Loewi, Otto

views updated May 18 2018

Loewi, Otto

(b. Frankfurt am Main, Germany, 3 June 1873; d. New York, N.Y., 25 December 1961)

Pharmacology, physiology.

In 1936 Loewi shared with Henry Dale the Nobel Prize in physiology or medicine for work relating to the chemical transmission of nervous impulses. He was the first child and only son of Jakob Loewi, a wealthy wine merchant, and his second wife, Anna Willstädter. At the Frankfurter Städtisches Gymnasium, where Loewi studied from 1882 to 1891, his record was much better in the humanities than in physics and mathematics, and he hoped to pursue a career in the history of art. For pragmatic reasons, however, his family wanted him to study medicine, and in 1891 he matriculated as a medical student at the University of Strasbourg, Loewi found the preclinical studies there uninteresting and preferred during his first two years to attend the lectures of the philosophical faculty. After barely passing his first medical examination (Physikum) in 1893, Loewi spent the next two semesters at Munich and then returned to Strasbourg, where Bernhard Naunyn’s clinical lectures now attracted his attention. Nevertheless, with little or no preparation in the subject, Loewi chose to write his dissertation on a topic in pharmacology. Under the direction of the renowned teacher and pharmacologist Oswald Schmiedeberg, he worked on the effects of various drugs on the isolated heart of the frog. Although quite typical of the work done in Schmiedeberg’s laboratory, this choice of topic adds force to Loewi’s own retrospective testimony that his interest in basic science had been aroused in part by reading Walter Holbrook Gaskell’s Croonian lecture of 1883 on the isolated heart of the frog.1

After graduating M.D. from Strasbourg in 1896, Loewi took a course in analytical inorganic chemistry from Martin Freund in Frankfurt and then studied physiological chemistry for several months in Franz Hofmeister’s laboratory in Strasbourg. In 1897-1898 Loewi served as Carl von Noorden’s assistant in internal medicine at the city hospital in Frankfurt. Assigned to wards for advanced tuberculosis and epidemic pneumonia, Loewi was discouraged by the lack of therapy and resultant high mortality for these cases and later claimed that it was because of this experience that he chose basic research over a clinical career.2 From 1898 to 1904 Loewi was assistant to Hans Horst Meyer at the pharmacological institute of the University of Marburg. His Habilitationschrift, which brought him the title of Privatdozent in 1900, dealt with nuclein metabolism in man. During 1902-1903 Loewi spent several months in England, which he believed had by then replaced Germany as the world’s leading center for physiology.3 At E. H. Starling’s laboratory in London, where he spent most of this time, and during a brief visit at Cambridge, he met and exchanged ideas with the leading English physiologists of the day, including Walter Gaskell, John Newport Langley, Thomas Renton Elliott, and Dale. Despite the brevity of this trip, it clearly exerted an important influence on Loewi’s later research interests and achievements.

In 1904 Loewi was appointed assistant professor at Marburg and briefly succeeded Meyer as director of the pharmacological institute there. In 1905 he followed Meyer to the University of Vienna to serve again as his assistant. He was appointed assistant professor at Vienna in 1907 and in 1909 accepted a post as professor and head of pharmacology at the University of Graz, Despite offers from more famous universities, including Vienna, Loewi remained at Graz until his expulsion by the Nazis in 1938. Like other male Jewish citizens of Graz, Loewi and two of his four children were imprisoned in March of that year. He was released two months later and in September was allowed to leave for London, but only after the Gestapo had forced him to transfer his Nobel Prize money from a bank in Stockholm to a bank under Nazi control.4 Meanwhile the Nazis detained his wife, Guida Goldschmidt (whom he had married in 1908), while seeking to dispossess her of some real estate in Italy. Stripped of all property and means, Loewi managed during the next year or so to secure invitations to work at the Franqui Foundation in Brussels and then at the Nuffield Institute, Oxford. From 1940 until his death he was research professor of pharmacology at the College of Medicine, New York University. In 1941 his wife was at last able to rejoin him, and in 1946 Loewi became a naturalized citizen of the United States. While in his adopted country, he spent his summers at the Marine Biological Laboratory in Woods Hole, Massachusetts, where his remains are buried.

Although the range of Loewi’s research interests and studies was vast, his most influential work fell into two broad categories: (1) protein and carbohydrate metabolism; and (2) the autonomic nervous system, especially the cardiac nerves. Other major interests were the pharmacology and physiology of the kidney and the physiogical role of cations. Loewi produced work in all of these areas quite early in his career, and the later fame of his work on the chemical transmission of nerve impulses ought not to obscure his continued interest in other areas.

