ARC Institute Achieves 930,000 Base-Pair Genome Inversion in Human Cells with New Bridge Recombinase Technology

Researchers at the ARC Institute have unveiled a groundbreaking genome-editing technology, "Bridge recombinases," capable of making megabase-scale DNA rearrangements in human cells without relying on unpredictable cellular repair pathways. This advancement, detailed in a paper published in Science in 2025, marks a significant leap in genetic engineering, offering unprecedented precision and scale for manipulating the human genome. The new tool demonstrated the ability to invert up to 930,000 base pairs and excise 130,000 base pairs of DNA, "with no apparent distance dependency," as highlighted by Niko McCarty in a recent social media post.

Unlike existing CRISPR-based gene-editing tools, which depend on a cell's natural repair mechanisms that can lead to varied and unpredictable outcomes, Bridge recombinases operate independently. This innovative system comprises a protein (recombinase) that cuts and rejoins DNA strands, and a guide RNA (Bridge RNA) that precisely directs the recombinase to specific genomic locations. The dual-recognition capability of Bridge RNAs allows for coordinated rearrangements, enabling the manipulation of large genomic regions with high specificity and an insertion efficiency of up to 20%.

The potential applications of Bridge recombinases are vast and transformative. Researchers successfully used the tool to edit a gene linked to Friedreich’s ataxia, a neurodegenerative disorder caused by excessive GAA repeats. In a cell culture model, the technology efficiently removed over 80% of these disease-causing repeats, suggesting a promising therapeutic avenue for repeat expansion disorders. Senior author Patrick Hsu, an Arc Institute Core Investigator, stated that "Bridge recombinases could transform how we create genetic therapies by offering one versatile medicine per patient population instead of thousands of individual treatments."

Beyond therapeutic interventions, the technology holds promise for creating advanced disease models. For instance, Bridge recombinases can accurately recreate large-scale genomic rearrangements characteristic of various cancers, such as the chromosome translocations seen in chronic myeloid leukemia and Ewing’s sarcoma. This capability allows scientists to better understand disease mechanisms and develop targeted treatments. Lead author Nicholas Perry, an Arc scientist, noted that the platform's applications are "particularly exciting and could apply broadly across many kinds of scientific projects."

The development of Bridge recombinases, initially adapted from natural transposases and optimized through systematic engineering of the ISCro4 system, represents a paradigm shift from merely observing to actively designing genomes. Researchers are now focused on expanding the platform's capabilities, including testing in clinically relevant immune and stem cells, and developing efficient therapeutic delivery methods for even larger DNA segments. This new tool moves the field closer to a future where "genome design" is a tangible reality, prompting a re-evaluation of fundamental questions in biology and medicine.