In many hereditary diseases, the problem lies deep in the genes: A single «wrong letter» in the DNA can trigger severe metabolic disorders or degenerative diseases. New approaches such as base editing promise to correct these errors precisely. But one crucial question has remained unanswered so far: Where in the body does gene therapy actually work—and in which cells?
A research team at the University of Zurich has now found an answer. In collaboration with partners from Canada and the USA, they developed a method that shows where in the tissue the genetic material has been successfully modified. The technique, called in situ sequencing, was recently presented in the journal Nature Biomedical Engineering and is regarded as an important step towards better assessing the safety and effectiveness of future gene therapies.
A window into the cells
In situ sequencing allows researchers to make the molecular «footprints» of gene editing visible directly in tissue samples without destroying them. The method combines modern microscopy with image-based sequencing. Individual RNA molecules that reveal the genetic modification are detected in their natural environment. For the first time, this enables scientists to see, with high spatial resolution, which cells were actually edited and where the therapy was active within an organ. Until now, analyses of gene editing results were only possible as averaged values across the entire tissue.
Successful application in the brain and liver
In experiments on mice and macaques (non-human primates), the researchers tested the new technique on two organs that are particularly important for gene therapies: The brain and the liver. They found that so-called base editors—enzymes that specifically alter individual nucleotides in the genome—were mainly active in nerve cells, while astrocytes were less often affected. In the liver, analyses showed that nearly all functional zones—from regions near the blood vessels to metabolically active areas—were evenly edited.
Professor Gerald Schwank summarized the significance of the findings: «Our data show that spatial editing patterns can be reliably detected from mice to macaques. This shortens the bridge to clinical applications, since we can already see in preclinical studies whether the right cell types in the relevant organ zones are being reached.»
The researchers also demonstrated that the therapy remained stable and safe even after multiple rounds of treatment. To do so, they used RNA-encoded base editors, a technology similar to the well-known mRNA vaccines. With repeated doses, editing efficiency remained constant, and no harmful immune reactions occurred.
Significance for the future of gene therapy
With this new method, researchers will be able to better understand how and where gene therapies take effect in the body. The precise mapping of edits within tissues helps fine-tune therapeutic approaches and detect unwanted effects early. In situ sequencing also allows comparisons of the spatial distribution of edited cells across different disease models—such as between the brain, heart, and liver. This makes the technique an essential link between basic research and clinical practice, helping to make gene therapies both more precise and safer.
Challenges and next steps
As promising as the method is, the researchers also see challenges ahead. In situ sequencing depends on the activity of the target genes. If a gene is only weakly expressed, edits become harder to detect. The technical demands are also high: Image acquisition and data analysis require specialized equipment and software. Nevertheless, the potential is great enough that in situ sequencing could one day become a standard tool for quality control in gene therapy.
This study highlights Switzerland’s strong position in cutting-edge biomedical research. Innovations like the in situ sequencing technology developed in Zurich contribute to making gene therapies safer and more precise, bringing the vision of personalized medicine a step closer. Because only if we understand where gene editing takes place, we can ensure that it achieves the desired effects.
Sources
1. Janjuha, S., Haenggi, T., Chamberlain, T.C. et al. Spatial profiling of gene editing by in situ sequencing in mice and macaques. Nat. Biomed. Eng. 19 September 2025. DOI: 10.1038/s41551-025-01512-7
(Image: Google DeepMind / Unsplash)
