Picture this: a breakthrough technology that could potentially erase devastating genetic diseases from our lives, but only if we fully grasp its quirks in the most complex parts of our body. CRISPR-Cas9 has been hailed as a game-changer for fixing faulty genes across various ailments, yet when it comes to tackling brain-related genetic disorders, things haven't been smooth sailing in the lab. Now, scientists have uncovered the root of the problem, revealing that neurons and other cells that don't divide play by entirely different rules when it comes to genome editing. This could transform how we approach therapies for neurological conditions—sounds intriguing, doesn't it? But here's where it gets controversial: what if harnessing this knowledge means navigating uncharted ethical waters? Let's dive in and unpack what this means for the future of medicine.
The study, detailed in a paper published in Nature Communications (link: https://www.nature.com/articles/s41467-025-66058-3), comes from experts at Gladstone Institutes, the Innovative Genomics Institute, and UC Berkeley. They show that neurons (the specialized cells in our nervous system that transmit signals, much like electrical wires in a vast network) and other nondividing cells handle CRISPR-Cas9 gene editing (a method to precisely alter DNA sequences) in ways that starkly contrast with dividing cells, such as those found in skin or blood that replicate regularly.
'Our discoveries could reshape the blueprint for developing gene editing treatments,' notes Bruce Conklin, MD, a Gladstone Senior Investigator who spearheaded the research. He adds, 'To achieve the desired results from genome modifications, we must master the art of DNA repair after the cuts. And these repair processes are especially poorly understood in cells that don't divide.'
At its core, gene editing employs a protein named Cas9 as tiny molecular scissors to snip specific sections of DNA and modify the genetic code. In this fresh investigation, the team unearthed that these edits yield vastly different results in neurons compared to the dividing cells traditionally studied. 'The majority of CRISPR research has centered on cells that multiply, but we've learned the guidelines for genome editing shift dramatically in nondividing cells like neurons,' explains Gokul Ramadoss, a Ph.D. candidate in Conklin's lab and the study's lead author. 'This stems from the fact that various cell types mend DNA damage—such as the incisions from Cas9—in wholly unique manners.'
The researchers hypothesized that neurons' distinct DNA repair arsenal might alter their response to Cas9's precise cuts. And this is the part most people miss—understanding these differences could unlock safer and more effective treatments, but it also raises questions about predictability and control.
To explore this, they first needed a reliable method to introduce controlled amounts of CRISPR-Cas9 into neurons. Conklin partnered with Jennifer Doudna, Ph.D., a Gladstone Senior Investigator and Nobel laureate for pioneering CRISPR technology. Her team created nanoparticles known as 'enveloped delivery vehicles'—think of them as tiny, safe carriers—that can shuttle gene editing tools into cells effectively. Together, they proved these vehicles work for delivering Cas9 into neurons, opening the door to studying neuronal responses.
Next, the team turned to induced pluripotent stem cells (iPS cells), which are versatile cells derived from sources like skin or blood that can be reprogrammed to become almost any cell type, including neurons. By comparing dividing iPS cells with their nondividing neuronal counterparts (both from the same genetic blueprint), they eliminated genetic variability and focused on the key distinction: one divides, the other doesn't.
Even with identical Cas9 doses and DNA targets, the outcomes differed wildly. Cas9 lingered far longer in neurons—for up to a month—versus just a few days in dividing cells. 'This raises significant safety flags,' Conklin warns. 'A longer presence of Cas9 increases opportunities for intended edits, which is great, but it also boosts the risk of unintended, off-target changes we want to avoid. We'll need to account for this in therapeutic designs.'
But here's where it gets even more fascinating—and potentially divisive. Once the DNA cuts healed, the repaired sequences in neurons were strikingly different, offering only a narrow range of possible modifications compared to the broad spectrum in dividing cells. Conklin illustrates this with a vivid analogy: 'Think of the Mona Lisa being slashed with a razor. Would you prefer a crowd of amateurs patching it up haphazardly—one with duct tape, another with glue, and yet another with staples? Or a single skilled restorer who consistently uses the best techniques?'
Because neurons have fewer repair options, their outcomes are more consistent and accurate—a double-edged sword, perhaps, as it might limit flexibility but enhance reliability. Even more astonishingly, the edited neurons switched on DNA repair genes that scientists believed were off-limits to nondividing cells. By delving into these genes, the team discovered fresh strategies to steer neuronal editing toward better results. 'We also applied these tactics to other crucial nondividing cells, like heart muscle cells,' Conklin shares. 'Overall, these insights will empower us and fellow researchers to fine-tune the safety and effectiveness of gene editing.'
While they're still puzzling out why neurons activate these unexpected repair genes, they've crafted innovative solutions. Collaborating with Niren Murthy, Ph.D., a UC Berkeley bioengineering professor, they engineered lipid nanoparticles to deliver gene editing tools alongside inhibitors for specific neuronal repair genes. This all-in-one system allows precise DNA cuts while dictating the repair process. 'It's akin to performing surgery on the genome,' Ramadoss says. 'Previously, we could make the incision but not guide how the DNA is sewn back together. Now, we're forging the repair instruments to guarantee the correct outcome.'
Crucially, this adaptable platform extends to other editing proteins, cell types, and diseases, broadening its impact. 'Our endgame is to master gene editing for transformative treatments,' Conklin concludes. 'With these new tools, we're closer to getting it precisely right.'
For more details, check out the full study by Gokul N. Ramadoss et al., 'Characterizing and controlling CRISPR repair outcomes in nondividing human cells,' in Nature Communications (2025), DOI: 10.1038/s41467-025-66058-3 (https://dx.doi.org/10.1038/s41467-025-66058-3).
This article was originally published on phys.org as 'The genome editing playbook is different in neurons and other nondividing cells, researchers discover' (2025, November 18), retrieved 18 November 2025 from https://phys.org/news/2025-11-genome-playbook-neurons-nondividing-cells.html. Copyright applies; reproduction without permission is prohibited.
So, what do you think? Does this discovery excite you about the potential for curing brain disorders, or does the idea of lingering Cas9 and off-target edits make you uneasy? Could precise genetic control in neurons lead to unprecedented treatments, or does it veer too close to playing God with our DNA? Share your views in the comments—do you agree this is a step forward, or should we tread more cautiously?
