By switching genes on and off, artificial intelligence software might make it possible to produce zinc fingers, the first simple, modifiable proteins.
The technique, which was developed by scientists from the University of Toronto and NYU Grossman School of Medicine, promises to hasten the widespread development of gene therapies.
Errors in the sequence of DNA letters that code for each human cell’s operating instructions lead to diseases like cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. In some circumstances, gene editing techniques that rearrange these letters can help scientists 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 (epigenetics). A gene, which contains the instructions for making a certain protein, frequently collaborates with molecules known as transcription factors to instruct the cell how much of that protein to produce. When this process goes wrong, neurological disorders, diabetes, and cancer are all caused by overactive or underactive genes. As a result, scientists have been looking into ways to get epigenetic activity back to normal.
Zinc-finger editing is one such method that has the ability to alter and regulate genes. Zinc fingers, one of the most common protein structures in the body, can control DNA repair by grabbing onto enzymes that resemble scissor-like structures and telling them to remove the wrong sections of the DNA code.
Similar to this, zinc fingers have the ability to attach to transcription factors and draw them toward a region of the gene that needs to be regulated. By changing these instructions, genetic engineers can modify the activity of any gene. The difficulty of designing artificial zinc fingers for a particular task is a disadvantage, though. Due to the complicated groups in which these proteins bind to DNA, it would be necessary for researchers to be able to determine how each zinc finger interacts with its neighbor for each intended genetic change.
The authors of the study developed a new technique called ZFDesign that circumvents this issue by modeling and creating these interactions using artificial intelligence (AI). The information needed to create the model was generated by screening over 50 billion potential zinc finger-DNA interactions in the labs of the researchers. The journal Nature Biotechnology will publish a paper about the tool online on January 26.
According to research main author David Ichikawa, Ph.D., a former graduate student at NYU Langone Health, This algorithm can select the proper grouping of zinc fingers for any mutation, making this type of gene editing faster than ever before.
Ichikawa points out that zinc-finger editing presents a potentially safer alternative to CRISPR, a crucial gene-editing technology with uses ranging from developing novel strategies to eradicate cancer cells to creating more nutrient-dense crops. CRISPR, which stands for clustered regularly interspaced short palindromic repeat, relies on bacterial proteins to interact with genetic code, in contrast to the wholly human-derived zinc fingers. Patients’ immune systems may be triggered by these “foreign” proteins, which could lead to them being attacked like an infection and resulting in severe inflammation.
The authors of the study suggest that, in addition to posing a lesser immunological risk, the smaller size of zinc-finger tools may offer more versatile gene therapy procedures than CRISPR by opening up additional options for delivering the tools to patients’ appropriate cells.
According to research senior author Marcus Noyes, Ph.D., this technique paves the way for using these proteins to control several genes at the same time by speeding up zinc-finger design paired with their lower size. Future applications of this strategy could aid in treating conditions including heart disease, obesity, and many forms of autism that have several genetic origins.
Noyes and his team used a specially made zinc finger to interfere with a gene’s coding sequence in human cells in order to evaluate the AI design code of the computer. Additionally, they developed a number of zinc fingers that successfully reprogrammed transcription factors to attach close to a target gene sequence and alter the expression of that gene. This demonstrated that they could modify epigenetics using their approach.
While promising, zinc fingers can be challenging to manage, according to Noyes, an assistant professor in NYU Langone’s Department of Biochemistry and Molecular Pharmacology. Some combinations can alter DNA sequences outside of their intended target since they are not always exclusive to a single gene, which can result in unintentional modifications to the genetic code.
In order to create more exact zinc-finger groupings that only trigger the necessary change, Noyes says the team will next improve its AI algorithm. Additionally, Noyes belongs to the Institute for System Genetics at NYU Langone.
