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Details of Grant 

EPSRC Reference: EP/T000562/1
Title: An Artificial Ribosome
Principal Investigator: Turberfield, Professor AJ
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: Oxford Physics
Organisation: University of Oxford
Scheme: Standard Research
Starts: 01 October 2019 Ends: 30 September 2023 Value (£): 664,201
EPSRC Research Topic Classifications:
Biological & Medicinal Chem. Biophysics
Chemical Biology Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
EP/T000481/1
Panel History:
Panel DatePanel NameOutcome
13 Jun 2019 EPSRC Physical Sciences - June 2019 Announced
Summary on Grant Application Form
We propose to create an artificial ribosome.

Life depends on precise, sequence-controlled polymer synthesis. The ribosome is the natural molecular machine that 'reads' information stored in genes and 'writes' the corresponding proteins by concatenating molecular building blocks chosen from a small set of natural amino acids. The creation of artificial machinery capable of translating a genetic code into a completely synthetic sequence-defined polymer would have profound implications. Directed evolution by molecular machinery working on reaction- and time-scales orders of magnitude smaller than currently possible would allow exploration of vast new regions of chemical space and lead to the development of non-natural polymers that match and extend the functionalities of peptides and proteins. Nanomachines capable of programmed product synthesis in situ could realize the longstanding promise of nanotechnology to deliver 'smart' therapeutics. On a more fundamental level, we could recreate complex biological behaviours such as gene regulation, bringing the creation of artificial living systems -the grand challenge of synthetic biology- a step closer. We will combine our expertise in DNA nanotechnology and polymer chemistry to build artificial ribosomes capable of translating a nucleic acid genetic code into sequence-defined, non-natural polymers.

Several groups, including our own, have made progress towards this goal. The ribosome has been 'engineered' to accept unnatural building blocks, but this technique is extremely time-consuming and the pool of building blocks remains limited. Molecular machines synthesised entirely from scratch have been developed that perform sequential chemical synthesis, but the syntheses are laborious and there is no readily readable and rewritable artificial genetic code. A middle ground between these two approaches is to make use of nature's genetic code - DNA - and integrate it with an artificial machine constructed in a modular fashion from simple components. We use DNA nanotechnology, which makes use of the predictable base-pairing of the DNA double helix, to construct these machines. We and others have used this approach to create autonomous molecular machines that can perform sequential chemical synthesis. However, these early attempts have been severely limited by two problems. First, the building blocks used are highly reactive and so degrade to become useless over time. Second, the machines have no way of recognising if a reaction has occurred successfully or not, so often skip intermediate building blocks.

In this ambitious programme we will address these issues by developing DNA machines that activate building blocks to become reactive only when they are needed and that are capable of sensing when a reaction has occurred before progressing to the next step. Integrating these two advances will allow us to create an 'artificial ribosome' capable of autonomous, multistep synthesis of sequence-controlled polymers. We will demonstrate some of the potential future applications of this transformative molecular technology by synthesising a functional product, performing multiple syntheses in parallel in the same reaction vessel, and triggering synthesis of particular products in response to different environmental signals.

This work will result in significant advances in the areas of molecular machines, synthetic biology and polymer chemistry, and could have numerous practical applications, for example in nucleic acid sensing for point-of-care diagnostics. Through a programme of dissemination, workshops and knowledge exchange we will ensure that our new technologies reach beneficiaries who can make practical use of them.

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Organisation Website: http://www.ox.ac.uk