Principal Supervisor: Dr Alexander DarlingtonLink opens in a new window

Co-supervisor: Dependent upon the project selected (see below) - Dr Chis Corre, Dr Fabrizio Alberti, Dr Lona Alkhalaf, John McCarthy, Dr Christopher Rodrigues:

PhD project title: Synthetic/Engineering biology: Improving performance within host and biotechnological constraints

University of Registration: University of Warwick

Project outline:

Research. Synthetic biology and microbial biotechnology offer sustainable routes to the manufacturer of commodity and high value chemicals from agricultural by-products instead of petrochemical feedstocks. However, at present the engineering of these biomanufacturing strains is a time intensive and expensive process requiring multiple rounds of experimentation and redesign. A key cause of this is our difficulty in predicting the impact of the novel functions on the host’s physiology. Synthetic enzyme/protein production utilises the host gene expression machinery and drains metabolites. These interactions perturb the host’s homeostasis, resulting in changes to resource supply which do not benefit either pathway performance or host growth. In addition to these internal constraints, these microbial cell factories are subjected to industrial constraints including environmental heterogeneity, fermentation strategy, and cost.

Our group aims to tackle these roadblocks to the industrialization of synthetic biology by developing quantitative mathematical models that can inform and guide the engineering of biological systems. We are developing new frameworks of whole microbial physiology and growth, within which we embed real world industrially relevant biotech processes and use mathematical techniques to identify key bottlenecks which limit performance. Using this knowledge, we design control strategies which dynamically balance host and engineered processes to improve efficiency and performance. We are working with academic and industrial partners to extend these frameworks beyond the lab workhorse E. coli into industrially relevant strains to optimise real world bioprocesses.

Our group works closely with experimental colleagues to validate model predictions in vivo and implement the new design strategies we identify. We anticipate all students will spend significant time undertaking experimental work in a partner lab to generate data to refine their computational models and to validate the design strategies they uncovered during their research.

Specific research areas. Projects in the lab are highly flexible with aims that can be tailored to the student’s interest. We have ongoing or are developing new projects with:

• Dr Chis Corre: Controlling secondary metabolism in Streptomyces.
• Dr Fabrizio Alberti: Optimising yields from yeast and other fungi
• Dr Lona Alkhalaf: Natural product synthesis in bacteria
• John McCarthy: Engineering new genetic control systems in yeast
• Dr Christopher Rodrigues: Developing subtilis growth models

Training. Students will receive a comprehensive interdisciplinary training as needed for modern biological research including (i) mathematical modelling, (ii) programming, (iii) molecular biology and (iv) metabolic analysis. We also encourage students to take advantage of industrial links and participate in Warwick Innovations courses on university-industry partnerships.

Contact. Students should contact Dr Alexander Darlington (a.darlington.1 (at) warwick.ac.uk) as soon as possible to discuss their research interests and develop the scope of the specific project. Ideally entitle the email “MIBTP prospective student – [Your Surname]” so that it is not missed and easily tracked.

References:

Example work. Darlington, A. P. S. et al. (2018) ‘Dynamic allocation of orthogonal ribosomes facilitates uncoupling of co-expressed genes’, Nature Communications, 9, e695. doi: 10.1038/s41467-018-02898-6.

Background review on host constraints. Grunberg, T. W. and Del Vecchio, D. (2020) ‘Modular Analysis and Design of Biological Circuits’, Current Opinion in Biotechnology. 63, pp. 41–47. doi: 10.1016/j.copbio.2019.11.015.

Background review on overcoming host constraints. Boo, A., Ellis, T. and Stan, G.-B. (2019) ‘Host-Aware Synthetic Biology’, Current Opinion in Systems Biology. 14, pp. 66-73. doi: 10.1016/J.COISB.2019.03.001.

Background review on metabolic control. Hartline, C. J. et al. (2020) ‘Dynamic control in metabolic engineering: Theories, tools, and applications’, Metabolic Engineering, 63, pp. 126-140. doi: 10.1016/j.ymben.2020.08.015.

BBSRC Strategic Research Priority: Understanding the rules of life – Systems Biology, and Microbiology, and Renewable Resources and Clean Growth - Industrial Biotechnology.

 

Techniques that will be undertaken during the project:

• Mathematical skills. Dynamical modelling, flux balance analysis, optimisation, other techniques as needed from Systems and Control Engineering.
• Programming languages. Python, MATLAB (with initial and advanced training provided).
• Molecular biology techniques (including Gibson assembly).
• Enzymatic assays, High performance liquid chromatography.
• Advanced techniques (dependent upon final collaborations): Streptomyces molecular biology, Pseudomonas molecular biology, RNA-seq analysis, High throughput DNA assembly

 

Contact: Dr Alexander DarlingtonLink opens in a new window