Bridge RNAs: The Next Frontier in Precision Genome Editing Beyond CRISPR

In a very interesting new paper that was just published in Nature titled “Bridge RNAs direct programmable recombination of target and donor DNA” by Durant et al. (2024), they introduce what looks like a groundbreaking discovery in genetic engineering that uses a new class of non-coding RNAs (ncRNAs) called bridge RNAs that enable programmable DNA recombination. This expands the capabilities of nucleic-acid-guided systems beyond existing technologies like CRISPR.

This study reveals that IS110 insertion sequences, which are minimal mobile genetic elements, express structured ncRNAs that specifically bind to their encoded recombinase. These bridge RNAs contain two internal loops that base-pair with target and donor DNA, facilitating sequence-specific recombination. This discovery is particularly significant because the target-binding and donor-binding loops of the bridge RNA can be independently reprogrammed, allowing for programmable DNA insertion, excision, and inversion. 

I think this discovery of bridge RNAs as programmable tools for DNA recombination could be the next big thing in genome editing, taking us beyond what RNA interference (RNAi) and CRISPR have done so far. Bridge RNAs allow insertion, removal, or flipping DNA sequences without breaking the DNA strands, which means fewer mistakes and a more stable genome.

What would the future of genetic tools be building on this concept look like? Complex DNA changes could be designed with comparably high precision, combining bridge RNAs with other mechanisms to not only edit genes but also control their activity. For example, genes could be turned on or off or even tweaked their expression levels, giving a powerful way to study how genes work and develop new therapies.

Speculating even further, these new tools might also interact with more than just DNA. Think about targeting RNA transcripts to edit RNA sequences or modulate RNA splicing, or even interacting with proteins to change their activity or where they are in the cell. This would open up a whole new world of possibilities.

In medicine, this third generation of RNA-guided tools could lead to new treatments for genetic diseases. By making targeted and reversible changes to the genome and transcriptome, it could create more effective and personalized therapies with fewer side effects. There could also be an improvement in the safety and efficacy of advanced cell and gene therapies by controlling genomic rearrangements and gene expression more precisely.

Overall, these new RNA-guided tools could revolutionize genome engineering, offering new possibilities for research, biotechnology, and medicine. By building on the principles of RNAi, CRISPR, and bridge RNAs, it could be possible to manipulate biological systems with greater accuracy and flexibility, leading to innovative applications and groundbreaking advancements.