Scientists develop novel one-step method for multiple genome edits
Researchers at Gladstone Institutes have created a groundbreaking technique that allows for simultaneous, precise edits at multiple locations within a cell’s genome, potentially revolutionising genetic research and therapeutic development.
A new frontier in genome editing
In a significant leap forward for genetic engineering, scientists at Gladstone Institutes have unveiled a novel method that enables multiple, precise edits to a cell’s genome in a single step. This innovative approach, detailed in a study published in Nature Chemical Biology [1], utilises molecules called retrons to create a tool capable of efficiently modifying DNA in bacteria, yeast, and human cells.
The breakthrough, spearheaded by Associate Investigator Seth Shipman, PhD, and his team, addresses a longstanding limitation in genome editing technology. Until now, researchers were constrained to editing cells in one location at a time, a process that was both time-consuming and laborious. “We wanted to push the boundaries of genomic technologies by engineering tools to help us study the true complexity of biology and disease,” says Shipman, who is also an associate professor in the Department of Bioengineering and Therapeutic Sciences at UC San Francisco and a Chan Zuckerberg Biohub Investigator.
The power of multitrons
The cornerstone of this new method is the development of engineered retrons, dubbed ‘multitrons’. These molecular tools are capable of generating different portions of DNA simultaneously, allowing for multiple edits to be made to a cell’s genome in one go.
Alejandro González-Delgado, PhD, a postdoctoral scholar in Shipman’s lab and one of the first authors of the study, explains the significance of this advancement: “If you wanted to edit a cell in multiple locations of the genome that are not near each other, the standard approach before now was to make the modifications one after the other. It was a laborious cycle: you would first make an edit, then you would use the edited cells to introduce another edit, and so on.” The multitron system not only streamlines this process but also introduces the ability to delete large sections of the genome. González-Delgado elaborates: “With multitrons, we can make sequential deletions to cut out and collapse middle portions of the genome region we’re targeting, bringing the far-apart ends closer together until the entire region is completely deleted.”
Applications in molecular recording and metabolic engineering
The researchers have already demonstrated immediate applications for their new method in two key areas: molecular recording and metabolic engineering. In the field of molecular recording, multitrons expand upon previous work by Shipman’s team, which used retrons to create a detailed log of a cell’s activity and environmental changes. The new system enhances this capability, allowing for the simultaneous recording of both weak and strong signals, thereby increasing the sensitivity and dynamic range of cellular recordings.
“Eventually, we could imagine implementing this type of tool in the gut microbiome to record a signal like inflammation,” González-Delgado suggests, hinting at potential future applications in monitoring complex biological processes.
In the field of metabolic engineering, the team showcased the multitrons’ ability to simultaneously edit multiple genes in a metabolic pathway, rapidly increasing the production of targeted substances within cells. As a proof of concept, they successfully boosted the production of lycopene, a powerful antioxidant, by threefold.
Implications for complex disease modelling
The development of multitrons represents a significant step towards more comprehensive modelling of complex genetic diseases. Shipman emphasises the potential impact of this technology: “In order to start modelling complex genetic diseases and eventually find treatments or cures, we need to make many different mutations to cells at once. Our new approach is a step toward that.” By enabling researchers to introduce multiple genetic modifications simultaneously, this technique could accelerate the pace of genetic research and potentially lead to breakthroughs in understanding and treating complex disorders with genetic components.
Future prospects
While the current study demonstrates the efficacy of multitrons in bacteria, yeast, and human cells, the potential applications of this technology are far-reaching. As researchers continue to refine and expand upon this method, it could open new avenues for genetic research, drug discovery, and personalised medicine. The ability to make multiple, precise genetic modifications simultaneously not only streamlines the research process but also allows for the creation of more accurate models of complex genetic interactions. This could prove invaluable in unravelling the intricacies of polygenic disorders and developing targeted therapies.
Reference:
1. González-Delgado, A., Lopez, S. C., Rojas-Montero, M., et. al. (2024). Simultaneous multi-site editing of individual genomes using retron arrays. Nature Chemical Biology.
https://doi.org/10.1038/s41589-024-01665-7
