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The CRISPR/Cas gene scissors have revolutionized genetic engineering in the ten years since their discovery. Researchers have now discovered another gene scissors: The so-called Fanzor system occurs in eukaryotic organisms such as fungi, plants and animals and, like the bacterial CRISPR, can make precise changes in the genome. Although less effective than CRISPR so far, it could offer advantages in the future, such as accuracy and avoidance of side effects.
Whether cancer, HIV or hereditary diseases such as Duchenne muscular dystrophy: since the CRISPR/Cas gene scissors were discovered in 2012, there has been hope that these diseases can be treated with the help of targeted interventions in the genome. The CRISPR/Cas system originally comes from bacteria and helps them to cut up the genetic material of invading viruses. However, it can be reprogrammed in such a way that it cuts out and replaces precisely specified parts of the genome – a revolution in genetics and medicine. One of the challenges when using it on humans is to transport the gene scissors to their site of action. In addition, despite the high precision of the gene tool, undesirable collateral damage can occur if the system not only cuts the specified site, but also damages surrounding DNA segments.
First gene scissors in eukaryotes
A team led by Makoto Saito from the Broad Institute of MIT and Harvard in Cambridge has now discovered a new gene scissors that, unlike CRISPR/Cas, does not come from bacteria but occurs in eukaryotic organisms such as fungi, plants and animals. These are so-called Fanzor proteins. Similar to CRISPR/Cas, they use RNA as a guide to dock onto precisely defined sites on the DNA using suitable base sequences and cut them precisely. "CRISPR-based systems are widespread and powerful because they can be easily reprogrammed to target different sites in the genome," explains Saito's colleague Feng Zhang. "This new system is another way to make precise changes in human cells and complements the genome editing tools we already have."
Fanzor is also the first gene scissors to be discovered in eukaryotes, i.e. organisms with a cell nucleus, to which we humans also belong. However, the basis of the current discovery was initially provided by another RNA-guided system, called OMEGA, which the team found two years ago in prokaryotes, i.e. living beings without a cell nucleus, which mainly include bacteria. "These OMEGA systems are the ancestors of CRISPR and are among the most abundant proteins on the planet," Saito explains.
Using molecular analyses, Saito and his team found that the eukaryotic Fanzor proteins share many similarities with the bacterial OMEGA systems. "Our results show that Fanzor is a eukaryotic OMEGA system," the researchers write. They assume that the Fanzor genes were transferred from bacteria to eukaryotes by so-called horizontal gene transfer. "Due to their wide distribution, it makes sense that they could jump back and forth between prokaryotes and eukaryotes," says Saito.
Starting point for further development
For their study, the researchers isolated Fanzor proteins from algae, amoebas, fungi and clams. To test whether Fanzor is actually able to edit the human genome, they treated cell cultures of human cells with various Fanzor proteins. "Indeed, the various Fanzor proteins created insertions and deletions in the human genome," reports the team. "The efficiency was up to 11.8 percent." That's not much compared to CRISPR/Cas, but it indicates the fundamental potential of the technology.
By genetically modifying the Fanzor gene from the Spizellomyces punctatus fungus, the researchers have already succeeded in increasing the activity of the Fanzor protein and improving its performance. They also found no unwanted activity in the fungal Fanzor protein that could lead to collateral damage to DNA near the target site. "Taken together, these data show the potential of Fanzor for human genome engineering applications," the team writes. "The eukaryotic origin of Fanzor and its relatively small size compared to Cas9/12 make it an attractive starting point for further development from a bioengineering perspective."
Source: Makoto Saiko (Broad Institute of MIT and Harvard, Cambridge) et al., Nature, doi: 10.1038/s41586-023-06356-2