Small archive of material consisting of two autograph letters dated 1944 by Loewi to William Ruthrauff Amberson (1915-1977), plus one autograph letter fragment, of Loewi’s to Amberson, including the remains of a February 7, 1944 letter, describing Loewi’s discovery of acetylcholine. Plus, two typescript copies of the text of that letter, with corrections. The archive includes a carbon of Loewi’s “The Story of a Discovery”, dated 7/31/1946. The text may have been written to be given as a lecture. We can find no evidence that the account, as written here, apparently the text of a lecture, was ever published. It is not cited in biographical references on Loewi. However, Loewi wrote about his discovery in 1934, and later, in his An Autobiographic Sketch, 1960.

      Otto Loewi was born June 3, 1873, in Frankfurt-am-Main, Germany, the son of Jacob Loewi, a wine merchant, and Anna Willstätter. Loewi attended his local Gymnasium, and in 1891 entered the Universities of Munich and Strassburg as a medical student. Apart from his attendance at the inspiring anatomy courses of Gustav Schwalbe, however, he seldom went to the medical lectures, being more inclined to those held in the philosophical department. Only in 1893 did he begin to prepare for his first medical examination, which he just managed to pass. It was not until the autumn of 1894 that his indifference to medicine suddenly gave way to almost enthusiastic interest. In 1896 he was awarded his medical degree at Strassburg University, his thesis dealing with a subject suggested by Professor Oswald Schmiedeberg, the famous “Father of Pharmacology”. Also instrumental in his medical education were: Bernhard Naunyn, clinician and experimental pathologist, Oscar Minkowski, And Adolph Magnus-Levy.

         After graduation he took a course in inorganic analytical chemistry with Martin Freund, in Frankfurt, and afterwards spent a few months working in the biochemical institute of Franz Hofmeister in Strassburg. During 1897-1898 he was assistant to Carl von Noorden, clinician at the City Hospital in Frankfurt. There he witnessed the high mortality in the countless cases of advanced tuberculosis and pneumonia, left without any treatment because of a lack of therapy, he decided to drop his intention to become a clinician and instead to carry out research in basic medical science, particularly pharmacology. In 1898 he became the assistant of Professor Hans Horst Meyer, the renowned pharmacologist at the University of Marburg-an-der-Lahn, from 1904 Professor of Pharmacology in Vienna. In 1905 Loewi became Associate Professor at Meyer’s laboratory, and in 1909 he was appointed to the Chair of Pharmacology in Graz.

During his first years in Marburg, Loewi’s studies were in the field of metabolism. As a result of his work on the action of phlorhizin, and another one on nuclein metabolism in man, he was appointed Lecturer in 1900. Two years later he published his paper Über Eiweiss syntese im Tierkörper,(On protein synthesis in the animal body), proving that animals are able to rebuild their proteins from their degradation products, the amino acids – an essential discovery with regard to nutrition. That year he also published the first part of a series of papers about experimental contributions to the physiology and pharmacology of kidney function.

            In 1902, Loewi also spent some months in E. H. Starling’s laboratory in London, where he also worked with W. M. Bayliss, Starling’s brother-in-law. And it was in this laboratory that he first met his lifelong friend Henry Dale, who was later to share the Nobel Prize with him.

          After his return to Marburg in 1902 Loewi continued to study the function of the kidney and the mechanism of the action of diuretics. In Vienna, where he arrived in 1905, Loewi, along with Alfred Fröhlich, of syndrome fame, he demonstrated that small doses of cocaine potentiate the responses of sympathetically innervated organs to epinephrine and sympathetic nerve stimulation. Perhaps his interest in the vegetative nervous system was aroused in 1902 by a visit to Cambridge where T.R. Elliott was conducting his classical work on the action of epinephrine. In Graz with his longtime associate Adolph Jarisch, Loewi elucidated the mechanism of Claude Bernard’s piqûre, and the hyperglycemic effect of epinephrine. Alone, or with many visiting collaborators and students (Walter Fletcher from England, Velyan Henderson from Toronto, Franklin C. McLean, later of Chicago and many others), throughout many years, he also demonstrated the part played by cations. Thus he concluded that the effects of digitalis glucosides are due to sensitization of the frog’s heart to calcium.

           Loewi’s greatest discovery, published in 1921, was the discovery of the chemical transmission of nerve impulses, the research of which was greatly developed by him and his co-workers in the years following, culminating ultimately in his demonstration that the parasympathetic substance “Vagustoff” is the neurotransmitter acetylcholine and that a substance closely related to adrenaline played a corresponding role at the sympathetic nerve endings. It was for these researches that he received the Nobel Prize in 1936, jointly with Sir Henry Dale. This and other discoveries in the fields of chemistry, physics, and pharmacology have since then led to a complete renewal of the concepts of the sympathetic nervous system.

      The materials in this archive deal with the history of this discovery in Loewi’s own words, there is an element of mystery and drama in the way that Loewi came to demonstrate experimentally the chemical transmission of nervous impulses. Loewi’s elegant experiment, occurred to him in the midst of sleep on two successive nights.

       When the Nazis invaded Austria in 1938, Loewi and his two sons were imprisoned. He and his sons were released and allowed to leave Germany after the Nobel Prize money was transferred to Nazi controlled banks.

       After spending some time as Visiting Professor at the Université Libre in Brussels, and at the Nuffield Institute, Oxford, Loewi accepted an invitation to join the College of Medicine, New York University, as research Professor of Pharmacology, and to work in George Wallace’s Laboratory. He arrived in the United States in 1940. In America Loewi came into close contact with many outstanding biologists from all over the world and here he found much inspiration for his work.

