale, individual cells coordinate to build and maintain a given organ. We will apply and verify these theories to concrete biological examples, in collaboration with developmental and cell biology laboratories. In particular, we are interested in septins, an understudied component of the cytoskeleton, which we believe plays a key role in integrating mechanical and chemical outputs within cells, and is increasingly implicated in key diseases.

Each cell in our bodies must generate forces, in order to perform their tasks, such as transporting proteins, dividing to produce new cells or changing shape to sculpt organs during embryo development. To do so, each cell contains molecular motors, with these motors able to convert chemical energy into physical motion. This physical motion is then transmitted within the cell by networks of filaments (the cytoskeleton), and across different cells by cell-cell adhesion molecules. However, this raises a number of outstanding theoretical questions: how do individual motors coordinate to produce coherent forces within an entire cell? How do different cells coordinate their force generation to allow for robust biological function (such as collective cell movements during wound healing or formation of organs during embryogenesis)? The tools of theoretical physics are well-suited to help answer these questions, as they offer systematic ways to describe this emergence, i.e. how large-scale patterns emerge from many interactions of molecular processes. During this project, we wished to understand how force generation and the mechanics of the cytoskeleton are integrated with the tight genetic and biochemical regulation that cells exert on all their components. Indeed, many existing models treat these two aspects ("mechanics" and "biochemistry") separately, and we believe that developing integrated theoretical models of the two is likely to help us understand a number of key biological processes. We thus developed mechano-chemical theories, inspired from physical principles, to understand i) how can spatio-temporal waves of signalling and mechanics are formed in cellular layers and how they can be used by cells to guide themselves towards an open space, e.g. a wound, ii) how mechanics and signalling can interplay with each other to generate self-organized patterns during embryogenesis. Although our work is theoretical, in each case, we have worked with experimental biologists to apply and verify these theories to concrete biological examples. For instance, we have investigated questions i) and ii) on in vitro monolayers of cells, as well as question ii) to understand the first stages of zebrafish embryogenesis as well as how stem cells physically shape intestinal morphology during mammalian development.