Scientists have discovered Fanzor proteins, which work like CRISPR but are smaller and easier to deliver to cells, and used them to edit human DNA. Researchers have discovered a new gene-editing system similar to CRISPR in complex organisms, demonstrating for the first time that DNA-modifying proteins exist in all kingdoms of life.
Feng Zhang, a biochemist at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, led the team and previously co-discovered the gene-editing potential of the CRISPR-Cas9 system, which functions as a kind of “molecular scissors” that remove sections of DNA, thereby disabling genes or allowing them to be replaced with new ones.
Before this discovery, such systems had only been found in simple organisms like bacteria and archaea, which use them as a kind of rudimentary immune system to shred the DNA of invaders. The researchers found the new system, called Fanzor, in fungi, algae, amoebae and one species of mollusc, significantly expanding the groups known to use these genetic tools.
After publishing their first paper on CRISPR in 2013, Zhang and his colleagues began studying how these systems evolved. During this work, the group identified a class of proteins in bacteria called OMEGAs, which are thought to be early ancestors of Cas9 proteins, the “scissors” of the CRISPR system. They began to suspect that Fanzor proteins, a type of OMEGA, could also modify DNA.
Scientists have discovered a CRISPR-like system in complex cells for the first time. ARTUR PLAWGO/SCIENCE PHOTO LIBRARY
The team searched online databases for the proteins and were surprised to find several in samples isolated from fungi, protozoa, arthropods, plants and giant viruses. Zhang said the idea is that the genes needed to make Fanzor proteins were shuffled from bacteria into complex organisms through a process known as horizontal gene transfer. The genes encoding Fanzor proteins were integrated into the genomes of eukaryotic organisms in transposable elements, pieces of DNA that can move around the genome and replicate.
During their experiments, the researchers found that Fanzor proteins have some similarities with CRISPR. Fanzor proteins also interact with guide RNA, a molecule that directs proteins to the DNA they are meant to cut. This molecule, called omegaRNA, complements the target DNA strand. When they match, the two pieces snap together, and Fanzor can then cut the DNA.
The team tested the Fanzor system on human cells, but initially found that it was relatively inefficient at adding or removing DNA fragments, completing the process successfully about 12% of the time. However, after some creative engineering to improve and stabilize the system, the researchers raised the efficiency to just over 18%.
Fanzor is likely to complement CRISPR technology, which has been used in both research and experimental treatments for diseases such as blindness and cancer. Compared with CRISPR, “Fanzor systems are more compact and therefore have the potential to be more easily delivered to cells and tissues,” Zhang said, and they are less likely to accidentally degrade nearby RNA or DNA — so-called off-target or side effects. That makes Fanzor attractive for use in gene therapy.