Establishing a synthetic biology toolbox for biosensor development in important probiotic host organisms.

The fundamental impact of microbiome-based bacteria upon human health is increasingly understood. Dysbiosis is an imbalance of microbiome bacterial constituents that is strongly linked to the pathology of a wide range of conditions. This project will develop new approaches to rebalance the microbiome to treat and prevent such diseases. This project will engineer probiotic organisms to detect metabolic changes that are characteristic of pathologic states and trigger the deployment of appropriate treatments at the site of interest. This will require the development of engineering tools for probiotic lactic acid bacteria, as well as bioinformatics approaches to identify new sensing components required to create the required biosensors.

We currently lack the tools necessary to detect and selectively remove bacterial constituents of the microbiome that cause dysbiosis. This limits therapeutic intervention. Novel, next-generation therapeutic bacteria (NTB) capable of sensing and precisely resolving dysbiosis represent a new frontier in the treatment of microbiome related disorders. This project will develop key dysbiosis-sensing components to create new bacterial therapies, by creating a biosensing toolbox enabling genetic engineering of lactic acid bacteria that can sense and react to metabolic changes characteristic of microbiome dysbiosis. Ultimately, these bacterial biosensors will control the deployment of specific bactericidal payloads into the microbiome by NTB.

A bioinformatics approach will be taken to identify new sensing components that govern transcriptional regulation in response to external signals. These will then be repurposed as biosensors for the detection of the state of the microbiome. To better be able to engineer probiotic bacteria, a synthetic biology toolbox will be created for suitable hosts. For therapeutic use in the human microbiome, lactic acid bacteria such as Lactobacillus spp. are an ideal choice given their Generally Regarded As Safe (GRAS) status. However, few characterised promoters, ribosome binding sites, terminators and vectors are described for Lactobacillus spp., addressing this need will therefore transform our ability to reliably engineer these types of organism.

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.