Otto Loewi
The German-American pharmacologist and physiologist Otto Loewi (1873-1961) shared the Nobel Prize in Physiology or Medicine for his discoveries relating to the chemical transmission of nerve impulses.
Otto Loewi, the son of Jacob Loewi, a wine merchant, was born in Frankfurt am Main on June 3, 1873. In 1891 he became a medical student at the University of Strasbourg. He studied also philosophy and the history of art, both at Strasbourg and at the University of Munich (1893-1894). On his return to Strasbourg he devoted himself to medical studies, and he graduated as a doctor of medicine in 1896. While he was an assistant physician at the City Hospital, Frankfurt, he became disheartened by the ineffectiveness of medical treatments in certain common diseases, and he therefore decided to give up clinical work and become a medial scientist.
In 1898 Loewi was appointed an assistant in Hans Horst Meyer's department of pharmacology in the University of Marburg, where he was successively lecturer and associate professor. When Meyer moved to Vienna in 1904, Loewi followed him and was his associate professor for 5 years. While at Marburg and Vienna, Loewi did important work on nitrogen equilibrium, and he also worked on carbohydrate metabolism, the function of the kidneys, and the action of diuretics. About 1902 he became interested in the autonomic nervous system, and to acquire the technique requisite for the researches that he envisaged, he later spent some months in E. H. Starling's laboratory at University College, London. In 1909 Loewi was appointed to the chair of pharmacology at Graz.
The Chemical Transmission of the Nerve Impulse
In 1903, while reflecting on the fact that some drugs mimic the action of autonomic nerve fibers, Loewi wondered whether these nerve fibers might liberate chemical substances at their terminations. He thought no more about the matter, and nothing was done. During the next few years two other scientists suggested substances which might be
released, but a crucial experiment was very difficult to devise.
During the night before Easter Sunday, 1920, Loewi awoke with the idea for an experiment clearly in his mind. He wrote a few notes on a scrap of paper, went to sleep again, and in the morning found that he could make nothing of his notes. On the following night he awoke at 3 A.M. with the same idea for a crucial experiment. He arose and dressed, went to his laboratory, performed the experiment, and before morning one form of the chemical transmission of the nerve impulse was proved.
Loewi's experiment was as follows. It had long been known that an impulse in the vagus nerve slows the heart. If the vagi are cut, the inhibitory impulses cease and the heart rate increases. Loewi isolated the hearts of two frogs. Into the cavity of one heart he introduced some Ringer's solution—a nutrient fluid—and stimulated the vagus. The expected immediate slowing of the heart rate occurred. He then transferred some of the Ringer's solution to the cavity of the second heart, and its beat was immediately slowed. Since there had been no stimulation of the vagus of the second heart, its inhibition must have been due to a chemical substance in the fluid transferred from the first heart. Loewi then repeated the experiment, but he stimulated the accelerator nerve to the heart instead of the vagus. When he transferred fluid from the first heart to the second, the rate of the latter was accelerated.
Later on, Loewi improved the experiment by passing fluid continuously from the first heart into the second, so that stimulation of the vagus to the first heart was followed very rapidly by inhibition of the second. This method also showed that the inhibition produced by a single stimulus lasted for a very short time in both hearts. He gave his first public demonstration of this experiment before the German Pharmacological Society in September 1921, and it was published in the same year. This was the first of a long series of papers on this subject by Loewi and his coworkers, extending over many years.
Loewi cautiously referred to the inhibiting substance as the Vagusstoff (vagus substance), and in 1926 he showed that it was inhibited by atropine and that it was rapidly destroyed. These characteristics were exhibited by only one of the four known chemicals that mimicked the action of the vagus, namely, acetylcholine, first discovered—in an ergot extract—by (Sir) Henry Dale in 1914. Loewi suspected that his vagus substance was acetylcholine, but he had no proof as the substance was broken down before it could be collected for analysis. Further, acetylcholine had never been discovered in the animal body. But Loewi, with E. Navratil, showed in 1926 that the substance was broken down by an esterase in the heart and that this esterase was inhibited by eserine (physostigmine). Dale had already suggested that, if acetylcholine was a parasympathetic transmitter, it must be rapidly destroyed by an esterase.
In 1929 Dale and H. W. Dudley first discovered acetylcholine in the animal body, and Loewi then concluded that his vagus substance must be acetylcholine. The proof of this correct conclusion was given in 1933 by W. S. Feldberg and J. H. Gaddum in Dale's laboratory. In 1936 Loewi showed that the substance that transmits the impulses of sympathetic—in contradistinction to parasympathetic—fibers is probably adrenaline. For these researches he and Dale shared the Nobel Prize in 1936.
Later Life
Within 24 hours of the annexation of Austria by the Nazis in 1938, Loewi was thrown into prison with his two younger sons. Liberated within 3 months, he was forced to emigrate. He and his wife lost everything they had. After a brief stay in London, he was appointed Franqui Professor at the Université Libre in Brussels. He was in England when war broke out and was unable to return to Brussels. For some time he worked at the Nuffield Institute in Oxford. He was then appointed Research Professor of Pharmacology at the Medical School of New York University, where he continued his experimental work until 1955. In 1946 he became a naturalized American citizen. Loewi died in New York on Christmas Day, 1961.
Loewi received many honors apart from his Nobel Prize. He was elected a Foreign Member of the Royal Society in 1954. He was awarded the Physiology Prize of the Royal Academy of Sciences at Bologna, the Lieben Prize of the Academy of Vienna, and in 1944 the Cameron Prize of the University of Edinburgh. He received honorary degrees from five universities, and he was an honorary member of many foreign learned societies.
Further Reading
There is a biography of Loewi in Nobel Lectures, Physiology or Medicine, 1922-1941 (1965), which also includes his Nobel Lecture. See also his autobiographical sketch, reprinted in F. Lembeck and W. Giere, Otto Loewi (1968). Extracts, in English translation, from some of Loewi's papers are given in E. Clarke and C. D. O'Malley, The Human Brain and Spinal Cord (1968). □