Loewi’s concern with the problems of metabolism emerged while he was still a medical student at Strasbourg. Naunyn was himself a pioneer in the area of metabolism, as were two members of his staff, Adolph Magnus-Levy and Oscar Minkowski, who had just begun his famous experimental studies on the relationship between the pancreas and diabetes mellitus. Loewi later included one of Minkowski’s contributions in a list of the five papers that had most inspired his own career.5 While working in Schmiedeberg’s laboratory, Loewi was introduced to Johann Friedrich Miescher’s classic papers on the metabolism of the Rhine salmon during its freshwater phase. It was this work to which Loewi later variously referred as his “scientific bible,” as jointly responsible (with Gaskell’s paper of 1883) for arousing his interest in basic science, and as the chief influence on his choice of physiology in particular as a calling,6 Another probable influence on Loewi’s interest in metabolism.

In his earliest publications on metabolism Loewi argued that of the components of urinary secretion, only the uric acid depended on diet. These studies were followed by papers on phlorizin-induced glycosuria and on the question whether fat could be converted into sugar in dogs; Loewi concluded that it could not. His greatest contribution to metabolic studies, dealing with protein synthesis in the animal body, appeared as early as 1902. Since no one had previously been able to maintain nitrogen balance in animals by feeding them with the degradation products of protein in place of the original protein itself, it was supposed that animals were incapable of protein synthesis. By his own account Loewi became interested in the question after reading a paper by the biochemist Friedrich Kutscher, a colleague at Marburg, who in 1899 showed that extended trypsin digestion of a pancreas could yield end products none of which displayed any longer the chemical reactions characteristic of protein.7 This result somehow led Loewi to believe that animals might be able to synthesize protein if their diet consisted of the degradation products of a whole organ rather than of an isolated protein, and he immediately undertook a series of nutritional experiments to test his idea. Although the dogs he used found this diet unpalatable at first, Loewi persisted and eventually established that animals were indeed capable of synthesizing proteins from their degradation products, even from the most elementary end products, the amino acids. This work established Loewi’s early-reputation and greatly influenced later work in nutrition, including perhaps that of Frederick Gowland Hopkins, who met Loewi during his visit to England and who was to win the Nobel Prize in 1929 for his discovery of “accessory food factors,” or vitamins.8.

Between 1902 and 1905, Loewi—in collaboration with Walter Fletcher, Nathaniel Alcock, and Velyian Henderson—produced a series of five papers on the function of the kidney and the action of diuretics. In the classic monograph, The Secretion of the Urine (London, 1917), Arthur Cushny made important use of these studies while criticizing Loewi’s early attempt (1902) to strike a compromise between the filtration and vital theories of kidney function. Nonetheless, Loewi’s ultimate position, as represented in the last paper of this series, seems to conform quite closely to Cushny’s own modified filtration theory.

From 1907 to 1918, Loewi published six additional studies on metabolism, chiefly with regard to the function of the pancreas and glucose metabolism in diabetes 9; and after Frederick Banting and Charles Best discovered insulin in 1921, he undertook with H. F. Haüsler a long series of studies on the mode of action of insulin and its antagonists. By 1929 Loewi was forced to disavow some of the results of his earlier work on insulin and thereby to withdraw support from his earlier hypothesis that insulin promoted the binding of glucose to erythrocytes. In the 1930’s Loewi and his co-workers claimed to have discovered a proprioceptive metabolic reflex (“a mechanism through which the central nervous system … is informed of the state of the metabolism in individual organs”)10 and pursued some of the issues raised by the work of Bernardo Houssay on the role of the pituitary gland in carbohydrate metabolism.

By his own account, Loewi “imported” from England (and particularly from Gaskell, Langley, and Elliott) his interest in the “vegetative,” or autonomic, nervous system.11 His earliest publications in the field. all of which postdate his visit to England, concern vasomotor action, salivary secretion, and the action of adrenalin, all topics under active investigation at Cambridge during his visit there. Loewi’s first really original contribution in this area was his demonstration with Alfred Fröhlich in 1910 that cocaine increases the sensitivity of autonomically innervated organs to adrenalin, a response so specific that it came to be used as a test for the latter drug.12 In 1912 Loewi published a series of three communications on the action of the vagus nerve on the heart, dealing particularly with the effects on vagal action of various drugs and of variations in the calcium ion concentration of the nutrient saline solution. Between 1913 and 1921 Loewi pursued these interests in a series of three publications on the role in heart action of physiological cations (especially calcium) and in a series of six publications on the physiological relationship between calcium ions and the series of digitalis drugs, especially with respect to their action on the frog’s heart. In the latter studies Loewi emphasized that the digitalis series affects the heart as it does chiefly because digitalis sensitizes the heart to calcium, a conclusion with clinical consequences that Loewi sought to specify.

