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ACDC – Artificial Cells with Distributed Cores to Decipher Protein Function

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Description

ACDC will employ a rapidly expanding living technology platform of transformational artificial cell technologies towards the next generation of small molecule drug discovery, protein biophysics, and biochemical energy production. This will be executed through a future paradigm of sensory and synthesis regimes, based on programmable and re-configurable, (bio)chemical processes, built with precision, order, and as hierarchical cellular constructs, in a design mirrored in living systems. In effect, we aim to emulate the structure and dynamics of living cells and cellular tissues by embedding biochemical and biophysical systems capable of sensing, reconfiguration, synthesis, electrochemical gradient production and biochemical energy production - all essential processes of living cells - built from the bottom up and middle-out approaches. We will accomplish this by producing microscale, liquid-based, chemical compartmentalisation (cores), with inter-compartmental (core-core) communication, just as one finds in organelles, cells and tissues. In the future, the resulting technology will enable creation of simplified artificial cell technologies based on cores as a platform for technical innovation, precisely for 1) the high throughput screening of small molecule libraries against defined protein targets, such as membrane proteins, 2) the definition of precise biophysical aspects of targeted protein systems, 3) the elucidation of targets for future antibiotics, 4) the definition of a scale-up of this core technology, and 5) the development of the multi-level mathematics underpinning the complexity of such artefacts of living technology but also of natural living systems. ACDC will focus on developing this next generation technology through a detailed workplan that heavily involves the nontrivial tasks of integrating diverse state of the art technologies including microfluidics, microwave resonators, DNA-based supramolecular assembly, in vitro gene expression and the integration of membrane channels into a functional platform. To exemplify the future potential of this integrated platform we will perform initial tests using high throughput screening of a small molecule library against the membrane protein target FeoB in phospholipid vesicles. Once demonstrated, a future implementation includes genetic mutation screening of ion channels for high value targets. The development of in situ protein expression systems for expressing target proteins, will be further applicable beyond screening and biophysical characterisation, to repurposing as bespoke sensing and communication components. This will enable the creation of modular pathways within programmable capsules for applications, in a future embodiment of this project, that includes using artificial cell technology as programmable and reconfigurable matter for specific applications including theranostics and personalized medicine, sensing and actuation in the environments for bioremediation, and discovery of potential antibiotics from complex soil environments. All of these future applications will rely on the fundamental functionalities developed in ACDC including modular functional capsules, reconfiguration, remote read-out, core-core and core-environment communication. We have assembled an international, interdisciplinary team from academia, industry and public engagement including expertise in engineering, physics, computer science, and chemical biology, to undertake this work. Our outreach and engagement programme will define the impact in both the public and economic sectors. Further, building upon 55 years of collective start-up enterprise experience, we will explore a new, agile, innovative vehicle to accelerate the translation of new intellectual property generated into commercial advantage and job creation for the European Union. The overall objective of the ACDC project is to manufacture compartmentalised, liquid-based chemistries, as discrete, yet interactive and multifunctional cores, within micro-scale containment capsules as communicating micro-laboratories. Analogous to current ICT, we imagine the tremendous opportunities and potentialities that exist when chemical and biochemical processes are miniaturized in programmable discrete units that provide on demand functionality. For example, we hope one day to be able to produce biochemical apps that could be installed in a portable chemical laboratory the size of a mobile phone that can then produce insulin, antibiotics or other high value medicines on demand. Another app could in principle detect toxins or disease in the environment or user. Another app would monitor daily nutritional parameters including mental or physical performance. As the first steps towards that future vision, we aim to produce an artificial technological construct and process that recapitulates some aspects of living systems on the microscale, and therefore this project will produce exemplars of secondary living technologies concentrating on the wetware class [1] but also a multi-level mathematical framework.

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