New one-step method to make multiple edits to a cell’s genome

Genome editing is a widely adopted technology for modifying DNA in cells, enabling scientists to study diseases in the lab and develop therapies that repair disease-causing mutations. However, current methods allow for editing cells at only one location at a time. So scientists have developed the New one-step method to make multiple edits to a cell’s genome.

Date	July 9, 2024
Source	Gladstone Institutes
Summary	Scientists have created a new, highly efficient method for making several precise edits to human cells simultaneously. This breakthrough technique uses molecules called retrons to enable precise modifications in multiple locations within a cell at once. The tool has proven effective in altering DNA in bacteria, yeast, and human cells.

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What are Retrons

Shipman is a pioneer in the emerging field of retrons, molecular components from a bacterial immune system that can produce large quantities of DNA. In 2022, his lab combined retrons with CRISPR-Cas9 genome editing to create a system for quick and efficient human cell editing.

New Study of Retrons

In their new study, the researchers sought to overcome the limitation of current genome editing methods. “If you wanted to edit a cell at multiple genome locations that aren’t near each other, the standard approach was to make the modifications sequentially,” explains Alejandro González-Delgado, PhD, one of the study’s first authors and a postdoctoral scholar in Shipman’s lab. “This laborious cycle involved making an edit, using the edited cells to introduce another edit, and so on.”

Experiment of Retrons

The team encoded a retron to generate different DNA portions. When delivered to a cell, these engineered retrons—called multitrons—can make multiple edits simultaneously. Another advantage of multitrons is their ability to delete large genome sections. “Multitrons allow us to make sequential deletions, collapsing middle portions of the genome and bringing far-apart ends closer until the entire region is deleted,” Gonzalez-Delgado explains.

Application of New one-step method to make multiple edits to a cell’s genome

• Shipman and his team demonstrated immediate applications for their new method in molecular recording and metabolic engineering.
• Retrons can record molecular events in a cell, providing a detailed log of the cell’s activity and environmental changes.
• Multitrons expand this approach, allowing for recording with greater sensitivity. “Multitrons let us record both very weak and very strong signals simultaneously, broadening the dynamic range of our recordings,” says Gonzalez-Delgado. “We could eventually implement this tool in the gut microbiome to record signals like inflammation.”
• In metabolic engineering, the scientists showed that multitrons could simultaneously edit multiple genes in a metabolic pathway, rapidly increasing the production of a targeted substance.
• They tested their approach on a powerful antioxidant called lycopene, successfully increasing its production threefold.

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Next Aim of Experiment:

“To model complex genetic diseases and eventually find treatments or cures, we need to make many different mutations to cells at once,” says Shipman, also an associate professor in the Department of Bioengineering and Therapeutic Sciences at UC San Francisco and a Chan Zuckerberg Biohub Investigator. “Our new approach is a step toward that goal.” This is the aim of the new one-step method to make multiple edits to a cell’s genome.

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