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    HomeBiologyCellREADR allows scientists to add any protein to a specific cell type

    CellREADR allows scientists to add any protein to a specific cell type

    An RNA-based editing tool has been created by Duke University researchers that targets specific cells rather than genes. Any cell type can be precisely targeted, and any protein of interest can be added only to that cell type. According to researchers, the CellREADR tool could make it possible to manage disease by changing very specific cells and cell functions.

    A team led by neurobiologist Z. Josh Huang, Ph.D., and postdoctoral researcher Yongjun Qian, Ph.D., showed using an RNA-based probe that they could introduce into cells fluorescent tags to label particular types of brain tissue, a light-sensitive on/off switch to silence or activate neurons of their choice, and even a self-destruct enzyme to precisely remove some cells while leaving others alone. The article debuts in Nature on October 5.

    Every animal’s cell contains the ADAR enzyme, which is essential to their specific cell monitoring and control system. Even though CellREADR (Cell access through RNA sensing by Endogenous ADAR) is still in its early stages, Huang said that it seems like there are no limits to the ways it could be used and the kinds of animals it could work with.

    According to Huang, the ability to monitor and control all cell types in any animal is now possible thanks to this technology. Despite their initial genetic susceptibility, he claimed that it was possible to change how some types of cells function in order to treat certain diseases. “With current treatments or medications, that is not possible.”

    A sensor, a stop sign, and a set of blueprints are the three main components that make up the adaptable string of RNA known as CellREADR.

    The research team first chooses the particular cell type that they want to study and then locates a target RNA that is only produced by that cell type. The remarkable tissue specificity of the tool depends on the production of a unique signature RNA by each type of cell.

    The complementary strand of the target RNA is then designed as a sensor sequence. RNA has the same magnetic potential to link with another piece of RNA if it has matching molecules, just as the rungs of DNA are made up of complementary molecules that are naturally attracted to one another.

    Both pieces of a sensor bind together to form a piece of double-stranded RNA after the sensor enters the cell and locates its target RNA sequence. Because of this new RNA fusion, the enzyme ADAR looks at the new product and changes one nucleotide in its genetic code.

    People think that all animal cells have the ADAR enzyme, which is a cell defense system made to fix double-stranded RNA when it happens.

    Knowing this, Qian used the exact same nucleotide that the ADAR edits in double-stranded RNA to create the stop sign for CellREADR. CellREADR’s sensor is very specific to a certain type of cell because the stop sign that keeps the protein blueprints from being built is only taken away when it docks to its target RNA sequence.

    The blueprints can then be read by cellular machinery that creates the new protein inside the target cell after ADAR removes the stop sign.

    Huang and his team tested CellREADR to the limit in their paper. “I recall when Yongjun built the initial iteration of CellREADR and tested it in a mouse brain two years ago,” Huang recalled. “To my astonishment, it worked brilliantly on his first attempt.”

    The team’s meticulous planning and design paid off, as they were able to show that CellREADR successfully added activity monitors and control switches where needed and accurately labelled specific brain cell populations in living mice. Rats and human brain tissue obtained from epilepsy surgeries both responded favorably to it.

    Dr. Derek Southwell, M.D., Ph.D., co-author and assistant professor in Duke’s department of neurosurgery, said, “With CellREADR, we can pick and choose populations to study and really begin to investigate the full range of cell types present in the human brain.”

    Southwell hopes that CellREADR will help him and others learn more about the wiring diagram for human brain circuits and the cells that make them up. This will help them find new ways to treat neurological disorders, like the promising new way he is testing to treat drug-resistant epilepsy.

    Given that this is what initially drew them both to science, Huang and Qian are especially optimistic about CellREADR’s potential as a “programmable RNA medicine” to potentially treat diseases. They have submitted a patent application for the technology.

    I was very naive when I majored in pharmacology as an undergraduate, said Qian. “I had a lot of ideas about what you could accomplish, like curing cancer, but it’s actually very challenging. But now I believe that perhaps we can pull it off.

    The US National Institute of Mental Health (1DP1MH129954-01), the US National Institute of Neurological Diseases and Stroke (Neurosurgery Research Career Development Program), and the Klingenstein-Simons Foundation all provided funding for the study.

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