An engineering rulebook for interfacing living and non-living cells

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Can we reverse engineer living cells and manufacture artificial cells that resemble their biological counterparts from the bottom up? Can these artificial cells be used as micromachines that perform bespoke tasks in physiological environments and as models to gain insights into biological processes? Recent years have seen tremendous advances relating to both these questions, heralding an era of making biology by design. These advances have been made possible by borrowing precision engineering principles long associated with mechanical/electrical devices that helped shape the modern world. Artificial cells have cellular dimensions, incorporate biological machinery (DNA, proteins, lipids, metabolites), and can be designed to possess some of the fundamental features of life. A convergence of technologies has allowed them to be manufactured and manipulated with fine control of the size, morphology, content, compartmentalisation, and function. Artificial cells can now be programmed to swim up concentration gradients, manufacture proteins in response to external stimuli, replicate, and communicate with one another. These accomplishments mean that real-world application of artificial cells - as therapeutic agents, biosensors, self-healing materials, bio/enzymatic reactors - is nearing a reality. In this fellowship, the aim is to go beyond mimicking cells and start using biological cells as integral functional components in a composite system where living and synthetic matter are intermingled - in essence, to use living cells as embedded modules, directly harnessing the power and versatility of biology. Bypassing the limitations associated with making new modules from scratch, and instead hijacking cellular components that have been sculpted through evolution, will enable a step change in artificial cell sophistication and capabilities, and will open up unchartered research areas in biodesign.Over the past three years as an ESPRC Postdoctoral Fellow, I have (i) developed the physical science innovations and technological groundwork that will underpin this endeavour through pioneering advances in microfluidics, optical trapping, and biomembrane engineering that amount to a toolkit for artificial cell construction, and (ii) demonstrated the feasibility of this biohybrid approach through preliminary studies. In this fellowship, building on these advances will achieve full integration between biological and synthetic cells, with the former being used as batteries, sensors, and reactors. Chemically and physically 'wiring up' synthetic and living components will require new technologies to be developed and an engineering rulebook to be devised. Three different hybridisation routes will be explored: (i) Physical hybridisation, where biological and artificial cells are encapsulated within one another to form a unified entity. (ii) Population hybridisation, where biological and artificial cell populations communicate with another through space, exchanging information and material. (iii) Networked hybridisation, where artificial and biological cells are linked through artificial gap junctions in a large-scale tissue-like network.In summary, I will determine how far living and synthetic systems can be fused, and start establishing the foundations of an emerging research area that bridges artificial and living biology. This project is highly ambitious and multi-disciplinary. It covers the physical and life sciences, engineering, and medical spheres. The project relies on industry engagement and includes placements at two industrial partners. It also has a series of leadership objectives, which are of equal importance to the research-focussed ones, and contains a training programme to help me become a scientific leader. For these reasons, the flexible, long-term, and cross-council support offered by the UKRI Future Leaders Fellowship is critical.