Establishing a Periodic Table Toolbox for Nanoassembly and Superselectivity

Synthetic biology refers to taking an engineering approach to biology, allowing biological building blocks to be assembled and function in a controlled and predictable way. Synthetic biology has potential to generate major changes in areas including energy, healthcare and agriculture. Proteins are powerful tools in synthetic biology because of their diverse activities, including catalysing reactions and sensing changes in their environment. Our group has established a specific unbreakable way to connect proteins, from harnessing an unusual protein chemistry from bacteria. The periodic table of protein architectures helps to understand the symmetry of how proteins can come together into teams. The toolbox we develop here will make it possible, simply by mixing with the appropriate partner, to assemble a protein into teams ranging from 2 to 720 members and over a wide size range. Teamwork matters, even at the molecular level, so this assembly will enable tuning of how proteins bind, signal and move in living systems. Many therapies depend upon distinguishing between healthy cells with some level of a receptor versus unhealthy cells having higher receptor levels. Normally it is difficult to generate drugs to kill the unhealthy cells without toxic side-effects from the drug also sticking to many healthy cells. Superselectivity is a principle established on non-living systems that could reduce these side-effects. Here we will harness the new protein teams so we can find out how to achieve superselectivity on living cells.

Who will benefit from this research?
Apart from academic scientists, the beneficiaries will include companies involved in synthetic biology and biotechnology, some of whom have started to use SpyTag assembly already. Companies in diverse areas have licensed SpyTag/SpyCatcher and its variants from us, or are currently performing evaluations. Patents applying SpyTag have been filed for example by Roche and Encodia (in sequencing), Virogin and Regeneron (in gene therapy), and Algentech and Agrivida (in agriculture). Developing these novel nanostructures will greatly extend the ability to assemble and control protein function. Products by these companies, harnessing covalent protein and peptide assemblies, should enhance detection speed and sensitivity, so having an impact on disease diagnosis in animals and humans, beneficial to the general public, the farming community and the National Health Service.
How will they benefit from this research?
The systematic toolbox should allow stable, simple and defined-orientation protein assembly in biosensors, nanoparticles for drug delivery or gene therapy, or protein microarrays. The new modules may directly comprise part of a commercial product/kit, or facilitate research leading to the generation of other products.
Areas such as gene therapy (e.g. GSK, AstraZeneca) and diagnostics (e.g. Oxford Nanopore) are important for UK economic competitiveness and so the development of enabling tools for nanoassembly should be beneficial.
The likely time-scale for commercial evaluation of IP arising from the symmetry toolbox is in the third year of the award and for the superselective assemblies is in the year following the end of the award. For products relating to kits, these can reach the market as fast as 1 year after testing. For products relating to medical use, 5-10 years are likely before reaching general use.
This project will provide important training for the postdoctoral researcher in:
-developing and executing a multidisciplinary project which creates new tools and applies them in synthetic biology, identified as a priority training area by the UK government
-development of presentation skills, through presenting within the University and at conferences, and discussing science and commercialisation with potential industrial partners
-advancing their entrepreneurship and innovation skills through workshops at Oxford University Business School and the Oxford Foundry
-communicating their findings to non-expert audiences, including at the Oxford Science and Ideas Festival.
What will be done to ensure that they benefit from this research?
Publishing in high impact international journals is an effective way for us to communicate our findings to potential industrial partners. We will work with OUI, who look after Oxford University IP, to ensure protection of all new IP arising. As we achieve key results, we will communicate with the University of Oxford press office and the EPSRC and with OUI's network of industrial contacts, to ensure that significant findings are communicated widely to the public and potential industrial partners. We will publish detailed protocols in open access journals, including video demonstrations, to facilitate adoption of the new toolbox and superselective technologies by other users, as we have done previously for the tools developed by the lab in Nature Protocols and Methods in Enzymology. We will also provide rapid e-mail feedback to users, as we have done for the large number of laboratories using SpyTag, SpyCatcher and streptavidin-based tools for diverse applications.