Engineering biological complexity in yeast: synthetic pattern formation and emergence

Engineering increased biological complexity is a key goal for biodesign engineering. Theoretical studies have uncovered simple mathematical rules that generate robust heterogeneity in spatial and temporal patterns within cell populations that can be considered as 'engineering principles'. Division of labour and other forms of heterogeneity also underlie the emergent properties of a multicellular entity, often enabling higher efficiency as a whole in important functions like metabolism, transport, structural stability, and feedback control. An ambitious and timely challenge for synthetic biology is to understand how to reverse engineer and rationally design symmetry-breaking events and the emergent interactions that then follow in a community of cells.

This interdisciplinary project will develop synthetic biology tools to predictively design and instruct synthetic developmental decision-making in yeast. To control multicellular growth pattern and morphogenesis, we will use synthetic gene regulation to modulate the timing and frequency of cell division and growth, and to instruct orthogonal adhesion between sets of cells. Cells will be programmed to differentiate in response to cell-to-cell communication and to lateral activation/inhibition. In order to expand the modular DNA resources for engineering multicellular complexity, this project aims to create a novel molecular machine for a self-organising symmetry-breaking events.

To do this, we will transfer a well-characterised morphogen system from plants that provides a concentration-dependent molecular switch. In plants, accumulation of the hormone auxin coordinates differential cell fate and growth regulation. Auxin moves between cells with the aid of the efflux carrier PIN proteins, which show polar localisation within a cell. Auxin is already a well-established chemical inducer of synthetic gene regulation in the yeast. By introducing the PIN module into cells with auxin-regulated gene control, we will be able to program intercellular auxin flow and asymmetrical concentration gradient within a yeast colony. Data analysis of the images, videos, and flow cytometry data, along with Bayesian statistical methods will be used to generate parameters to populate mathematical models of the intracellular gene circuits and complementary agent-based models describing how the different cells interact, communicate and adhere.

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.