In June 2024, two back-to-back papers in Nature introduced bridge RNAs: a class of programmable, RNA-guided DNA recombinases discovered in bacterial insertion sequences that can insert, delete, invert, and translocate DNA at user-defined sites — without ever creating a double-strand break and without the size limits that constrain prime editing. The technology came from the Arc Institute's Patrick Hsu lab and from collaborators at the University of Tokyo, and it has been called the most significant new gene editing modality since the original CRISPR-Cas9 papers.
For the first time, a single enzyme may be able to perform all of the operations that previously required separate CRISPR, prime editing, and PASTE systems — and may eventually move kilobase-scale cargo at high precision. Whether bridge RNAs live up to the hype is still being tested, but the molecular biology is genuinely new.
What Are Bridge RNAs?
Bridge RNAs are non-coding RNAs encoded by IS110-family insertion sequences — a class of mobile genetic elements in bacteria that have been known for decades but whose mobilization mechanism was a mystery. The Hsu lab showed that IS110 transposases use a structured "bridge RNA" with two binding loops: one that base-pairs with the target DNA (the site where the IS110 element will insert) and another that base-pairs with the donor DNA (the IS110 element itself).
This was the breakthrough conceptual insight: a single RNA simultaneously specifies both ends of a recombination reaction. Change the RNA sequence, and you change both the target site and the donor — making the system fully programmable in two dimensions at once. By contrast, CRISPR specifies only the target; the donor must be supplied separately and integrated by cellular repair machinery.
The two foundational papers are:
- Durrant, Perry, Pai et al., 2024 (Nature). "Bridge RNAs direct programmable recombination of target and donor DNA." Patrick Hsu, Silvana Konermann, and colleagues at the Arc Institute and UC Berkeley.
- Hiraizumi, Nishimasu et al., 2024 (Nature). A simultaneous structural paper from the University of Tokyo solving the cryo-EM structure of the IS110 recombinase–bridge RNA complex.
How Bridge RNAs Work at the Molecular Level
The IS110 recombinase is a serine recombinase — a class of enzymes long known to catalyze DNA strand exchange via a covalent serine-DNA intermediate. What was new in 2024 was the discovery that an RNA could direct this recombinase to programmable sites.
The mechanism unfolds in five steps:
1. Bridge RNA assembly. The recombinase binds a single ~177 nt non-coding RNA encoded just outside the IS110 element. The RNA folds into a structured scaffold with two distinct duplex-forming regions.
2. Dual base-pairing. One stem of the bridge RNA — the "target-binding loop" — base-pairs with the genomic target site (typically 14 bp). The other stem — the "donor-binding loop" — base-pairs with the DNA to be inserted. This is the key innovation: both substrates are recognized by RNA, not protein.
3. Synapsis. The recombinase brings the target and donor DNAs into a four-way synaptic complex.
4. Strand exchange. The serine recombinase catalyzes strand exchange via a covalent intermediate, swapping DNA strands between target and donor. No double-strand break is generated as a free end.
5. Resolution. Depending on how the donor and target are configured, the result is an insertion, deletion, inversion, or translocation. By altering the bridge RNA sequence, the same enzyme performs all four operations.
In their 2024 paper, the Hsu lab demonstrated all four reactions in E. coli with editing efficiencies above 60% for some targets. Activity in human cells was lower in the initial publication but is being optimized rapidly.
Key Papers and Milestones
- Durrant, Perry, Pai et al., 2024 (Nature, June). First demonstration of programmable bridge RNA recombination.
- Hiraizumi et al., 2024 (Nature, June). Cryo-EM structure of the IS110 recombinase–bridge RNA–DNA complex.
- Arc Institute preprints, 2024–2025. Continued optimization for human cell activity, expanded enzyme variants from related IS-family elements.
- Industry response, 2024–2026. Multiple stealth biotechs founded around bridge RNA chemistry; major CRISPR companies have publicly disclosed bridge RNA evaluation programs.
Applications and Use Cases
Bridge RNAs are still very early — most published work is in bacteria. But the theoretical application space is unusually broad:
Large gene insertions. The dream application. Because the recombinase moves whole donor cassettes, there is no fundamental size limit imposed by repair templates the way prime editing has. Kilobase-scale insertions for cystic fibrosis CFTR, dystrophin, factor VIII, or full-length genes for inherited blindness become tractable in principle.
Targeted gene deletion. By placing two compatible target sites on the bridge RNA, large genomic regions can be excised cleanly — useful for excising integrated viral genomes or removing toxic gain-of-function alleles.
