The next quantum leap in gene technology is just around the corner

Breaking new ground 4. okt 2021 2 min Research director, professor Guillermo Montoya Written by Kristian Sjøgren

A new tool for cutting genetic material holds enormous potential because it can do things that current technologies cannot. However, the tool must be studied in more detail and refined, and researchers in Denmark have enabled this by mapping the structure of the genetic scissors.

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Most people who are interested in gene technology have heard of CRISPR, the common name for the CRISPR-Cas9 technology.

Over the past decade, this has revolutionized how researchers can very precisely cut DNA to remove parts of the genome or insert new elements, providing numerous associated advances in research and medical science.

The next step towards even better CRISPR technology may be just around the corner.

CRISPR-Cas9 has a distant cousin called the CRIPSR-Cas12j (also known as Cas_phi) family, and this gene-editing enzyme can probably be developed into an even more potent genetic engineering tool.

First, however, the structure of CRISPR-Cas12j must be mapped so that researchers can refine these genetic scissors, and researchers in Denmark have just done this.

“CRIPSR-Cas12j has already been tested in cells from both humans and plants, so we know that it works. However, it needs to be improved, and this requires knowing the structure of the Cas12j enzyme. We have now mapped it and found that it is different from the other CRISPR systems,” explains a researcher behind the study, Guillermo Montoya, Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The research has been published in Nature Communications.

Originates from bacteria’s worst nightmare

CRISPR-Cas12j comes from the archenemy of all bacteria: bacteriophages, which are viruses that infect bacteria.

The bacteriophages probably use CRISPR-Cas12j to defend themselves against other viruses by cutting their genome into pieces. This happens when the bacteriophages compete to be the first to infect a bacterium.

This property makes CRISPR systems interesting in research and in clinical practice. However, the various genetic scissors differ.

CRISPR-Cas12j has one overriding advantage over CRISPR-Cas9: the Cas12j enzyme is only half as big as Cas9.

“Because it is only half the size, we can use it for things we cannot use CRISPR-Cas9 for. For example, when we need to get the genetic scissors into a cell, we wrap them in an adenovirus, which means that there may be a lack of space if we combine the scissors with other regulatory elements that have a relatively long structure. With CRISPR-Cas12j, we have more space in the adenovirus, and this opens the possibility that we can use the genetic scissors to perform genetic editing that cannot be done with CRISPR-Cas9,” says Guillermo Montoya.

Mapping the structure by taking hundreds of images

Researchers from the University of Copenhagen used cryogenic electron microscopy to map the structure of CRISPR-Cas12j.

In cryogenic electron microscopy, researchers take many hundreds of images of a protein and then assemble the images into one three-dimensional structure.

Guillermo Montoya says that the mapping has revealed that the structure of CRISPR-Cas12j differs completely from that of CRISPR-Cas9 and other genetic scissors, but the actual cutting mechanism of the molecular scissors, in which it recognizes the DNA, has been preserved.

“The structure is different, but it retains the basic properties of an endonuclease enzyme. A kitchen, for example, enables you to cook. Cooking is the function of that space, but the way the kitchen is designed can differ vastly,” he explains.

Making the scissors more efficient

Now that the structure of CRISPR-Cas12j has been mapped, researchers can now study the enzyme in greater detail to improve its function.

As things stand, CRISPR-Cas12j can cut genetic material, but the enzymatic activity needs to be made better, more accurate and more efficient.

Once the researchers have solved those problems based on the new mapping, they can start using the next generation of genetic scissors.

These scissors can perform genetic clipping that researchers can only dream of today.

“This study enables us to see the enormous potential of CRISPR-Cas12j, primarily because it solves the package problem of getting the genetic scissors mechanism and other support molecules into an adenovirus,” says Guillermo Montoya.

Structure of the mini-RNA-guided endonuclease CRISPR-Cas12j3” has been published in Nature Communications. Several authors are employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The Montoya Group works to illuminate the molecular details of cellular processes. This knowledge is the basis for the understanding of diseases and t...

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