Thus, for several years before 1921 Loewi had been turning increasingly to the physiology and pharmacology of the frog’s heart and its nerves. But none of this research led directly to the work for which he won the Nobel Prize. In fact, there is an element of mystery and drama in the way Loewi came to demonstrate experimentally the chemical transmission of nervous impulses. By the time he did so, in 1921, the hypothesis of chemical transmission was nearly twenty years old. Credit for the hypothesis is usually given to Elliott, who published the suggestion in 1904.13 In 1929, after Loewi’s work had become well known, another Cambridge physiologist, Walter Fletcher, recalled that Loewi had independently proposed the chemical transmission hypothesis in 1903, in a private conversation with Fletcher, who was then working in Loewi’s laboratory at Marburg.14 Before this reminder from Fletcher, Loewi had completely forgotten the conversation; but he thereafter attached considerable significance to it, undoubtedly to emphasize the independence of his own work. However, as Dale suggested more than once, it is hard to believe that Loewi’s mind had not been at least somewhat prepared for the idea by his meeting with Elliott and in general by his visit to Cambridge, where the meaning of the neuromimetic effects of drugs was then a topic of intense interest and discussion.15

In any case, by 1920 no decisive experimental evidence for chemical transmission had yet been found, and the hypothesis had fallen into rather general discredit. Loewi revived it with an elegant experiment which, by his own account, occurred to him in the midst of sleep on two successive nights:

The night before Easter Sunday of [1921] I awoke, turned on the light, and jotted down a few notes on a tiny slip of thin paper. Then I fell asleep again. It occurred to me at six o’clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. The next night, at three o’clock, the idea returned. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission that I had uttered seventeen years ago was correct. I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design. I have to describe briefly this experiment since its results became the foundation of the theory of the chemical transmission of the nervous impulse.

The hearts of two frogs were isolated, the first with its nerves, the second without. Both hearts were attached to Straub canulas filled with a little Ringer solution. The vagus nerve of the first heart was stimulated for a few minutes. Then the Ringer solution that had been in the first heart during the stimulation of the vagus was transferred to the second heart. [This second heart] slowed and its beats diminished just as if its vagus had been stimulated. Similarly, when the accelerator nerve was stimulated and the Ringer from this period transferred, the second heart speeded up and its beats increased. These results unequivocally proved that the nerves do not influence the heart directly but liberate from their terminals specific chemical substances which, in their turn, cause the well-known modifications of the function of the heart characteristic of the stimulation of its nerves.16

So dramatic an account of a scientific achievement naturally arouses skepticism, but Dale has testified that Loewi told him essentially the same story in 1921 and repeated it virtually unchanged several times during the next four decades.17 Some of the mystery was dispelled when Loewi eventually realized that the method he used to demonstrate chemical transmission for the cardiac nerves was essentially the same method he had used in two slightly earlier studies “also in search of a substance given off from the heart.”18 For Loewi the remarkable nocturnal experimental design then became nothing more than a sudden unconscious association between the old hypothesis and the recent method.19

Loewi’s classic experiment was described in a four-page article in Pflügers Archiv. in 1921, the first in a series of fourteen papers on humoral transmission which Loewi and his several collaborators published in the same journal during the next fifteen years. The initial paper is considerably more modest in its claims than the retrospective accounts of Loewi and others might suggest: although it clearly emphasized chemical mediation of nerve impulses as one plausible interpretation of the experimental results, it also raised the alternative possibility that vagomimetic and accelerator-mimetic substances might be products of altered cardiac activity and thus not directly products of nerve stimulation. In the second paper of the series (1922) Loewi rejected the latter interpretation in favor of direct chemical mediation. The next immediate task, pursued in several papers in the series, was to determine the chemical nature of the substances released by stimulation of the vagus and accelerator nerves. The fact that the action of the vagus-transmitting substance (Vagusstoff) was abolished by atropine greatly simplified the search for its chemical equivalent; and as early as the second paper Loewi argued that the Vagusstoff must be a choline ester. But not until the tenth and eleventh papers (both published in 1926) did Loewi and his collaborator E. Navratil positively identify the Vagusstoff with acetylcholine. For some, notably Dale, this identification seemed to be approached with excessive caution in view of what was already known about acetylcholine, much of it as a result of Dale’s own work a decade earlier.

