About the Project
This project addresses the important problem of heterogeneity in yeast cell populations, specifically as it concerns the use of yeast for the production of high-value proteins (e.g. vaccines and therapeutics). The global market for these yeast-derived products is over $40Bn per annum. This project will investigate a key biological problem that impacts this sector. Cell populations become heterogeneous over time, developing mixed phenotypes that vary between cells. This can lower production yields over time with the emergence of cell subpopulations that perform sub-optimally. However, this significant problem has not yet been addressed. Therefore, this interdisciplinary project is exceptionally timely. Yeast diversity in this context also presents intriguing academic questions. The project will test the key hypotheses that; (i) high-yield production drives diversification and selection in yeast cultures, and (ii) natural yeast diversity could be exploitable to address this problem. The project focuses on the yeast Saccharomyces cerevisiae, with which the supervisory team have extensive experience and resources.
The student will study key yeast products of interest (e.g. VLP vaccines, albumin and enzymes), corroborating key findings with other recombinant products. Production by individual cells within populations will be compared by analysis of fluoro-tagged product with time-lapse microscopy and image-streaming flow cytometry. The student will benefit from our microfluidics capability (CellASIC) for single-cell studies, with options also for fermentation scale-up. Individual cells showing low or high production will be FACS-sorted for further characterisation to indicate genotypic or non-genotypic bases for the heterogeneity, including through whole-genome resequencing. Using reagents available in our laboratories, the student will then select or refine strain backgrounds to develop novel strains with decreased heterogeneity. These will be profiled for their production characteristics, hence the potential for improved manufacturing. Therefore, the project will deliver a high-quality research experience aligned with the potential to improve industrial practice.
The student will be based in the University's fungal biology grouping, a vibrant environment attracting significant research investment. The project offers outstanding training in state-of-the-art technologies in industry-relevant research as well as wider transferable skills, opening different career-path possibilities. A three-month placement with the industry partner, Phenotypeca Ltd, will include training in broader aspects of commercial R&D. The academic School hosts relevant platform technologies for Imaging, FACS/flow cytometry and Deep Seq for next-generation sequencing, including single-cell sequencing. The cross-sector supervisory team combines extensive inter-disciplinary expertise in yeast biology, bioinformatics, microbial fermentation and production. The cross-sector balance means that the student will benefit from an integrated public and private sector training in one project, ensuring a high quality research experience.
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