A new AI-powered gene-editing technique could be set to replace CRISPR

CRISPR may be in for a fight thanks to this new, faster, safer, AI-powered zinc-finger gene-editing technique.
Christopher McFadden
Could this new technique replace CRISPR?


A new study has developed what the researchers call the "world's first" simple, modifiable proteins. Called "zinc fingers," these special proteins were developed partially through artificial intelligence.

Scientists from the University of Toronto and the NYU Grossman School of Medicine came up with the method, which is expected to speed up the development of gene therapies. This could be a game-changer for how doctors treat DNA mistakes that happen over time. This is partly because our genes change naturally as we age, which makes it inevitable that mistakes will happen. Or, of course, from genetic disorders inherited at birth.

Errors in the sequence of DNA letters that code the instructions for each human cell lead to diseases like cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. With the help of gene editing techniques that rearrange these letters, scientists may sometimes fix these errors.

Other disorders are brought on by issues with how the cellular machinery reads DNA rather than a flaw in the coding itself (called epigenetics). A gene, which tells the cell how to make a specific protein, often works with other molecules called transcription factors to tell the cell how much of that protein to make.

Overactive or underactive genes play a role in neurological diseases, diabetes, and cancer when this process goes wrong. As a result, scientists have been looking into ways to get epigenetic activity back to normal.

Zinc-finger editing is one such method that can alter and regulate genes. Zinc fingers are one of the most common types of protein structures in the body. They can guide DNA repair by grabbing enzymes that look like scissors and telling them to cut out the wrong parts of the code.

In case you are unaware, a zinc finger is a small protein structural "motif" characterized by the coordination of one or more zinc ions by a group of amino acid residues. Zinc fingers are usually made up of several beta sheets and alpha helices, and cysteine and histidine residues hold the zinc ions together.

They are found in various proteins, including transcription factors, DNA-binding proteins, and enzymes. They are essential to many biological processes, such as repairing DNA, controlling how genes work, and interacting with other proteins.

Zinc fingers can attach to transcription factors and draw them toward a region of the gene that needs to be regulated. Genetic engineers can adjust any gene's activity by altering these instructions. The fact that it's hard to make artificial zinc fingers that can do a specific job is a disadvantage, though.

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Researchers would have to be able to figure out, out of a huge number of possible combinations, how each zinc finger interacts with its neighbor to make each desired genetic change. This is because these proteins connect to DNA in complex ways, so they would have to figure out how each zinc finger interacts with its neighbor.

AI was employed to help solve this incredibly complex problem

ZFDesign, a new technology created by the study's authors, gets around this problem by modeling and designing these interactions using artificial intelligence (AI). The screen of over 50 billion potential zinc finger-DNA interactions in the researchers' labs produced the data used to build the model.

“Our program can identify the right grouping of zinc fingers for any modification, making this type of gene editing faster than ever before,” says study lead author David Ichikawa, Ph.D., a graduate student at NYU Langone Health.

Ichikawa says that zinc-finger editing could be a safer alternative to CRISPR, a key gene-editing technology that can be used to find new ways to kill cancer cells and make crops with more nutrients. Clustered Regularly Interspaced Short Palindromic Repeat, or CRISPR, uses proteins from bacteria to interact with genetic code, while zinc fingers are made only by humans.

These "foreign" proteins may cause patients' immune systems to become activated, which could cause them to attack them like any other infection and cause harmful inflammation.

The authors think zinc-finger tools may be more beneficial for gene therapy than CRISPR because they are smaller and pose less risk to the immune system. This is because there are more ways to get the tools to the suitable cells in a patient.

“By speeding up zinc-finger design coupled with their smaller size, our system paves the way for using these proteins to control multiple genes [simultaneously],” says senior study author Marcus Noyes, Ph.D., an assistant professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone.

“In the future, this approach may help correct diseases [with] multiple genetic causes, such as heart disease, obesity, and many cases of autism,” he added.

Noyes and his team used a specially made zinc finger to mess with the coding sequence of a gene in human cells. This was done to test the computer's AI design code. Also, they made several zinc fingers that changed the way transcription factors attached to a target gene sequence and how that gene was expressed.

This proved that they could apply their technology to alter epigenetics.

Zinc fingers are interesting, but Noyes says they can be hard to deal with. Since some combinations are not necessarily unique to a single gene, they can change DNA sequences that are not the target. This can cause unintended changes to the genetic code.

Noyes says that because of this, the team's AI algorithm will be improved to make more accurate groups of zinc fingers that only trigger the needed change.

You can read the study for yourself in the journal Nature Biotechnology.

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