how a dream discovered how nerves talk

The Mechanism

Otto Loewi was born on 3 June 1873 in Frankfurt am Main into a well-off German-Jewish wine-merchant family. He took his medical doctorate at Strasbourg in 1896 under Bernhard Naunyn, and by 1909 was Professor and Chair of Pharmacology at the Karl-Franzens-University in Graz, Austria. Since a 1903 conversation with the English physiologist Thomas Renton Elliott — whose 1904 note in the *Journal of Physiology* first suggested that a chemical released at nerve endings might carry the signal to the muscle — Loewi had privately wondered whether the transmission of nerve impulses to organs was electrical or chemical. Everyone in physiology assumed it was electrical. Loewi could not think of a clean experiment to decide the question. On the night before Easter, 1921 — the night of Saturday, 26 March into Sunday, 27 March — he woke around three o'clock in the morning with a fully worked-out experimental design in his head. He fumbled a pencil onto a scrap of paper by the bed, jotted a few lines, and fell back asleep. In the morning he tried to decipher the scribble and could not. Loewi remembered afterwards that this was one of the worst mornings of his life: he had, he was sure, thought of something important, and he had lost it. Easter Sunday he spent in an agony of half-remembering. That night, at three in the morning, the same dream returned. This time Loewi got out of bed, dressed, and walked straight to the university laboratory, where he did the experiment before dawn. He dissected two frog hearts and mounted them in separate baths of Ringer's solution — the physiological salt solution invented by Sydney Ringer in 1882. Heart A he left with its vagus nerve attached and intact. Heart B he left denervated. Both hearts kept beating. He stimulated the vagus nerve of Heart A with a small electric current; Heart A promptly slowed, as had been known since Ernst Heinrich Weber's 1846 observation of vagal cardiac inhibition. Then Loewi drew a small volume of Ringer's solution from the bath around Heart A and pipetted it into the bath around Heart B. Heart B, whose vagus was not there to be stimulated at all, slowed within seconds — as if it too were being commanded to slow by an invisible nerve. When Loewi instead stimulated a sympathetic nerve trunk near Heart A, Heart A sped up; the fluid transfer then also sped up Heart B. Something soluble in the Ringer's solution around Heart A — released by the vagus when stimulated — was carrying the same command to Heart B. The signal from nerve to muscle was chemical. He called the substance released from the vagus *Vagusstoff* (vagus-substance), submitted the results to *Pflügers Archiv für die gesamte Physiologie* under the title "Über humorale Übertragbarkeit der Herznervenwirkung" ("On the humoral transmission of the action of the cardiac nerves"), and by summer 1921 it was in print — the founding paper of chemical neurotransmission. Over the following decade Henry Hallett Dale at the National Institute for Medical Research in London — an old friend who had co-authored papers with Loewi since before the war — identified Vagusstoff chemically as acetylcholine, and the substance released by sympathetic fibres as noradrenaline. Loewi and Dale shared the Nobel Prize in Physiology or Medicine in 1936 "for their discoveries relating to chemical transmission of nerve impulses." Two years later, in March 1938, the Anschluss brought Nazi Germany into Austria; the Gestapo arrested Loewi in his Graz apartment along with his two eldest sons on the night of 11 March, took him to Graz prison for two months, and released him only after he signed his Nobel Prize money (deposited in a Swedish bank) over to a Nazi-controlled institution. He escaped Austria in September 1938 with his laboratory notebooks in a suitcase, eventually settled in New York as a research professor at the New York University College of Medicine, and died there on 25 December 1961, aged 88. Every message your brain uses to speak to itself — every thought, every muscle movement, every heartbeat regulation — travels the last thousandth of a millimetre across a synapse as a chemical. A dream in Graz in 1921 first proved it.