An engineering rulebook for interfacing living and non-living cells

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.

Although this fellowship proposal is of a blue-skies nature, it will deliver impact across the UKRI remit and to UK plc. Indeed, feasibility milestones to demonstrate impact are worked into the work programme across all three workstreams. These will form the basis of more application-led projects long-term. Placement with non-academic project partners will facilitate impact in their respective sectors. Activities to maximise impact are included in the Pathways to Impact document. Specific areas of impact include:

PATIENT CARE. I will be developing stimuli-responsive vesicles which can communicate with biological cells. On the c. 10 year horizon, this can be used as a new mode of dynamic drug delivery, where the release of content can be turned on/off by an external user or indeed by the presence/absence of a diseased state. I will be exploring this potential in my partnership with AZ, who will provide drug-like molecules to test and consult on the technical aspects of this application. Such approaches could lead to more effective pharmaceuticals with decreased side effects, and can apply to small-molecule drugs, but also to protein and DNA-based therapeutics, which are suited to being encapsulated (and synthesised) in vesicle-based artificial cells.

DRUG DISCOVERY PROGRAMMES. Synthetic cells allow drug/membrane interactions to be systematically probed in a model environment (e.g. to measure the effect of drug chemical structure on membrane diffusion rates). My microfluidic technologies will help alleviate this longstanding bottleneck in the pharma pipeline. Moreover, one of my workstreams will be devoted to devising technologies for the construction of synthetic tissues that contain cellular modules. These have potential to be used as spheroid/organoid constructs, as tissue-on-chip models, and as platforms to assay drug pharmacokinetics (on the 5-10-year timescale). Collaborations with OxSyBio and AstraZeneca will be used to explore both these applications.

INDUSTRIAL BIOTECHNOLOGY. Constructing cells that are encapsulated in vesicle microsystems has potential for co-culture applications, for example in bacterial biosensing for industrial bioprocess (c. 5-year timescale). The membrane will shield the encapsulated engineered microorganism from the bulk culture, thus preventing undesirable interactions and interference. I will work with my collaborator K. Pollizi to explore the feasibility of such applications. Furthermore, living/synthetic systems could allow biological production and downstream chemical modification to be integrated into a single microreactor, e.g. for the production of high-value chemicals. Finally, chloroplasts and cyanobacteria that are embedded in synthetic cells (milestones conducted in collaboration with Dr L. Barter) could be used as a novel way of powering internal processes (e.g. protein expression) by replacing costly energy-carrying modules with those derived from photosynthesising organisms (>15-year timescale for commercial applications).

CULTURAL AND ARTISTIC SPHERES. There have already been several landmark examples of synthetic biology in these areas (e.g. self-healing biofabrics for high-end fashion). It is expected that living/synthetic hybrid materials will similarly be used in these areas in the long term (15+ years). One benefit of this will be drawing public attention to the cultural value of science, which is crucial given public concerns about biotechnology.