The Biophysics of Mesoscale, Reversible, Biomolecular Assemblies

Understanding how cells in biology really work can help us to find out what happens when cells go wrong, for example in diseases, and what we can then do to minimise or even prevent these problems from occurring, such as developing new drugs. To do this requires a high level of new insight at the level of the biomolecules involved in such structures, enabled through advanced experimental technologies developed from the physical sciences to probe these structures in cells, as well as complex theoretical methods to really understand how these structures form through interacting with other biomolecules and the environment inside the cell. In this fellowship, I aim to investigate fascinating and remarkable liquid droplets in bacteria called aggresomes that, from our early promising research, we now know form in response to a range of stress conditions imposed on cells, and help them to survive harsh conditions such as are imposed. It is only in the past decade that we have become aware of how ubiquitous and important biomolecular liquid droplets are to a wide range of cell processes. Such droplets form through a phenomenon known as phase separation, similar to the process that occurs when water vapour condenses to form water liquid, but the physical rules that govern how biomolecular liquid droplets form in cells are much more complex than non-biological processes and much is not unknown about these driving physical mechanisms. Here, I aim to develop and use new types of experimental technology and theoretical modelling to determine what the physical rules are that underpin the formation of bacterial aggresomes, and the role in this process played by the cell environment. I aim to use these physical rules to establish how to "tune" the conditions of aggresome formation to enable selective enrichment of specific biomolecules into aggresomes, since this will enable an ambitious opportunity to use aggresomes to act as purification vessels for these selected components. I will capitalise on these insights in the later stages of the project by applying selective enrichment to engineer aggresomes that contain a high content of a recombinant therapeutic biomolecule, with a view to making early progress in scaling up methods for industrial-level production to substantially improve the method of purification for such complex pharmaceutical products. Such an exciting healthcare technology development may have wide ranging impact for improving the production of a range of recombinant therapeutics used against a range of human diseases and health disorders. This fellowship will enable me to build on what I have been working towards since becoming an independent academic for two decades: changing our perception of what we can detect and quantify using advanced new home-built technologies focused around light microscopy, and opening up new inroads in improved healthcare technology. Bridging the physical and life sciences communities, as I am uniquely placed to do, I will use this fellowship to cement my position as a global leader in the physics of life, allowing me to extend my vision to the next generation of physics of life researchers, seeding a northern UK powerhouse of excellence in a key emerging area of biomolecular phase separation research that will benefit both the academic research community and the national economy, helping to create new jobs and ultimately helping to elevate the nation's problems of healthcare in an increasingly aging population through the development of better, more efficient, and ultimately cheaper drug manufacturing methods.