21EBTA: Engineering Biology with Synthetic Genomes (EBSynerGy)

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Yeast, Saccharomyces cerevisiae, has been used for centuries to bake bread and in brewing. Yeast is utilised across the world in many important industrial biotechnology applications, and is a model eukaryotic organism of great importance in fundamental research. Over the past decade, a large international consortium (Sc2.0) has been synthesising yeast chromosomes (16 in total). We aim to combine these chromosomes to create the world's first fully synthetic eukaryotic cell, which has a number of in-built design features to allow for its rapid optimization for new applications. For example, a genome scrambing function allows researchers to re-shuffle the genome like a deck of cards and can be applied to generate mutant strains with improved properties for industrial applications. However, genome scrambling can lead to the loss of essential genes which kills the cells. In light of this, we propose to relocate all the essential genes onto a dedicated "neochromosome" creating Sc3.0 cells. These new Sc3.0 cells will retain the essential genes during scrambling, so that more cells survive with desirable traits. We will exploit the synthetic yeast (Sc2.0/3.0), as a platform for the production of valuable natural products (e.g. antibiotics), cholesterol lowering agents (statins) and precursors required for manufacture of mRNA vaccines (e.g. Pfizer's COVID vaccine). Pathways to the target compounds will be introduced in the synthetic yeast and genome scrambling will be used to create large numbers of mutants producing the target compounds. We will also develop biosensors that can bind to the target products, triggering a fluorescent response to allow us to rapidly select the scrambled mutant cells that produce the highest levels of the target compound. In addition, we will develop novel imaging methods that can rapidly identify cells producing the desired compound. Finally, we will use the synthetic yeast to efficiently produce new generations of functionalized proteins. Nature produces proteins with an extraordinary range of functions, from enzymes that accelerate biochemical reactions needed for life to the antibodies that protect us from infectious diseases. These proteins are chains (polymers) made from only twenty building blocks called amino acids. In recent years an exciting technology has emerged called genetic code expansion (GCE) that allows us to produce proteins from more than these twenty building blocks. This technology is well developed for use in bacterial cells, but unfortunately many proteins can only be produced in higher organisms such as yeast - and here many of the important GCE tools do not operate effectively. Here we will develop yeast strains that are specifically optimized for the production of proteins with an expanded range of building blocks. These strains will underpin the development of new generations of protein therapies, catalysts and materials.