Beyond Bacteria: A New Gene Editing Tool Revealed in Complex LifeNews
The Context: CRISPR is a powerful gene editing tool that allows scientists to make changes in the DNA of cells for research or treatment purposes. The CRISPR system was originally discovered in bacteria, but scientists did not believe it could have a counterpart in more complex organisms.
The Study: A gene editing system similar to CRISPR – called ‘Fanzor’ after the proteins it employs – exists in complex life including fungi, algae, amoebas, and a species of clam. The Fanzor system uses RNA as a guide to edit DNA, and like the CRISPR system can be programmed by scientists to make specific edits to the genome of human cells. This research, published in Nature, was led by NYSCF – Robertson Stem Cell Investigator Alumnus Feng Zhang, PhD, of MIT.
The Importance: The Fanzor system is the first gene editing system discovered in eukaryotes. It holds several advantages over CRISPR, as it is more compact and could be more easily delivered to cells, making it a potentially beneficial option for gene therapies.
“CRISPR-based systems are widely used and powerful because they can be easily reprogrammed to target different sites in the genome,” Dr. Zhang told MIT News. “This new system is another way to make precise changes in human cells, complementing the genome editing tools we already have.”
Looking to the Natural World
Dr. Zhang is well known for his proclivity to search nature for clues as to how to develop tools that accelerate research and therapies in humans. His work with CRISPR was informed by bacteria, and he began wondering if a similar system existed in eukaryotes (complex species whose cells have nuclei, unlike bacteria).
Learn more about NYSCF’s gene editing research
“A number of years ago, we started to ask, ‘What is there beyond CRISPR, and are there other RNA-programmable systems out there in nature?’” he shared.
“People have been saying with such certainty for so long that eukaryotes couldn’t have a similar system,” Ethan Bier, PhD, a geneticist at the University of California San Diego, who uses gene editing in his work but was not involved in the study, told Live Science. “But it’s typical cleverness from the Zhang lab, proving them wrong.”
For years, the Zhang lab has been studying how the CRISPR system evolved in bacteria. One of CRISPR’s main components is its ‘scissors’ – made of proteins called Cas9 – that lets it make cuts in DNA. The team knew that these special scissor proteins evolved from a type of bacterial protein called OMEGAs, so they then wondered if other descendants of OMEGAs could be modifying DNA in other organisms.
Specifically, they turned their attention to a type of protein called ‘Fanzor proteins,’ who show similarities to the OMEGAs found in bacteria.
The scientists scoured databases of proteins to see which animals Fanzor proteins live in. The result: fungi, algae, amoebas, and a species of clam. Further analyses of the Fanzor proteins revealed that they can, in fact, make cuts like CRISPR’s Cas9 scissors by targeting RNA – the molecule that ‘reads’ DNA and tells it what kind of protein to make.
Gene Editing with Fanzor Proteins
Initial tests to see if Fanzor proteins could make designated edits in human cells were promising, if not perfect. The first tests showed 12% efficiency. Some tweaks bumped that up to 18%. But it’s early days, and even CRISPR, which is now extremely accurate, started out with shaky efficiency.
Excitingly, the Fanzor system is more compact and could be more easily delivered to cells than CRISPR, making it a potential future option for gene therapies.
Dr. Zhang suspects that the Fanzor proteins aren’t the only ones with gene editing capabilities in eukaryotes either.
“Nature is amazing. There’s so much diversity,” he said. “There are probably more RNA-programmable systems out there, and we’re continuing to explore and will hopefully discover more.”
Read more in:
Fanzor is a eukaryotic programmable RNA-guided endonuclease
Makoto Saito, Peiyu Xu, Guilhem Faure, Samantha Maguire, Soumya Kannan, Han Altae-Tran, Sam Vo, AnAn Desimone, Rhiannon K. Macrae & Feng Zhang. Nature. 2023. DOI: https://doi.org/10.1038/s41586-023-06356-2
Cover image: Pictured is a Cryo-EM map of a Fanzor protein (gray, yellow, light blue, and pink) in complex with ωRNA (purple) and its target DNA (red). A non-target DNA strand is in blue. Image credit: Zhang lab.