Modelling concerted microbial metabolic activities to mimic multicellular behaviour and its applications in biotechnology and biomanufacturing

Bacteria benefit from multicellular cooperation through cellular division of labour, accessing resources that cannot effectively be utilized by single cells, collectively defending against antagonists, and optimizing population survival by differentiating into distinct cell types. These cooperative structures can comprise of communities of different species, or of single-species assemblies. The division of roles within the structure can assist efficient utilisation of the environment and assist achieving competitive advantage, which could potentially be useful for biotechnological applications and in biomanufacturing. This project will focus on two commonly encountered bacterial population structures that demonstrate multicellular organism-like behaviour; biofilms and microbiomes and explore how this notion can effectively be exploited in biomanufacturing and biodegradation through a model-based analysis.

(i) Research on the biological degradation of plastics by microbial systems has recently gained momentum in response to the rapidly escalating severity of the environmental challenge associated with plastic waste accumulation. Several bacterial enzymatic routes have been identified for plastics utilisation, but the rates of degradation vary and are typically low. Recent research has demonstrated that the coordinated action of multiple bacterial species in a microbiome environment can be an effective solution to address the challenge of plastics degradation. This part of the project will investigate how the community structure assists efficacy of the degradation process through metabolic modelling. The principal species contributing to the microbiome of the mealworm gut will be investigated in silico, and the role of individual species in contributing to the community will be identified through the distribution of the metabolic fluxes within and across different bacteria.

(ii) Biofilms are surface-associated structures comprising populations of microorganisms surrounded by a self-produced matrix that allows their attachment to inert or organic surfaces. Microorganisms adopt a multicellular behaviour in a biofilm, which facilitates and/or prolongs survival in diverse environmental niches. As a survival strategy, the planktonic state allows for bacterial dispersion and the colonization of new environments, whereas in biofilms cells follow a coordinated, permanent lifestyle that favours their proliferation. The alternating cycle between planktonic and sessile states is a highly coordinated action, which requires a substantial rewiring of the metabolism. Biofilms are of biotechnological interest rendering a rational design of bi-modal growth necessary for understanding such applications. This section of the proposed work aims to explore the impact of this in the domain of enzyme biomanufacturing by Halomonas sp. The genome-scale metabolic network model of the species expressing recombinant enzymes will be reconstructed. This model will then be incorporated with the spatial model of sessile growth to identify the metabolic drive leading to the sessile lifestyle and back to planktonic state. The minimal metabolic networks will then be utilised to identify the tuneable parameters than enable the switch between two states.

In this project, the student will be trained in a range of tools and approaches in bioinformatics and metabolic modelling as the project requires the re-construction of coarse metabolic network models, fine tuning these models with the assistance of bioinformatics tools (e.g. BLAST), analysing them through linear/non-linear programming and systematically interpreting the results using statistical tools.
The project falls specifically within the Biological Informatics, Mathematical Biology, and Process systems: components and integration Research Areas within the EPSRC remit.

The CDT has a proven track record of delivering impact from its research and training activities and this will continue in the new Centre. The main types of impact relate to: (i) provision of highly skilled EngD and sPhD graduates; (ii) generation of intellectual property (IP) in support of collaborating companies or for spin-out company creation; (iii) knowledge exchange to the wider bioprocess-using industries; (iv) benefits to patients in terms of new and more cost effective medicines, and (v) benefits to the wider society via involvement in public engagement activities and impacts on policy.

With regard to training, provision of future bioindustry leaders is the primary output of the CDT and some 96% of previous EngD graduates have progressed to relevant bioindustry careers. These highly skilled individuals help catalyse private sector innovation and biomanufacturing activity. This is of enormous importance to capitalise on emerging markets, such as Advanced Therapy Medicinal Products (ATMPs), and to create new jobs and a skilled labour force to underpin economic growth. The CDT will deliver new, flexible on-line training modules on complex biological products manufacture that will be made available to the wider bioprocessing community. It will also provide researchers with opportunities for international company placements and cross-cohort training between UCL and SSPC via a new annual Summer School and Conference.

In terms of IP generation, each industry-collaborative EngD project will have direct impact on the industry sponsor in terms of new technology generation and improvements to existing processes or procedures. Where substantial IP is generated in EngD or sPhD programmes, this has the potential to lead to spin-out company creation and job creation with wider economic benefit. CDT research has already led to creation of a number of successful spin-out companies and licensing agreements. Once arising IP is protected the existing UCL and NIBRT post-experience training programmes provide opportunities for wider industrial dissemination and impact of CDT research and training materials.

CDT projects will address production of new ATMPs or improvements to the manufacture of the next generation of complex biological products that will directly benefit healthcare providers and patients. Examples arising from previous EngD projects have included engineered enzymes for greener pharmaceutical synthesis, novel bioprocess operations to reduce biopharmaceutical manufacturing costs and the translation of early stem cell therapies into clinical trials. In each case the individual researchers have been important champions of knowledge exchange to their collaborating companies.

Finally, in terms of wider public engagement and society, the CDT has achieved substantial impact via involvement of staff and researchers in activities with schools (e.g. STEMnet), presentations at science fairs (Big Bang, Cheltenham), delivery of high profile public lectures (Wellcome Trust, Royal Institution) as well as TV and radio presentations. The next generation of CDT researchers will receive new training on the principles of Responsible Innovation (RI) that will be embedded in their research and help inform their public engagement activities and impact on policy.