Exploiting cell individuality to improve production by yeast and other fungi
Lab rotation project description
Cell individuality describes the near-universal phenomenon whereby individuals within a population exhibit marked variation in phenotype, despite being genetically uniform. In an industrial production process using microorganisms, this means that only a portion of the population are likely to have optimal production activity and this is likely to be very wasteful. Therefore, harnessing this variation opens great opportunities for marked improvements to production processes. Yeast and filamentous fungi will be used for study here as they are highly amenable to experimental and genetic manipulation and because their activities drive billions of dollars worth of industrial biotechnology, including production of industrial enzymes, antibiotics, brewing, and biofuels. The rotation project will focus on detecting and demonstrating individuality (heterogeneity) in production of up to three key metabolites. This will involve the use fluorescent reporters, flow cytometry, microfluidics or other single cell technologies. Product(s) selected during this rotation can then provide the main focus for a PhD project. There will also be the opportunity to apply for a funded research placement with our collaborators at the University of Sao Paulo, Brazil.
LR1 and LR2
Linked PhD Project Outline
Cell individuality (phenotypic heterogeneity) describes the phenomenon whereby individuals within a cell or spore population exhibit marked variation in phenotype, despite being genetically uniform. Such heterogeneity is evident in virtually every phenotype that has been studied to date. This includes metabolic processes that are important for microbial production efficacy in industrial biotechnology. However, remarkably little is yet known about heterogeneity in a biotechnology context, despite the fact that heterogeneity is likely to have major impacts on production efficiency and revenue generation. For example, if production is largely attributable to a small subpopulation of cells with high activity, then it follows that there is great potential to improve productivity by engineering the system for optimal activity in all cells.
The project will focus on yeast and filamentous fungi as they are highly amenable to experimental and genetic manipulation and because their activities drive billions of dollars’ worth of industrial biotechnology, including production of industrial enzymes, antibiotics, brewing, and biofuels. The project will be complemented by research council and UK industry support for other Avery-lab projects focused on fungal heterogeneity. The production process(es) for further study will be selected during the rotation project. The next step will be to exploit available genetic and other tools to demonstrate the molecular mechanism that drives cell-cell variation in production. This insight will inform approaches for manipulating heterogeneity to create more uniformly high-producing cell populations. Our laboratories have excellent experience with these approaches, which the student will be trained in. If the basis for heterogeneity is complex, an alternative approach published recently in Nature Chemical Biology will involve preparation of genetic constructs which enable continual selection of the high-producing cells. Finally, improvements in production efficiency will first be measured in the laboratory, followed by optimisation then scale-up to fermenters. This project successfully integrates molecular-genetics and cellular research with industrial biotechnology, offering a diverse skills-set relevant to a career in industry or academic research. The project also offers the opportunity of a funded research placement with collaborators at the prestigious University of Sao Paulo, Brazil.