Katalin Karikó and Drew Weissman (University of Pennsylvania) show that the lack of base modifications in synthetic RNA is what causes it to be recognized as foreign by the innate immune system's Toll-like receptors (TLRs). By replacing conventional uridine with pseudouridine — a naturally occurring modified nucleoside — they achieve mRNA that evades this immune recognition, resolving the obstacle that had blocked development of mRNA-based therapies and vaccines for more than a decade. The paper was rejected by Nature and Science in 2005 before being published in Immunity; the authors received scant attention until the technology became the basis of mRNA vaccines against COVID-19. They received the Nobel Prize in Medicine in 2023.