Practicing neurologists earn their living by manipulating the synapse. Whether managing drug therapy in Parkinson disease, inhibiting cholinesterase in myasthenia, or dilating the eye for an ophthalmoscopic exam, we stimulate or inhibit chemical neurotransmission without batting an eye. We take it for granted that such a thing is not only possible, but also a natural part of our discipline. When neurology was in its infancy, though, it lacked a systematic approach to the chemistry of the synapse. For accidental historians, the discovery of chemical neurotransmission is a story of the origin of our art.
Dr. George K. York III, Chair of the AAN History Section, has written extensively on the history of medicine.
Consider Otto Loewi, born in Frankfurt in 1873. He received a medical degree at the University of Strasburg but put aside the practice of medicine to pursue pharmacological research. In the course of his early studies in Marburg and Vienna he spent time in London, where he met his lifelong friend Henry Dale. In 1909 he was appointed Professor of Pharmacology at the University of Graz in the southwest foothills of the Austrian Alps. During his early years in the laboratory, he engaged in studies on protein metabolism and renal physiology, showing that the body synthesizes proteins from amino acid precursors.
INSPIRATION FOR EXPERIMENT
In 1921, Loewi devised a classical experiment, the outline of which came to him in several dreams. He awoke on the night of Easter Saturday in 1921 and wrote a few notes on a scrap of paper. To his horror, the next morning he could not decipher his own scrawl. He spent the rest of Easter Sunday in a desperate and unsuccessful attempt to reconstruct his dream. He was finally able to fall asleep that night, and he again dreamt of an epochal experiment. He again awoke from his dream, but this time he trusted his handwriting. He immediately repaired to his laboratory and conducted the experiment that had come to him in his dream, which he finished by the end of Easter Monday.
It had been known for 70 years that stimulation of the vagus nerve slowed the heart. In a simple but visionary experimental twist, Loewi placed a beating frog's heart, with its vagus nerve still attached, in a saline bath. The saline in the bath was allowed to flow into a second bath containing a second beating heart, this time with the vagus nerve removed. Stimulating the vagus nerve slowed the first heart, as expected; after the latent period, the second heart also slowed.
Loewi reasoned that a soluble chemical, which he called “vagusstoff,” had transmitted the nerve stimulus to the second heart, indicating that the process of neurotransmission is inherently chemical. Chemical analysis of vagusstoff revealed it to be acetylcholine.
FATE AFTER NOBEL PRIZE
In 1936, Loewi shared the Nobel Prize with his friend Henry Dale for demonstrating chemical neurotransmission. His original experiment can be read in German in Pflügers Archiv für gesamte Physiologie des Menschen und der Tiere (1921;189:239); his Nobel lecture is printed in English at http://nobelprize.org.
Loewi's post-Nobel life had more than the usual twists of fate. He was arrested by the Nazis because he was Jewish, and increasing anti-semitic pressure forced him to resign his professorship, and to deposit his Nobel Prize money in a Nazi-controlled bank. A period of detention convinced him that he was no longer safe in Austria, and he was allowed to emigrate presumably because of his fame. After stops in Brussels and Oxford, he became Professor of Pharmacology at the New York University School of Medicine, where he spent the rest of his career. Here he inspired a generation of American scientists and physicians. He became an American citizen in 1946 and died in December 1961.
Practicing neurologists should remember Otto Loewi when they attend to the chemistry of their patients' synapses. The story of his Nobel dream is worth telling to our patients. His persecution by the Nazis tells us that the laboratory is not a shelter from the political world around us. His reduction of a complex question to a simple experiment tells that scientific insight favors the creative impulses of a prepared mind.