Programmable inversions and translocations. Bridge RNAs can engineer chromosomal rearrangements at defined sites — interesting for modeling cancer, for synthetic biology, and for engineering immune cells.
Crop and microbe engineering. The high efficiency in bacteria makes bridge RNAs immediately useful for industrial strain engineering and agriculture.
Bridge RNAs vs Prime Editing vs Standard CRISPR
| Feature | Bridge RNA recombination | Prime editing | CRISPR-Cas9 + HDR |
|---|---|---|---|
| Cuts DNA? | No double-strand break | Single-strand nick | Double-strand break |
| Insert size | Potentially kilobases | ~50 bp practical limit | Kilobases (low efficiency) |
| Operations supported | Insert / delete / invert / translocate | Substitutions, small indels | Insertion / deletion / replacement |
| Donor required | Yes (programmed by bridge RNA) | No (template in pegRNA) | Yes (separate ssDNA/dsDNA) |
| Human cell efficiency (2024) | Early, modest | High at many loci | Variable |
| Discovery | 2024 | 2019 | 2012 |
Why This Could Be Transformative
Three properties matter for therapy:
- No double-strand breaks. This avoids the chromosomal instability, p53 activation, and large-deletion risks that haunt all DSB-based editors.
- Single enzyme, four operations. Insert, delete, invert, translocate — all from one chassis. This dramatically simplifies regulatory and manufacturing pathways.
- No coding-sequence limit. The donor DNA is not delivered as a repair template that must squeeze into a pegRNA — it can be co-delivered as a separate molecule of arbitrary size.
If bridge RNAs become as efficient in human cells as they already are in bacteria, they would consolidate large parts of the editing toolkit into a single enzyme.
Connection to the Broader Gene Editing Ecosystem
Bridge RNAs represent the most significant theoretical advance over CRISPR since prime editing and arguably the largest since base editing. They sit at the intersection of multiple traditions: the RNA-guided programmability of CRISPR, the strand-exchange chemistry of serine recombinases (the same enzyme family that powers PASTE — see our twin prime editing and PASTE article), and the structural insights of mobile genetic elements. Like all gene editing tools, bridge RNAs face the same delivery system challenges as CRISPR — and arguably worse, because the cargo is novel and large. The Arc Institute itself, founded by Patrick Hsu, Silvana Konermann, and Patrick Collison in 2021, was created in part to enable exactly this kind of high-risk, foundational discovery work, and was the home institution for the bridge RNA papers.
Current Limitations and Challenges
- Human cell efficiency. Initial efficiencies in human cells are well below what was achieved in bacteria. This is the central question for translation.
- Specificity. Off-target recombination has to be characterized carefully — bridge RNAs depend on short base-pairing windows that may tolerate mismatches.
- Delivery. The recombinase plus bridge RNA plus donor DNA is a three-component system. Encapsulation in LNPs or AAV is not yet demonstrated for therapeutic dosing.
- Patent landscape. Bridge RNA IP is being filed aggressively by Arc Institute and partners, with implications for future commercial use.
- Reproducibility outside the originating labs. As of 2026, independent confirmation in diverse cell types is still building.
FAQ
Who discovered bridge RNAs?
Patrick Hsu's lab at the Arc Institute (Durrant, Perry, Pai et al., Nature June 2024), with a simultaneous structural paper from Hiroshi Nishimasu's group at the University of Tokyo.
How are bridge RNAs different from CRISPR?
CRISPR uses an RNA to find a target DNA, then cuts it. Bridge RNAs use a single RNA to find both a target site and a donor DNA, then catalyze recombination — no double-strand break required.
Can bridge RNAs insert large genes?
In principle, yes — that is the central excitement. There is no template-size constraint analogous to prime editing's pegRNA limit. In practice, demonstrating kilobase-scale insertions in human cells with high efficiency is still ongoing work.
Are bridge RNAs in clinical trials?
No. As of 2026, bridge RNA technology is preclinical. The first papers appeared in mid-2024, and the field is still optimizing human-cell performance.
Where do bridge RNAs come from in nature?
IS110-family insertion sequences in bacteria — mobile genetic elements that hop around bacterial genomes. The Hsu lab showed their hopping is directed by bridge RNAs, not by the protein recombinase alone.
Will bridge RNAs replace CRISPR?
Not in the foreseeable future. CRISPR is mature, clinically validated (see Casgevy), and backed by enormous infrastructure. Bridge RNAs may complement CRISPR for tasks like large-cargo insertion where standard approaches struggle.