But Loewi’s caution may well reflect the skepticism that his work aroused in others, particularly Leon Asher, against whose criticisms some of the papers in the series were specifically directed. Nor was all of the criticism misguided: however simple on the surface, Loewi’s famous experiment is not always easy to reproduce, and it is said that he often failed in his own attempts to do so.20 As Loewi pointed out in the third paper of the series (1924), success depended on achieving a combination of several intricate experimental conditions, including a test heart of appropriate responsiveness (which in turn could depend on species differences and the season of the year). Perhaps because of such difficulties, Loewi was invited to demonstrate his experiment before the Twelfth International Congress of Physiology at Stockholm in 1926. Although he apparently accepted the invitation with some reluctance, Loewi executed the demonstration with great success.21 By 1934 W. B. Cannon could describe the support for Loewi’s work as “conclusive,”22 a judgment confirmed by G. Liljestrand in his presentation speech at the Nobel Prize ceremonies in 1936.23

If Loewi proceeded cautiously toward the identification of Vagusstoff with acetylcholine, he moved even more cautiously toward an identification of the substance released by stimulation of the accelerator nerve. Even though Elliott had proposed the hypothesis of chemical transmission in the first place because of the sympathomimetic effects of adrenalin, it was not until 1936 that Loewi positively identified the Acceleransstoff or Sympathicusstoff with adrenaline (epinephrine). Like many others, Loewi apparently did assume immediately that his results for the cardiac nerves would apply as well to all other peripheral autonomic nerve fibers, and one of the earliest and most important pieces of evidence for this extension Was produced in Loewi’s laboratory by E. Engelhart.24 But the suggestion that chemical transmitters were also released by ordinary voluntary motor fibers or across other nonautonomic synaptic junctions aroused in Loewi what Dale characterized as “almost obstinate scepticism.”25 Chiefly because nervous impulses produce their effects so much more rapidly in voluntary and central nervous processes than in autonomic, Loewi doubted that chemical transmission could be involved in the former. In the end, as Loewi himself emphasized, it was Dale and his associates who were mainly responsible for establishing the existence of chemical transmission outside the postganglionic autonomic nervous system.26

In a sense, however, Dale’s ability to make this bold extension depended in part on Loewi’s caution. For in the course of their careful approach toward a definitive identification of Vagusstoff; Loewi and Navratil not only found that the effects of Vagusstoff faded rapidly because it was speedily metabolized by an enzyme but also that this enzyme could be inhibited (and Vagusstoff thereby protected) by the alkaloid physostigmine (eserine). These results, reported in the tenth and eleventh papers of the famous series, were important for several reasons. (1) Since acetylcholine was also speedily metabolized by the same enzyme (a specific cholinesterase) and also selectively protected by eserine, the identity of Vagusstoff and acetylcholine was virtually assured. (2) By this work Loewi and Navratil introduced the concept that the pharmacologic action of an alkaloid could be defined in terms of its inhibition of an enzyme, and thus helped to explain why alkaloids could be effective even in minute doses. (3) The ability of eserine to prevent the destruction of acetylcholine made it possible to develop new methods for detecting the transmitter in tissues where its low concentration or rapid destruction had kept it hitherto undetected. It was chiefly by the use of eserinized solutions that Dale and others were able to establish the existence of chemical transmission in warm-blooded vertebrates and in parts of the nervous system where Loewi himself had doubted its presence. (4) The knowledge that a specific cholinesterase was responsible for the destruction of the acetylcholine transmitter made it easier to understand and to determine why the speed and duration of nervous effects might vary in different species and in different parts of the nervous system. Among other things, these differences might be traced to differences in the amount of the cholinesterase normally present in different tissues. Along lines such as these, an explanation can be proposed for the difficulties encountered in the early attempts to reproduce Loewi’s original experiment. According to William Van der Kloot, the heart of the Hungarian frogs that Loewi used contains only a small amount of the cholinesterase, so that the acetylcholine released by vagus stimulation persists unusually well in it.27 In the era before eserinized solutions, those who used other species would naturally have experienced greater difficulty in detecting the vagus transmitter.

With the publication in 1936 of the fourteenth and final paper in the series on humoral transmission, the truly creative phase of Loewi’s research career came to an end. Especially after 1938, when the Nazis forced him out of Graz, Loewi’s main role was that of critic, reviewer, and guide for those who more actively pursued the new lines of research opened up by the discovery of the chemical transmission of nervous impulses. This discovery in fact inaugurated a conceptual revolution in neurophysiology. Besides offering an entirely new mode of thinking about such phenomena as inhibition and summation, the concept of chemical transmission had clinical implications as well, particularly with regard to certain symptoms of neurological hyperactivity formerly regarded as purely reflex in nature. Loewi himself often reflected on these questions as well as on the implications of chemical transmission for general physiology and biology. For him, the existence of chemical transmission seemed to give further support to the organismic conception of the living body as an adaptive, regulated, delicately coordinated, and peculiarly biological mechanism, In his inclination toward overtly teleological thinking, in his abiding love of music, art, and culture in general, and in his profound moral and humanitarian sensitivity, Loewi maintained to the end a kinship with that young aspiring historian of art who had been deflected by circumstance into a richly creative career in science.

