Cancer cells are excellent at evading detection, but subtle chemical differences distinguish them from healthy cells. Now a team of scientists from Wageningen University and Research Institute and the Van Andel Institute has identified a way to exploit this difference. They used a variant of CRISPR, the latest tool for DNA editing, to distinguish between tumor DNA and healthy DNA, selectively cutting only the former. This research today natureis an early but promising step toward cancer treatment that targets and destroys tumor cells with high precision.
The new method relies on methyl groups, small chemical tags attached to DNA that control turning genes on and off. This process, called DNA methylation, changes within cancer cells and acts as a molecular “fingerprint” that distinguishes malignant cells from healthy ones.
High-precision gene editing with ThermoCas9
The research team conducted the study using ThermoCas9, a CRISPR variant discovered in bacteria several years ago by Dr. John van der Oost from Wageningen. Like other CRISPR systems, researchers can program ThermoCas9 to find and cut specific parts of DNA within cells. Dr. Hong Li and her lab at VAI analyzed the structure of ThermoCas9 and found that it can distinguish between unmethylated and methylated genes.
The team then introduced ThermoCas9 into human cells grown in culture dishes. That is, one set of dishes contains healthy cells and another set contains tumor cells. This approach worked. ThermoCas9 cut the DNA of tumor cells while leaving healthy DNA intact. The system thus proved capable of detecting and acting on subtle chemical differences between healthy and tumor cells.
ThermoCas9 is the first CRISPR-associated enzyme that responds to the most abundant type of DNA methylation differences in humans and other eukaryotic cells. This means we now have a system that can specifically target tumor cells. ”
John van der Oost, Ph.D., Wageningen University and Research
This study is the first time that a CRISPR-based method relies on methylation to target human cancer cells.
“ThermoCas9 uses methylation like an address to precisely target cancer cells while leaving healthy cells unaffected,” Li said. “This discovery could be a game changer.”
accurate molecular fit
The explanation for ThermoCas9’s selective behavior lies in the way ThermoCas9 binds to DNA. Before the CRISPR system can cut DNA, it must first bind to a short recognition sequence next to its target known as PAM (protospacer adjacent motif). ThermoCas9 is unique in that the PAM sequence contains a human methylation site, meaning it can contain methyl groups.
“The CRISPR system binds to this recognition code very precisely,” Van der Oost explained.
Compare it with a screwdriver that perfectly fits the corresponding screw head. If there are any protrusions in the groove, the screwdriver will not fit into the groove and will no longer function as a screwdriver. Similarly, methyl groups break the compatibility between ThermoCas9 and DNA, preventing binding and leaving the DNA sequence intact.
“ThermoCas9 is a perfect example of the value of basic research. We need to know how these individual parts work together,” Li said. “We have used biochemistry and structural biology to discover mechanisms that may one day lead to more precise and effective cancer treatments.”
Steps toward clinical research
There is still a long way to go before this technology can be applied to potential cancer treatments. New research shows selective DNA cutting, but has not yet shown that this effect can kill tumor cells. The next step focuses on damaging tumor DNA enough to cause cell death.
Aberrant methylation patterns are also implicated in many other diseases, including childhood cancers such as neuroblastoma and autoimmune diseases. In the future, ThermoCas9 or similar CRISPR tools could evolve into versatile molecular strategies that recognize and selectively disable diseased cells through chemical “signatures.”
sauce:
Reference magazines:
Ross, Missouri; Others. (2026). Molecular basis of methylation-sensitive editing by Cas9. nature. DOI: 10.1038/s41586-026-10384-z. https://www.nature.com/articles/s41586-026-10384-z
