Ariana Drehsler/The New York Times

'Craspase' edits proteins instead of using RNA guide nucleases to make edits directly on the gene.

September 21, 2022

Cornell Prof. Discovers ‘Craspase,’ Utilizing Protein Cleaving Instead of Direct Gene Editing

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Prof. Ailong Ke, molecular biology and genetics, along with the Brouns Lab at Felt University of Technology in the Netherlands, recently discovered a relationship between a family of proteases and CRISPR that could change the way we understand gene editing technology.

CRISPR is a genetic engineering tool that identifies and alters a specific segment of DNA. The most common type of CRISPR system is RNA guided nucleases, which is when a ‘guide RNA’ guides the associated nucleus to the desired segment of the genome to edit the genome through base-pair interactions. 

Today, CRISPR is widely used in agriculture and even in genome editing of mosquitos to decrease the spread of malaria. Although CRISPR is more commonly used in non-human organisms, there are clinical trials to test if CRISPR can fix genetic defects and mutations that cause diseases and illnesses, such as cancer. 

One of the most dangerous aspects of CRISPR is that it edits directly onto the gene sequence, making permanent edits to the organism’s genome. For example, mistakes in gene editing can cause chromosome deletions, which typically leads to severe intellectual and physical disabilities.

These genetic edits could also cause unwanted mutation in heritable genes that can then be passed onto future generations. 

Although there is a lot of potential for RNA guided nuclease CRISPR systems the small percentage of error is still substantial enough for researchers to caution its application on human subjects. However, Ke and Brouns’ recent discovery of the ‘Craspase,’ a CRISPR guided caspase mediator between protease caspase and CRISPR, is less risky. 

Caspases are able to trigger cells to go through programmed cell death, safely removing them. Craspase is a system which utilizes CRISPR RNA guided RNA activated protease to edit proteins instead of using RNA guide nucleases to edit the genome bases directly. 

These proteases were once thought to be eukaryotic specific but this has since been debunked by Ke and his collaborators as they found that bacteria — a type of prokaryote — also have these caspase proteases that mediate cell programmed death, indicating its primitive nature. 

Ke explained that there is a lot of anticipation for Craspase because it will not edit and cleave base pairs directly on the genome but rather cleave the proteins that are generated by the nucleotides. 

Ke said that mistakes made during protein cleaving with ‘Craspase’ have minimal effects on the organism. He also added that CRISPR is inherently more dangerous because it uses enzymes, which cleave the building blocks of RNA and DNA, permanently changing genetic information.

“That’s why people are really excited when they see RNA guided proteases because we’re cleaving proteins,” Ke said. “If we make a mistake, then it’s not a big deal. So we can, in many cases, achieve the same therapeutic outcome without worrying about passing mistakes to the next generation.”  

The ability to cleave proteins instead of editing the genome directly has many implications for the future of gene therapy. This is a safer alternative that allows for a more varied application of the tool. 

This tool can also be programmed to trigger the cell death pathway, slow down growth of a signaling pathway or turn on a signaling pathway. Ke and his team were able to analyze macromolecules with atomic resolution, allowing for precise analysis and a deeper understanding of how these proteases function. 

Although CRISPR is still in the clinical trial stage and craspase hasn’t been used in health care yet, Ke is hopeful about the direction that gene editing technology is taking. He is hopeful that one day ‘craspase’ can be used for medical procedures.   

“I think that biology is entering a new era,” Ke said. “So with those powerful tools, I think we’ll be able to come up with therapeutics and new strategies against disease, aging and other outstanding problems. We can get there faster, with more powerful solutions.”