Nitric oxide, normal science, and lessons learned by a marginally prepared mind

The discovery in the late 1970s that the vascular endothelium plays a major role in regulating the caliber of blood vessels caused a minor paradigm shift in thinking about the cardiovascular system. That the gas nitric oxide (NO) was central to this discovery was unexpected and set the stage for a broader series of insights related to gaseous signaling molecules in biological systems. Over the last 25 years, the author’s lab has attempted to understand what NO does in alive, awake, exercising humans. This article recounts six lessons learned along the way, about luck, reductionism, and the translation of biomedical discoveries to therapy, as well as about philosophical questions related to big versus small science and curiosity-driven versus goal-directed approaches. The article also poses a fundamental question: would NO in specific and gaseous signaling molecules more generally have been discovered by sequencing, Big Data, and hypothesis-free science?.