For decades, the field of gene editing has primarily focused on making minor modifications to the genetic code of organisms. These modifications are often compared to correcting typographical errors in an extensive manuscript of life, addressing isolated points without altering the broader narrative of genetics. However, researchers at the Arc Institute are poised to shift this paradigm significantly with the introduction of a groundbreaking universal gene-editing system. This innovative technology not only allows for targeted modifications akin to traditional gene editing but also facilitates large-scale rearrangements of entire genomic segments—what can be described as cutting and pasting genomic paragraphs and chapters. This leap forward offers profound implications for the future of genetic engineering, potentially revolutionizing how we approach complex genetic diseases.
In a recent publication in the journal Science, the research team revealed the transformative potential of bridge recombinase technology in manipulating human DNA. Their findings indicate that this method enables scientists to engage with extensive segments of the genome, encompassing regions as large as one million base pairs. This capacity allows researchers to insert new genes, delete entire clusters of genes, and even invert regulatory sequences with unprecedented precision and efficiency. Such advancements may pave the way for more versatile and effective genetic therapies, where a singular treatment could address a wide array of genetic disorders rather than necessitating a myriad of individual solutions tailored to specific mutations or defects.
Patrick Hsu, a core investigator at the Arc Institute and a faculty member in bioengineering at the University of California, Berkeley, expressed the magnitude of this innovation. He emphasized that the ability to manipulate substantial genomic regions could redefine the genetic therapy landscape. Instead of developing countless bespoke treatments for individual patients, this technology has the potential to deliver a universal solution tailored to patient populations. Hsu noted that this fundamental shift in capabilities will allow researchers to engineer biological systems at the scale that has been directed by natural evolutionary processes, thus opening up new avenues for addressing complex diseases.
The discovery of bridge recombinases originated from natural mobile genetic elements that exhibit parasitic traits by integrating themselves into bacterial genomes as a means of survival. This team previously published their findings in the journal Nature, where they detailed the two elements comprising this novel approach: a structured guide RNA termed “bridge RNA” and a recombinase enzyme responsible for executing DNA rearrangements. By reprogramming the bridge RNA to target specific DNA sequences, they established a foundation for a new class of gene-editing toolkit—the bridge recombinases.
The distinction of this recent study lies in its demonstration of the system’s ability to achieve not only insertions in the human genome but also efficient excisions and inversions of genetic sequences in a programmable manner. The lead author of the study, Nicholas Perry, who conducted this research while pursuing his PhD at UC Berkeley, highlighted the broad applications of this platform across diverse scientific projects. The combination of insertion, deletion, and inversion capabilities significantly expands the toolbox available to geneticists and biologists worldwide.
Through an exhaustive process, the research team began with 72 natural bridge recombinase systems isolated from bacterial sources, assessing their activity within human cells. While approximately 25% of these systems displayed some degree of functionality, only one, identified as ISCro4, demonstrated sufficient measurability to warrant further optimization. Diligently testing thousands of variations of both the enzyme and RNA guide components, the team ultimately achieved notable efficiencies—20% for DNA insertions and 82% specificity when targeting intended genomic loci.
In contrast to the widely popular CRISPR technique that utilizes a singular guide RNA for targeting specific DNA locations, bridge RNAs present a unique advantage. They possess the capability to recognize two separate DNA targets through different binding loops. This dual-target recognition feature promotes coordinated genomic rearrangements; for instance, it allows distant chromosomal regions to be brought together for excision or inversion of sequences while the recombinase performs its rearrangement functions. This molecular architecture acts as a scaffold, facilitating intricate alterations to an organism’s genetic structure.
As a compelling proof-of-concept, the researchers devised artificial constructs simulating the toxic repeat sequences associated with Friedreich’s ataxia—an inherited neuromuscular disorder. Healthy individuals typically harbor fewer than ten copies of a critical three-letter DNA sequence; however, patients with this condition may have upwards of 1,700 copies. Such expansions are detrimental and disrupt normal gene functionality. Utilizing the engineered ISCro4, the team effectively removed these toxic repeats in artificial constructs, with some cases eliminating more than 80% of the expanded sequences.
Perry noted the significance of excising DNA repeats, emphasizing that even modest reductions in repeat length can correlate with alleviated disease symptoms. This aspect illustrates the potential for bridge recombinases to serve as therapeutic agents for any heritable conditions stemming from similar genetic expansions. Furthermore, the approach emphasizes its relative simplicity; it involves delivering RNA molecules rather than the more complex process of transporting proteins or DNA into human cells.
The research team also successfully applied bridge recombinases to replicate existing therapeutic approaches, such as removing the BCL11A enhancer, which is implicated in the FDA-approved treatment for sickle cell anemia. Importantly, the ability to manipulate substantial amounts of DNA heralds significant advancements in modeling the large-scale genomic rearrangements often associated with cancer. This versatility positions bridge recombinases as a technological cornerstone for future endeavors in genetic therapy and disease modeling.
Looking ahead, the researchers are focused on expanding the capabilities of the bridge recombinase platform. This includes testing their efficacy within clinically relevant immune cells and stem cells, developing effective methods for therapeutic delivery, and engineering variants capable of managing DNA segments larger than one million base pairs. Additionally, there is a keen interest in exploring applications within plant genetics and synthetic biology, promising exciting new avenues for genetic manipulation across various fields.
This research was characterized by extensive collaboration among multiple teams, showcasing the power of collective scientific inquiry. Key contributors included Liam Bartie, Dhruva Katrekar, Gabriel Gonzalez, and Matthew Durrant, while guidance from notable leaders in the field facilitated rapid advances. With the leadership of Patrick Hsu and Silvana Konermann and structural insights derived from Hiroshi Nishimasu, the research exemplifies how interdisciplinary efforts can push the boundaries of what is achievable within genetic research.
The implications of this work are profound, as it presents an opportunity to rethink how we genetically engineer organisms. By facilitating large genetic rearrangements with programmability and precision, bridge recombinases could enable scientists to tackle some of the most complex genetic diseases. The potential for streamlined therapeutic strategies that require fewer individualized treatments brings hope for improved health outcomes and enhanced quality of life for patients dealing with genetic disorders. As this research garners attention, the scientific community eagerly anticipates further developments, setting the stage for a new era of genetic manipulation powered by bridge recombinase technology.
Subject of Research: Cells
Article Title: Megabase-scale human genome rearrangement with programmable bridge recombinases
News Publication Date: 25-Sep-2025
Web References: https://www.science.org/doi/10.1126/science.adz0276
References: Perry, N. T., Bartie, L. J., Katrekar, D., Gonzalez, G. A., Durrant, M. G., Pai, J. J., Fanton, A., Martins, J. Q., Hiraizumi, M., Ricci-Tam, C., Nishimasu, H., Konermann, S., & Hsu, P. D. (2025). Megabase-scale human genome rearrangement with programmable bridge recombinases. Science. DOI: 10.1126/science.adz0276
Image Credits: Chiara Ricci-Tam
Keywords
Genetic engineering, bridge recombinases, gene therapy, genetic manipulation, human genome, biotechnology, synthetic biology, CRISPR technology, therapeutic applications, genetic disorders, interdisciplinary research, molecular biology.
Tags: Arc Institute research advancementscomplex genetic diseases solutionsengineered bridge recombinasesgenomic segment manipulationhuman DNA manipulation techniqueslarge-scale genetic modificationsprecision gene insertion and deletionprogrammable DNA rearrangementsregulatory sequence inversion in geneticstargeted gene editing technologiestransformative genetic engineering methodsuniversal gene-editing system
