Developing a framework for population-level cellular modelling employing agent-scale

Reliably predicting the behaviour of engineered cells remains an underexplored problem in synthetic biology and is of high importance to the biotech industry. This necessitates the construction of mathematical/computational models which are detailed enough to describe the intricacies of underlying biological systems, but simple enough to be computationally feasible and interpretable in a manner that can aid their design.

In this project, we propose the development of an agent-based population-level modelling framework, with nutrient concentrations and other environmental conditions explicitly modelled and treated as both spatial and temporal variables. The individual agents will employ principles of whole-cell modelling to couple their internal processes through shared cellular resource constraints, and allow modelling of phase transitions. Agents will be constructed from a coarse-grained perspective, and in a modular manner to allow for the iterative addition of fine-grained modules when required. Modularity and a coarse-grained approach will facilitate straightforward transition from microbial to multicellular (higher eukaryotic) systems. This modelling framework will be iteratively improved through selected experimental testing using the wet lab facilities available to the Stan and Ellis group.

The modelling framework proposed here has the potential to provide insight into the behaviour of both isogenic and non-isogenic population in a way that has previously not been possible, which would lead to an increased efficiency across the scope of the biochemical industry. Through exploring variable environmental conditions, whilst coupling cell growth to nutrient availability and the growth of other cells in the population, there is also potential to elucidate new behaviours at a cellular level that emerge as a result of their integration into the wider environment. The proposed framework lends itself towards both investigation of failure modes and mutation propagation within homogeneous populations, and dynamics and interactions in heterogeneous cultures, considering a range of competitive, communicative and symbiotic relationships. Both have significant implications for the efficiency and scope of experiments across the entire biotech industry.

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.