Proteins are made from only 20 standard building blocks, and a technique called genetic code expansion (GCE) lets researchers add hundreds of new ones, but the process is too slow and expensive for industry to use. This matters because proteins already do the heavy lifting in medicine and manufacturing—insulin treats diabetes, enzymes break down plastics in laundry detergents. But those proteins are limited by the narrow set of chemical tools nature provides. GCE can insert non-canonical amino acids (ncAAs) with entirely new functional side chains, enabling proteins that catalyse novel reactions, bind targets more precisely, or resist degradation. The problem is that current GCE methods produce low yields and require huge excesses of expensive ncAAs, making commercial production cost-prohibitive. If this project succeeds, it will deliver engineered bacterial strains that biosynthesise their own ncAAs and incorporate them efficiently into proteins at scale. Working with AstraZeneca, GSK, and Prozomix, the team will demonstrate the platform on next-generation biocatalysts and protein therapeutics. The result could be cheaper, more effective biologic drugs and industrial enzymes—things that quietly underpin everything from pharmaceuticals to sustainable manufacturing—without requiring a complete overhaul of existing production infrastructure.
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Proteins are biopolymers that perform a vast array of functions in nature, including speeding up the biochemical reactions needed for life, transporting molecules across membranes, providing structural support and controlling signalling processes. Beyond their natural functions, proteins are also used widely across chemistry, biotechnology and medicine - for example as therapeutics such as insulin or as biocatalysts used in laundry detergents or to break down plastics. Despite their remarkable structural and functional diversity, the vast majority of proteins are made from only 20 standard building blocks, the canonical amino acids. These amino acids only contain a narrow set of functional motifs, which ultimately restricts our ability to develop proteins with new and improved functions. To address this fundamental limitation, a powerful protein engineering technique called genetic code expansion (GCE) has been developed to allow proteins to be produced from >20 amino acid building blocks. Using this technique, hundreds of non-canonical amino acids (ncAAs) with new functional side chains can now be selectively introduced into proteins, leading to the development of new generations of biocatalysts, advanced materials and new biotherapeutics. However, despite great progress and its enormous commercial potential, the translation of GCE from academic labs into commercial protein products has been hindered by existing limitations of the technology. Current barriers to translation include the low yields of ncAA-containing proteins and the requirement for large excesses of ncAAs, which ultimately result in prohibitively high production costs. In this proposal we will develop a fully integrated engineering biology platform to translate GCE into commercial applications. Bringing together multidisciplinary researchers from across academia and industry, we will develop engineered strains capable of biosynthesizing new functional ncAAs and efficiently introduce them into proteins to deliver precisely functionalized proteins at substantially lower costs than existing platforms. To exemplify our technology, we will work in collaboration with our industrial partners AstraZeneca, GSK and Prozomix, to apply our engineered strains to the large-scale production of next generation biocatalysts and protein therapeutics. Moving forward, the versatile GCE platform and engineering biology tools developed within this proposal will enable the scalable production of diverse functionalized proteins in response to emerging societal needs.
Amanda Gail Jarvis (Co-Investigator)Anthony Green (Principal Investigator)Dominic Campopiano (Co-Investigator)Sarah Louise Lovelock (Co-Investigator)Yizhi Cai (Co-Investigator)
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