Competition for gene scissors: "Bridge RNA" to edit the genome more precisely

A group of researchers led by Patrick Hsu from the Arc Institute in Palo Alto, California, has demonstrated a new method that could be used to edit the human genome more quickly and, above all, more safely. The technique, which was developed together with scientists at the University of California in Berkeley, is called "Bridge RNA". It competes with the CRISPR gene scissors and has so far been tested on bacteria. The basic idea is to connect two pieces of DNA by creating a genetic bridge between them.

Bridging instead of just cutting

The process uses so-called transposons, also known as "jumping genes". These are already able to perform a kind of cut and paste in a natural way: they cut themselves out of the genome and reinsert themselves elsewhere. Hsu and his team use the IS110 transposon found in bacteria, which forms a bridge of RNA that can be manipulated. This allows both the area in the genome in which the desired DNA is to be inserted and the desired piece of DNA itself to be determined. In addition, the DNA strand is then closed again without leaving any residue, so unlike CRISPR, there are no free DNA fragments that can cause damage. "We are excited about the possibilities of making much more extensive genomic changes than we can currently do with CRISPR," Hsu told NewScientist. It is an "important step towards a comprehensive vision of genome design".

The two studies by Hsu & Co. have been published in the journal Nature. One deals with the basic possibilities of bridge RNA-guided recombination, the other with the "programmed insertion" of desired DNA segments. At the same time, a paper by Connor J. Tou and Benjamin P. Kleinstiver from Massachusetts General Hospital was published that deals with RNA-guided enzymes for "next-generation genome editing". Bridge RNA could, at least Hsu and colleagues hope, add, delete or modify DNA sequences of almost any length. The CRISPR gene scissors are, at least so far, even less precise. In addition, bridge RNA does not require so-called scars in the genome – the aforementioned extra pieces of DNA that CRISPR does not actually want, but which we have to live with.

Can the transfer from bacteria succeed?

Holger Puchta, Professor of Molecular Biology and Biochemistry of Plants at the Karlsruhe KIT, commented to the Science Media Center Germany that this is first and foremost basic research. "A new mechanism has been elucidated as to how a transposon can integrate sequence-specifically at certain sites in the bacterial genome. What is new is the discovery that [the enzyme] transposase uses a bridge RNA that has sequence homologies to both the sequence to be inserted and the target locus." Since the bridge RNA can be modified at will in both the target and insert recognition regions, a new programmable tool has been created to integrate "any DNA at any position in the genome".

"We urgently need an efficient technique for applications in human cells, but also in cultivated plants, to integrate longer sequences in the area of genes at specific locations in the genome. The principle that has now been found could actually provide a novel solution to this long unsolved problem," Puchta continues. However, he still sees hurdles in transferring the principle from bacteria to humans. For example, despite numerous attempts, insertions with bacterial transposons based on the CRISPR principle have not yet been efficiently established in mammalian cells, he says. Another problem is that the length of the recognition sequence in the bridge RNA - 11 to 15 base pairs - is not long enough for the target locus in the genome "to use the system outside of bacteria". Hsu and Co. are currently looking for ways to change this. The main problem is that the human genome is significantly larger than that of bacteria. Bridge RNA should therefore also have larger recognition areas.

(bsc)