In laboratories in Singapore, researchers have cracked open a longstanding puzzle: how the invisible folds of RNA molecules shape whether we get sick or stay well. The A*STAR Genome Institute of Singapore has developed sm-PORE-cupine, a breakthrough technology that reads individual RNA molecules and maps their unique structures, finally allowing scientists to see what was previously hidden in the blur of billions of identical-looking strands.
RNA has long been known as the cell's messenger, the molecule that carries genetic instructions from DNA to build proteins. But RNA is far more than a simple delivery system. Like a string that can twist, knot, and coil in countless ways, RNA can fold into different shapes—and those shapes matter enormously. The way an RNA molecule bends determines how quickly proteins get made, how long the RNA survives in the cell, and how diseases from viral infections to genetic disorders unfold. Until now, scientists could only see the average shape across millions of molecules, missing the crucial differences that occur in individual strands.
The challenge has always been RNA's restless nature. It bends and shifts constantly, never holding still long enough for a clear picture. Existing methods could not capture this dance at the level of single molecules. The team at A*STAR GIS solved this by combining chemical labeling with nanopore direct RNA sequencing. They used optimized chemical compounds to mark exposed parts of the RNA—the sections that aren't paired with other bases—leaving signposts that reveal the molecule's fold pattern. Then nanopore sequencing reads the entire RNA strand, and advanced computational analysis interprets what the signposts reveal. The result: scientists can now see how individual RNA molecules from the same gene fold differently and behave in distinct ways.
What they found was striking. Different RNA structures from the same gene correlate with different rates of protein production and different lifespans for the RNA molecules themselves. These differences in efficiency and stability are core to gene regulation, the master switch that controls when cells do what they're supposed to do. When gene regulation goes wrong, disease follows. By illuminating how RNA structure drives these outcomes, sm-PORE-cupine opens new windows into why cells malfunction in illness.
The implications ripple outward quickly. The researchers identified connections between RNA structure and viral function, including in SARS-CoV-2, suggesting that targeting specific RNA shapes could lead to new antiviral and antifungal treatments. RNA-targeted therapies, once theoretical, now look more achievable. Dr. Wan Yue, Executive Director at A*STAR GIS and lead author of the research published in Nature Methods, framed the moment clearly: the work "lays the foundation for more precise approaches to diagnosis and treatment." His colleague, Dr. Niranjan Nagarajan, emphasized the team's distinctive advantage: nanopore sequencing has given them a "unique capability to study the dynamics of how RNAs shape-shift."
Looking ahead, this technology promises to reshape disease diagnostics, drug discovery, and precision medicine. As researchers apply sm-PORE-cupine to more biological samples and organisms, they will likely uncover new therapeutic targets and understand disease mechanisms at depths previously unreachable. In the longer term, the ability to read RNA structure at single-molecule resolution could become as foundational to medicine as DNA sequencing has become to genetics.