Engineering lactate sensing/controlling systems in mammalian cells

This project is in partnership with FUJIFILM Diosynth Biotechnologies UK (FDBK). The project aims at engineering Chinese Hamster Ovary (CHO) cells that can operate a metabolic shift from lactate production to lactate consumption, in response to lactate build-up in industrial bioreactors.

Mammalian cells are the main expression platform for production of recombinant therapeutic proteins such as recombinant monoclonal antibodies. CHO cells, the predominant industrial cell line, are cultured in fed-batch bioreactors (1), where many by-products accumulate during their growth phase: cells produce large quantities of lactate in these high-density cultures. The accumulation of this metabolic product results in a pH drop that is detrimental to protein production yield and cell viability. The aim of this project is to engineer CHO cells that can regulate the amount of lactate they produce by operating a metabolic shift towards lactate consumption, as lactate levels in the bioreactor reach a critical threshold. This metabolic shift can be engineered by modulating expression of a few key enzymes (2,3), however its timing is critical: a balance should be reached between cell growth, protein production and lactate build up. Because the optimal shift trigger time will be directly linked to lactate levels in the bioreactor, monitoring lactate build-up in real time might be key to controlling a successful metabolic shift. As a result, the project also aims at engineering CHO cells that can sense lactate build-up and respond by switching on/off expression of custom-specified genes. Combining metabolic shift and lactate-dependent trigger in CHO cells will form an autonomous lactate monitoring system that directly acts on the cell metabolism to limit lactate accumulation. Such autonomously-regulating cells could benefit the recombinant protein production industry by regulating lactate build-up in mammalian cell bioreactors, thereby increasing cell viability and protein yield.

The project will be based in the Cachat Lab at the University of Edinburgh (https://www.ed.ac.uk/profile/elise-cachat), in the School of Biological Sciences at the Institute of Quantitative Biology, Biochemistry and Biotechnology (IQB3), where the successful candidate will gain in-depth training in key experimental techniques including cell culture, cell engineering, DNA circuit design and assembly, analytical and microscopy techniques. They will also have access to world-class facilities and interdisciplinary expertise at the Centre for Synthetic and Systems Biology (https://www.ed.ac.uk/biology/synthsys).

The project is a collaboration with FUJIFILM Diosynth Biotechnologies (https://fujifilmdiosynth.com), a company providing process development and manufacturing facilities for recombinant proteins, viral vaccines and gene therapies production. The student will have regular interactions with industry research scientists (including a 3-6 months industrial placement at FDBK).

Candidates should have a strong interest in synthetic biology and biotechnology, and have prior experience in molecular cloning. All interested applicants should send a cover letter and CV to Dr Cachat as soon as possible. Supervisory team: Dr Elise Cachat (1st supervisor, https://www.ed.ac.uk/profile/elise-cachat), Prof Susan Rosser (2nd supervisor, http://rosser.bio.ed.ac.uk).

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