Researchers would like to better understand four-stranded RNA structures called RNA G-quadruplexes (RG4s), which are reported to play key roles in neurodegenerative diseases and cancer. Certain RNA sequence regions fold readily into RG4s in potassium solution, and most scientists believed those regions also formed RG4s in cells, where potassium is plentiful. To evaluate that assumption, Junjie U. Guo and David P. Bartel of the Whitehead Institute for Biomedical Research and MIT developed a new technique that recognizes RNA regions capable of folding into RG4s (Science 2016, DOI: 10.1126/science.aaf5371). It reveals more than 10,000 such RG4-foldable regions in RNA from mammalian and yeast cells, over 100 times more than had been found before. But surprisingly, most of those regions remain unfolded in the cells. Bacteria have many fewer RG4-prone regions, but those regions fold much more readily into RG4s in bacteria. The findings suggest that some mechanism in eukaryotic cells actively prevents RG4 formation, whereas bacteria have evolved to deplete RG4-forming sequences, the researchers say. The study “provides unprecedented insights into the nature of RG4 formation” in cells and could have medical implications, comments Stefania Millevoi of the Cancer Research Center of Toulouse, an expert on the role of RG4s in disease.