Grant: Project Grant

Proteins play an indispensable role in modern medicine, with critical applications in molecular diagnostics, laboratory reagents, therapeutics, and bioprocesses. Creating new proteins with desirable activities remains a critical innovation space, in particular as our ability to design new proteins increases. However, the identification of suitable proteins from a vast pool of candidates remains a major bottleneck for two reasons: (1) obtaining the candidate genes, by synthesis or otherwise, is expensive, time consuming, and difficult, and (2) finding the genes that encode for proteins with the desired function is usually ad hoc and low-throughput. In this project, we will streamline and accelerate the development of new useful proteins by enabling researchers to synthesize and test many more protein candidates than were previously possible. We make use of a technology called "DropSynth" which our collaborators have developed that uses DNA-barcoded beads to separate gene parts that are later assembled in emulsions. We improved the bead synthesis process of DropSynth to enable hundreds-of-thousands of genes to be synthesized in one tube and showed that they work for gene synthesis. With such large-scale gene synthesis on the horizon, we need new approaches for testing so many genes. To meet this need, we developed an approach for testing genes at the scale of millions for various useful enzymatic activities. In this project, we pilot it to identify DNA cutting enzymes that will be valuable for correcting DNA synthesis errors, further increasing our impact in the gene synthesis space. Collectively, these innovations will make gene library synthesis and screening so easy that any lab can synthesize 160,000 genes and screen them for a desired enzymatic activity in a single day. This project will enable researchers to develop new proteins with desirable activities faster, cheaper, and easier than ever before, accelerating biotechnological innovation.