New DNA-editing mechanism discovered in bacteria may outshine CRISPR

A unique bacterial molecule might allow scientists to redesign genomes, enabling them to insert, delete, or flip large DNA segments. This technique, detailed in three recent papers in Nature and Nature Communications, uses jumping genes, which naturally insert themselves into genomes.

According to Sandro Fernandes Ataide, a structural biologist at the University of Sydney in Australia and an author on the Nature Communications paper, “if this works in other cells, it will be game-changing. It’s opening a new field in gene editing.”

The system, guided by a ‘bridge’ RNA, has successfully edited genes in bacteria and in vitro, though its potential in human cells remains uncertain. If adaptable, it could revolutionize genetic editing with its compact size and capability to modify DNA sequences thousands of bases long, surpassing the practical limits of CRISPR-Cas9 without causing DNA breaks.

CRISPR-Cas9 has often faced misleading headlines. It can rewrite small genome segments but isn’t the versatile cut-and-paste system some stories suggest. Typically, it changes only a few DNA bases by first breaking DNA and using the cell’s repair systems. This can cause unintended genetic damage.

Researchers seek multi-gene editing for targeted therapies

As CRISPR advances in human medicine, researchers aim to enhance their genome-editing tools to insert entire genes or multiple genes into specific locations. This approach could lead to therapies for individuals with multiple mutations in one gene, streamlining treatment. Moreover, editing multiple genes could enable engineering of immune cells to combat cancer from various angles, ensuring precise gene insertion into the genome.

Patrick Hsu, a bioengineer at the non-profit Arc Institute in Palo Alto, California, and a co-author of both Nature papers, emphasized the future goal of designing entire sections of the genome rather than individual bases.

To find suitable tools, Hsu and his colleagues investigated a variety of enzymes that enable mobile DNA elements in bacteria to move between locations. They focused on a specific group known as transposable elements, particularly IS110.

Enabling versatile DNA modifications

The IS110 enzymes use a unique RNA-based system for targeting, the team discovered. One end of the RNA attaches to the DNA segment intended for insertion, while the other end binds to a DNA snippet at the insertion site in the genome. This RNA acts as a bridge between the two DNA segments, leading the team to call these molecules ‘bridge RNAs’.

One sequence identifies the target location in the genome, akin to CRISPR, while the other specifies the DNA segment to be altered. This system enables adding, deleting, or reversing DNA sequences of almost any length.

Current methods achieve these tasks, but they often require multiple steps and leave behind unwanted DNA fragments, known as scars. Hsu noted that bridge editing avoids scarring, providing precise control over genome manipulation.

This capability extends beyond gene replacement; it could potentially reshape the genomes of plants and animals on a larger scale.

“What we’d like to do is to move beyond inserting individual genes to do chromosome-scale genome engineering,” Hsu noted.

The research was published in Nature on June 27.