The research interests of my group are the quantitative understanding of sensing and signalling in biological cells based on physical principles. While chemical sensing by cell-surface receptors and their intracellular pathways are often well characterized, it is rather unexplored what the physical limitations of sensing are and how constraints from the physical environment affect the design of sensory systems and pathways. In addition to chemicals, cells also sense mechanical stimuli, including shear from fluid flow, forces from cell-cell and cell-substrate adhesion, as well as physical properties of bulky objects. These stimuli are important for embryonic development, tissue formation and repair, and our immune response. In general, very little is known about how these types of stimuli are sensed and encoded in the biochemical signalling pathways. To conduct our research, we use computational tools from statistical physics, in combination with explicit biological data from experimental collaborators.
Chemotaxis allows bacteria to sense and swim towards nutrients and away from toxins, and is an example of how cells gain and process information. The pathway is experimentally well characterized and includes multipe types of receptors which predominantly cluster at the cell poles, and a small intracellular signalling pathway, which regulates the flagellated rotary motors. Chemotactic cells show remarkable signalling properties, including high sensitivity to small changes in ligand concentration, signal integration by multiple receptor types with different ligand specificities, and precise adaptation to persistent stimulation. These are being investigated and explained in collaboration with the experimental collaborators.
Physical limits of sensing
Many types of cells including amoeba, yeast, immune cells, and growing neural axons are able to accurately sense shallow gradients of chemicals across their diameters, allowing the cells to move toward or away from chemical sources. This chemotactic ability relies on the remarkable capacity of cells to infer gradients from small molecules randomly arriving at cell-surface receptors by diffusion. Whereas the physical limits of concentration sensing by cells have been explored, the physical limits of gradient sensing are less established.
We recently derived such a theory and calculated the accuracy of gradient sensing as set by diffusion of molecules. Since this is external noise about which cells cannot do much, the derived accuracy is the fundamental physical limit of gradient sensing. We found that the accuracy of sensing is significantly enhanced when cells prevent the molecules from unbinding the receptors, since such molecules could bind the receptors again and again. Measuring the same molecules many times does not convey any new information about the environment.There are two ways how cells could avoid such re-measurements. Cells can degrade bound molecules by enzymes on the cell surface, or internalize the receptor and its bound molecule. Both mechanisms exist in real cells but so far have not been attributed to increasing the accuracy of sensing. Research in my group extends these findings to realistic ligand-receptor binding and explicit biological examples.
Biophysical requirements of phagocytosis
Phagocytosis allows specialized cells of our immune system to bind, engulf, and destroy bacteria and inert particles. It is a spatio-temporally defined zipper-like multistep process including ligand-receptor binding, signalling to the cell's cytoskeleton for phagocytic cup formation, and membrane fusion for engulfment. A quantitative analysis is essential in order to understand better how these processes are coordinated and sensitive to the physical properties of the particle (size, shape, elasticity, ligand density).
There are a number of other research projects as well, including gene regulation and T-cell signalling.
- ERC Starting Grant
- Leverhulme Trust
- BBSRC grant BB/G000131/1 "Engineering principles of chemtaxis signalling pathways" (~340,000 GBP)
- 4-year MRes/PhD studentship from Chemical Biology Centre (~60,000 GBP)
Physics and biology of directed movement of cells and organisms, Heraeus conference, Physikzentrum Bad Honnef, Germany, 2013
Research Student Supervision
Tweedy,L, PhD student