Engineered phage for expanded host range and increased payload capacity

The rapid rise of antimicrobial resistance has resulted in renewed interest in alternative strategies to control the spread of pathogens including multidrug resistant ones. Phage (virus that infects and kills bacteria) therapy has gathered renewed interest as a viable alternative to antibiotics but selection and production of phages for biomedical applications to prevent or treat bacterial infections in humans and animals remains a challenging task. Current solutions can involve a complex cocktail of different phages to produce efficient results. Consequently, genetic engineering approaches are now being explored to optimize phage anti-microbial activity, e.g. by use of phages as CRISPR-Cas delivery vehicles, and address problems such as the narrow host range of individual phages that limit broader use as effective therapeutic interventions.

The project aims to create novel, engineered bacteriophages that will improve or add desired traits for therapeutic use by combining computational (i.e., artificial intelligence) with molecular genetic/synthetic biology approaches. Mining large, publicly available datasets using computational/bioinformatic tools will identify phage receptor variants and phage anti-defence systems that can be screened and assessed for functionality. Individual elements displaying favourable characteristics will be used to rationally design and genetically assemble novel phages with enhanced properties such as improved host range and infectious potential. Integration of additional modules encoding genetic payloads such as CRISPR-Cas systems with the potential to further increase efficacy of the modified phages will require the construction of minimal phage genomes able to accommodate the added genetic material. The selected phage(s) will be subjected to several rounds of genome reduction to determine the minimal viable genome(s) that will be used to re-assemble modified phages integrating the payload module.

The 2016 UK Roadmap Bio-design for the Bio-economy highlighted the substantial impact that synthetic biology can bring to the UK and global economies by developing: frontier science and technology; establishing a healthy innovation pipeline; a highly skilled workforce and an environment in which innovative science and businesses can thrive. Synthetic biology promises to transform the UK Bio-economy landscape, bringing bio-sustainable and affordable manufacturing routes to all industrial sectors and will ensure society can tackle many contemporary global Grand Challenges including: Sustainable Manufacturing, Environmental Sustainability Energy, Global Healthcare, and Urban Development. Whilst synthetic biology is burgeoning in the UK, we now need to build on the investments made and take a further lead in training next generation scientists to ensure sustained growth of a capable workforce to underpin the science base development and growth in an advanced UK bio-economy.
This training provided by this CDT will give students from diverse backgrounds a unique synthesis of computational, biomolecular and cellular engineering skills, a peer-to-peer and industrial network, and unique entrepreneurial insight. In so doing, it will address key EPSRC priority areas and Bioeconomy strategic priorities including: Next-generation therapeutics; Engineered biomaterials; Renewable alternatives for fuels, chemicals and other small molecules; Reliable, predictable, and scalable bioprocesses; Sustainable future; Lifelong health & wellbeing.
Advances created by our BioDesign Engineering approach will address major societal challenges by delivering new routes for chemical/pharma/materials manufacture through to sustainable energy, whilst providing clean growth and reductions in energy use, greenhouse gas emissions and carbon footprints. Increased industry awareness of bio-options with better civic understanding will drive end-user demand to create market pull for products. The CDT benefits from unrivalled existing academic-industry frameworks at the host institutions, which will provide direct links to industrial partners and a direct pathway to early economic and industrial impact.

This CDT will develop 80-100 next-generation scientists and technologists (via the funded cohort and wider integration of aligned students at the three institutions) as adept scientists and engineers, instilled with technical leadership, who as broadly trained individuals will fill key skills gaps and could be expected to impact internationally through leadership roles in the medium term. Importantly the CDT addresses key skill-gaps identified with industry, which are urgently required to create and support high value jobs that will enable the UK to compete in global markets. Commercialisation and entrepreneurship training will equip the next generation of visionaries and leaders needed to accelerate and support the creation of new innovative companies to exploit these new technologies and opportunities.

The UK government identified Synthetic Biology as one of the "Eight Great Technologies" that could be a key enabler to economic and societal development. This CDT will be at the forefront of research that will accelerate the clean growth agenda and the development of a resilient circular bioeconomy, and will align with key EPSRC prosperity outcomes including a productive, healthy and resilient nation. To foster wider societal impact, the CDT will expect all students to contribute to public outreach and engagement activities including: open days, schools visits, and science festival events: students will participate in an outreach programme, with special focus on widening participation.

This CDT will contribute to the development of industrial strategy through the Synthetic Biology Leadership Council (SBLC), Industrial Biotechnology Leadership Forum (IBLF), and wider Networks in Industrial Biotechnology and Bioenergy and Professional Institutes.