Artificial intelligence driven platform to aid experimental design of optimised plasmid DNA for in vivo expression of biologics

DNA-based in vivo expression of therapeutic molecules is an emerging platform aiming to deliver biologic compounds to the patient via administration of viral or non-viral DNA. It is now known that the presence of particular sequences (such as cruciform, hairpins, palindromes, micro-RNA targets, cryptic splice sites) within the plasmid DNA can have a strong impact on the structure of the DNA, can affect the quality of the DNA produced, and the performance of expression elements. Additionally, there is a complex relationship between the presence of particular DNA elements and downstream effects on structure, expression levels, immunostimulatory effects and plasmid production. Artificial intelligence-driven bioinformatics can aid the development of novel computation tools for the automated analysis of DNA elements and, combined with literature, used to guide the design of optimised plasmid systems. Synthetic biology can offer a route for characterisation of novel designs and their output for incorporation of structure considerations into nucleic acid-based therapeutics.

In this project we will optimise plasmid-based therapeutic design by adopting iterative experimental and computational approaches in addition to leveraging advanced machine learning algorithms. Following this systematic design approach our aim is to understand how to successfully transfer industrially-relevant therapeutic systems design within in vitro and, possibly, in vivo studies. Achieving an understanding of how to translate motif design rules into mammalian cell lines and in vivo systems will be a major achievement enabling us to revolutionise therapeutic production in the future.

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.