BBSRC-NSF/BIO Deciphering the Rules of Nucleus Architecture with Synthetic Cells and Organelles

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A near-universal aspect of cellular life is the non-uniform spatial distribution of molecules that make up cells, which most often takes the form of sub-cellular organelles. Organelles within eukaryotic cells are well defined spatial structures within cells that are specialized to perform defined biochemical tasks. Technological limitations have meant that the fundamental understanding of the underpinning principles that govern compartmentalization in cells is lacking. In this project, the investigators will address this oversight using a synthetic cell approach where new biological systems are constructed from molecular building blocks. Their hypothesis is that synthetic cells can become a unique and invaluable tool to study the fundamentals of organelles and cellular architectures. Working with Imperial College London, the investigators are developing a series of technologies and modeling tools that unlock the manufacture of synthetic organelles. Specifically, they are building and using synthetic systems to mimic the dominant feature of eukaryotes: the segregation of transcription and translation by the nucleus. The ability to assemble programmable membrane architectures, as well as integrating mathematical models, will allow the investigators to use the synthetic cells as a testbed to investigate outstanding fundamental questions relating to cell and nucleus biology. Included in this collaborative project are two community objectives that leverage the rapidly emerging interest in synthetic cells, their creation, study and applications in both the UK and the USA: (1) Build an international bridge for the Build-A-Cell (USA) and fabriCELL (UK) consortia. This collaboration will serve as a focal point to shape the respective communities and ensure the cross-fertilisation of ideas, expertise, and personnel that is needed to achieve the grand challenge of building a synthetic cell from scratch. (2) Actively engage with beneficiaries in the life sciences, biotechnology, and microfluidics sectors. This will be achieved through a series of impact activities, including organising an industry/academic horizon scanning workshop, attending conferences and symposia, and participating in a host of outreach activities. The collaborative work between expert UK and US teams is designed to achieve five scientific objectives and two community objectives. The scientific objectives will directly build from existing pilot work in their research groups: (1) develop microfluidic and membrane engineering tools to build synthetic organelles and nuclei; (2) develop modeling platforms for the design and analysis of compartmentalized synthetic cells; (3) examine the effects of compartmentalization on coupled biochemical processes; (4) investigate how transcription dynamics are affected by compartmentalization in a nucleus; (5) explore rules governing the nucleus: cytoplasm volume ratio. The first two objectives involve platform development for constructing and modelling synthetic organelles. The final three objectives involve using our platforms in fundamental studies relating to the role of cellular compartmentalisation and the central importance of the cell’s nucleus.This collaborative US/UK project is supported by the US National Science Foundation (NSF) and the UK Biotechnology and Biological Sciences Research Council (BBSRC), where NSF funds the US investigator and BBSRC funds the partners in the UK.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.