Orthogonal phages from non-linear sequence topologies: towards an artificial phage-host system

Precision engineering of biological systems can greatly benefit from expanding into chemical space to enact artificial life. Progress in de novo DNA synthesis enables routinely produced high-fidelity genomes to open up possibilities for engineering synthetic organisms. Earlier efforts focused on creating minimalist phages and cells and continue with the introduction of synthetic genomes into bacteria and yeast. Emerging efforts aim to purposely address persistent challenges especially in healthcare where engineering biology will impact most. One of the routes taken is the re-purpose of bacterial viruses, bacteriophages, for applications as diverse as antibacterial treatments and cures for alcoholic liver disease. All such efforts rely on pre-existing biological systems, both bacteriophages and hosts, and many are genetic modifications thereof, albeit with synthetic genomes. An effort to generate a purely artificial phage-like system, and its host by extension, has yet to emerge. The proposed research will fill this gap. Chemical and engineering biologists from the University of Tokyo and the UK’s National Physical Laboratory have established an international partnership to create a first-in-class chemically inspired phage and explore the basis for the host of its replication. Unlike existing biological phages or viruses, such a phage will assemble from short non-linear amino-acid sequences, which have no analogues in living systems and are not accessible to the genetic machinery of living cells. The project will use innovative tools for biodesign, genetic re-programming and protocells to introduce an artificial phage-host system as a commensal bio-orthogonal organism exemplifying the emergence of artificial life from the chemical space.