Zachary Cooper L&S Biological Sciences
High-Fidelity Bridge Recombinase Discovery for Genomic Engineering
As a SURF fellow in the Hsu Lab, I am advancing a new “search-and-replace” genome engineering paradigm using bridge recombinases. Unlike CRISPR-Cas9, which often relies on unpredictable host-mediated repair of double-strand breaks, these systems use a programmable bridge RNA (bRNA) to coordinate “scarless” megabase-scale modifications such as gene insertions, inversions, and excisions. A critical bottleneck for clinical use is that currently validated systems, like IS621, are limited to a 14-nucleotide specificity window, which poses a significant risk for off-target activity within the 3.2 billion base pairs of the human genome. My research this summer will focus on metagenomic diversity mining to discover novel IS110-family orthologs that have naturally evolved longer, more specific guide architectures. By leveraging high-throughput library screens and Unique Molecular Identifiers (UMIs), I will quantify the recombination kinetics and specificity of a thousand novel systems in human cells. Ultimately, this project aims to transition bridge recombination into a high-fidelity, therapeutic-grade platform capable of navigating the complex genomic landscape with absolute precision.
Message To Sponsor
I am sincerely grateful for the support of my research through the SURF program this summer. My project focuses on mining metagenomic diversity to discover high-fidelity bridge recombinases, driven by my interest in developing precise, "scarless" gene-editing tools for complex diseases. This opportunity allows me to advance from computational discovery to therapeutic validation within the Hsu Lab at the Arc Institute. Thank you for investing in my development and the future of genomic medicine.