Weizmann-led team finds nature already uses a trick behind modern RNA drugs

An international team co-led by Prof. Schraga Schwartz of the Weizmann Institute of Science has discovered the first known natural chemical modification of the RNA backbone. The study, published in the journal Cell on 18 September 2026, brought together researchers from Israel, Japan, Germany, the United States, France, Poland and Austria, including groups at Tokyo Metropolitan University, the University of Regensburg and Tel Aviv University.

More than 150 chemical decorations of RNA were already known, but all of them sit on the molecule's bases or sugars. None had been reliably found on the phosphate backbone that links the RNA chain together. The team developed new sequencing and mass-spectrometry methods able to pinpoint such changes letter by letter, and used them on RNA from archaea, single-celled microbes that thrive in boiling hot springs. They found phosphorothioates, spots where a sulfur atom replaces one of the backbone's oxygen atoms, at highly specific and conserved positions in the ribosomal and transfer RNAs that build proteins, including near the ribosome's catalytic heart.

The amount of modification rose and fell with the availability of sulfur and with temperature, and the researchers identified a previously unknown family of enzymes that installs it. Microbes lacking these enzymes either could not grow at all or grew poorly at high temperatures, suggesting the sulfur swap helps stabilise RNA in extreme heat. All of the natural modifications had the same mirror-image form.

The finding has a practical side. Phosphorothioate linkages are built into most RNA-based drugs, such as antisense and silencing therapies, because they protect the molecules from being chewed up by enzymes in the body. Making them chemically produces a mixture of two mirror-image forms, so the newly discovered enzymes could offer a way to produce cleaner, more uniform RNA medicines. As Regensburg co-author Dina Grohmann put it, archaea had developed this form of RNA stabilisation long before chemists did.