Cambridge researchers have cracked a problem that has stumped diagnosticians for decades: how to accurately measure the genetic mutations that trigger muscular dystrophy, Huntington's disease, and amyotrophic lateral sclerosis in a fast, reliable way. Their solution borrows an elegant metaphor from paper folding—they've developed an "RNA origami" technique that folds genetic material into precise shapes, then threads it through a nanopore to read its blueprint with unprecedented accuracy.
The stakes are enormous. Repeat expansion disorders affect approximately one in every 280 people, yet as many as 90 percent of those living with these conditions remain undiagnosed. The reason is frustratingly simple: current diagnostic tools were designed to work with DNA, not RNA, and they're notoriously bad at measuring the exact length of repeated genetic sequences. The traditional polymerase chain reaction method—the same PCR technology that became household knowledge during the COVID-19 pandemic—can distort the true size of these repetitions, while newer sequencing approaches frequently stumble when reading through repeated sections.
Why such precision matters becomes clear when you look at specific diseases. In myotonic dystrophy type 1, the most common form of muscular dystrophy in adults, a patient with roughly 50 repeats in the DMPK gene might experience only mild symptoms. But each additional repeat can dramatically shift the disease's trajectory toward a more severe presentation—one that may pass down to children with even more serious consequences. In congenital central hypoventilation syndrome, a difference of just six repeats can determine whether a newborn breathes normally or faces dangerous respiratory failure during sleep.
The Cambridge team, led by Gerardo Patiño‑Guillén from the Cavendish Laboratory, took a different approach entirely. Working with colleagues from the University of Belgrade in Serbia, they engineered a method to stretch RNA molecules into labeled nanostructures using short pieces of DNA, then guided those folded molecules through a nanopore—a tiny glass hole that reads the electrical signals produced as the RNA passes through. The pattern of electrical signals reveals exactly how many repeats the molecule contains, with a resolution of just 18 nucleotides, the basic building blocks of RNA and DNA. That level of precision is enough to distinguish between healthy and disease-associated repeat sections.
"RNA is incredibly informative in terms of what it can tell you about the disorders we want to study, but it's also incredibly fragile and often challenging to study," Patiño‑Guillén explained. "Current techniques were designed for DNA, so they often lose the information in RNA that signals disease. We wanted to fix that."
The breakthrough carries practical significance beyond mere accuracy. Clinical settings often work with only tiny amounts of patient material, yet this RNA origami method requires extremely small quantities to produce reliable results—a feature that caught the attention of the Serbian collaborators. The findings were published in Nature Communications, representing a foundational advance in how doctors might diagnose these disorders in the future. While the team has achieved promising results in the laboratory, their next focus is translating this technology into real clinical diagnostics that could transform how millions of undiagnosed patients access answers.