The single molecule biophysics of secretion in situ

Much of inter-cellular communication relies on secretion - the transport of soluble cargo (hormones, like insulin, or neurotransmitters, like serotonin) from the inside of cells to the extracellular space. For this reason, secretion is key to normal health and if the process becomes dysregulated, it invariably leads to major defects or disease.

Secretion is exquisitely regulated in time and space, mediated by the coordinated actions of a number of highly conserved molecules on the nanoscale, both temporally and spatially. Over the last several years we have worked up a variety of photonic and spectroscopic techniques that allow the study of these and other biological processes where and when they happen - i.e. inside living cells, and at the level of very large cohorts of single molecules. In this talk I will explain how we can dissect the pathways of fundamental processes on these scales by combining data describing the positions, movements, interactions and dynamics of single molecules with mathematical modelling to integrate diverse data streams. Such models can in turn predict the effects of biological perturbations like mutations or deletions, allowing for an experimental approach iterating real biological data with in silico forecasts. We used these multi-disciplinary approaches to determine why vesicles - the ~400 nm-diameter cargo-carrying structures inside cells - move like they do, presenting a fundamental hypothesis that helps unify many apparently conflicting reports over several years. I hope this story and these techniques will be of broad interest.