       In 1908 he married Gulda Goldschmiedt, daughter of Dr. Guido Goldschmiedt, then Professor of Chemistry in Prague, and later in Vienna. They had three sons, Hans, Victor, Guido, and one daughter Anna. Professor Loewi became an American citizen in 1946. He died December 25, 1961.

           Loewi’s correspondent here, William R. Amberson (1915-1977), was a professor at the University of Tennessee Medical School at Memphis, 1930-1937, advisor to the Southern Tenant Farmers’ Union and trustee of the Delta and Providence cooperative farms in Mississippi. Amberson later taught at the University of Maryland School of Medicine in Baltimore 1939-1959, and the Marine Biological Laboratory in Woods Hole, Mass., after 1960.

      “155 East 93^rd Street, New York City, January 4, 1944

       My Dear Amberson,

            I have to apologize for the delay of my answer. I use to be very prompt. As a matter of fact I immediately after receipt of your letter have written. I left it in the mistake in order to complete it by the literate wording about the discovery which I have at home. I fell however again sick from a new bronchitis which kept me at home until today. I hope however that next Monday I shall be allowed to go out of doors. Then you will immediately get the letter and the quotation. I really never had such a bad feel since as I have had it this winter. I hope that this bronchitis will be the last one for this year. Who knows?

With very best wishes

Cordially yours

O. Loewi”

      “New York University College of Medicine January 24, 1944

       My Dear Amberson,

Thanks for your kind letter. I am sorry that we cannot speak about the whole matter. I can answer only briefly. It would take too much time to go into details.

1.     Ac. Ch. and transmission in C. N. S. : my experiments in regard to the control of receptor fibres have been fully confirmed by MacIntosh (j.o. Phy. 99, 436, 1940) and in addition he has shown that the sensory parts of the C.N.L. are also the poorest in Ac. Ch. Both results however do not prove definitely that Ac. Ch. Is not responsible for the transmission from sensory fibres. It may be that for this question only very little Ac. Ch. Is needed. – As to the transmission from motor fibres within the C. N. L. we have to consider the experiments of Burn a. Buelbing (j.o. Ph. 100. 337. 1941) The results are so complicated that I do not feel that the question is decided so far.

2.     Ac. Ch. And the propagated impulse within the nerves. The experiments of Parker and others seem to support the assumption that Ac. Ch. May be involved in this process. Here too the direct proof is still lacking. As you know N. assumes that nervous stimulation provokes Ac. Ch. release followed by the hydrolysis a.s.o. In order to examine correctness of this view we have applied to frogs so much colene that within the nerves no trace of Ac. Ch. any longer is hydrolysed for the propagated impulse was not prevented a bit since we cannot determine Ac. Ch. absolutely but only to 90- 95% it may be that just these 5-10% were not prevented from being hydrolysed, if one is inclined to make such an artificial assumption. I should like to stress that Nathanson’s experiments are absolutely reliable and at anyrate very interesting.

In the whole in my opinion there does not exist any direct proof that Ac. Ch. is involved in the   transmission in the C. N. S. in the propagated impulsex  On the other hand we are not permitted to deny the probability of such an involvement.

3.     Enclosed you will find a copy of how in general I put the discovery.

I would love to see you again and to deliver a lecture to the students. I have been however so much suffering from bronchitis and asthma during this winter that I had even to cancel most of the [?] lectures. There remain however a lot of other lectures to be delivered by me in 1944. Last week Conklin has given an admirable talk on: ‘Means as well as ends in life and evolution”. He really is a wonderful person. … I had to give the “opening address” to the freshmen in our school. I intend to send you a reprint when I shall get it. By and large I am very busy and feel very happy about it.

 With best whishes to you and your family most cordially yours O. Loewi xx

x.) As you may know we have got Walter B. Cameron as visiting professor at our school for three months. He [?] the experiments performed by Lissatt in his laboratory (Am. J. of Phys.) where the postganglionic sympathetic fibres do not contain a trace of Ac. Ch. only Adrenaline and yet are conducting impulses.   

xx.) I can only to day February 7th can finish and forward the letter since from Jan. 24 until to day I have been again sick and at home.”

[Fragment of Loewi’s above referenced account of his discovery, see number 3]

“In 1921 I succeeded in proving the correctness of this chemical view by a most simple experiment: my conception has been to examine whether by stimulation of a nerve a chemical substance was liberated from its endings which in its turn was able to would produce the same effect as the nerve stimulation. As a matter of fact in the year 1921 I succeeded improving In order to test the correctness of this view I isolated the heart of two frogs one with the nerves connected with the (donor heart) one without (recipient heart). In both hearts a small glass cannula was inserted filled with a small amount of Ringer solution, a salt solution, which is able to maintain the function of the heart for hours. Then for a short time I stimulated the vagus, the inhibitory nerve of the donor heart and thereafter I transferred its content to the reciprocal heart. The result was that this behaved exactly like the donor heart during the vagus stimulation: its function was inhibited. When instead of the vagus I stimulated the accelerator nerve of the donor heart and transferred its content to the reciprocal heart this content produced exactly the same  stimulation augmentory effect as stimulation of the accelerator nerve of the donor heart…”

[The above fragment has condition issues, but is accompanied by two typed transcripts of the entire letter, with ink and pencil corrections.]

References:

American National Biography, volume 13, pp., 827-828

Dictionary of Scientific Biography, volume VIII, pp., 451-457

Finger, Stanley, origins of Neuroscience A History of Explorations into Brain Function (Oxford: 1994) pp., 283-284

Haymaker, Webb and Schiller, Francis, The Founders of Neurology (Springfield: Charles C. Tomas, 1970, second ed.) pp.,293-296

Otto Loewi – Facts. NobelPrize.org. Nobel Media AB 2020. Thu. 24 Sep 2020. https://www.nobelprize.org/prizes/medicine/1936/loewi/facts/