NOTES

1. Loewi, “Prefatory Chapter,” p. 2.

2. Loewi, “An Autobiographic Sketch,” p. 7,

3.Ibid., p. 10.

4.Ibid., p. 21.

5. Loewi, “Prefatory Chapter,”p. 2.

6.Ibid., p. 2; and Loewi, “An Autobiographic Sketch,” p. 6.

7. Loewi, “An Autobiographic Sketch,” p. 9.

8. See Dale, “Otto Loewi,” p. 70.

9. Of the work done during these two decades, Loewi himself chose to emphasize the following: “One of these studies proved that the preference of pancreatectomized dogs for fructose rather than glucose, as had been demonstrated by Minkowski, is not specific for this deficiency but is shared by dogs deprived of their glycogen by other means, e.g., by phosphorus poisoning. It was further shown that the heart, in contrast to the liver, cannot utilize fructose. It was finally discovered that epinephrine injections into rabbits completely depleted by starvation of their liver glycogen brought the glycogen back to almost normal values in spite of continued starvation.” See Loewi, “An Autobiographic Sketch,” pp. 12-13.

10.Ibid p. 15.

11.Ibid., p. 13.

12.Ibid., p. 13. Cf. Loewi, “The Ferrier Lecture,” p. 300.

13. See T. R. Elliott, “On the Action of Adrenalin,” in Journal of Physiology, 31 (1904), xx-xxi; and Ibid., 32 (1905), 401-467.

14. See Loewi, From the Workshop of Discoveries, p. 33; “An Autobiographic Sketch,” p. 17; and the sources cited in note 15 below.

15. See H. H. Dale, “T. R. Elliott,” in Biographical Memoirs of Fellows of the Royal Society, 7 (1961), 64; and “Otto Loewi,” pp. 70-73.

16. Loewi, “An Autobiographic Sketch,” p. 17. In an obvious oversight, Loewi here places the nocturnal event in 1920 rather than 1921. For a virtually identical version of the story, but with the correct date, see Loewi, From the Workshop of Discoveries, pp. 32-33.

17. Dale, “Otto Loewi,” pp. 76-77.

18. Loewi, “An Autobiographic Sketch,” p. 18. Loewi does not identify the two studies he has in mind, but the likeliest candidates are “Über Spontanerholung des Froschherzens bei unzureichender Kationenspeisung. II, Mitt. Ein Beitrag zur Wirkung der Alkalien aufs Herz,” in Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, 170 (1918), 677-695; and “III. Mitt. Quantitative mikroanalytische Untersuchungen über die Ursache der Calciumabgabe von seiten des Herzens,” ibid., 173 (1919), 152-157, written with H. Lieb.

19. Loewi, “An Autobiographic Sketch,” p. 18.

20. Letter from William G. Van der Kloot to G. L. Geison, 2 June 1972.

21. Loewi, “An Autobiographic Sketch,” p. 19; Dale, “Otto Loewi,” pp. 77-78. Incidentally, neither account corroborates a remarkable claim which Loewi made many years later to William Van der Kloot, who was chairman of the pharmacology department at New York University during Loewi’s last years there. According to Van der Kloot (see note 20) Loewi told him that during this demonstration in Stockholm he had been “obliged to stand at one end of the room and simply give instructions, so that the possibility of his secreting some chemical under his fingernails and dropping it on the preparation could be eliminated.” This claim also appears to conflict with a photograph taken of Loewi at the time of the demonstration (see Holmstedt and Liljestrand, Readings in Pharmacology, p. 194).

22. Walter B. Cannon, “The Story of the Development of Our Ideas of Chemical Mediation of Nerve Impulses,” in American Journal of the Medical Sciences, n.s. 188 (1934), 149.

23. See Nobel Lectures Including Presentation Speeches and Laureates’ Biographies: Physiology or Medicine 1922-1941 (Amsterdam, 1965), pp. 397-401, esp. p. 399.

24. See e.g., Otto Loewi, “Chemical Transmission of Nervous Impulses,” in George A. Baitsell, ed., Science in Progress, 4th ser. (New Haven, 1945), p. 102.

25. Dale, “Otto Loewi,” p. 79.

26. See, e.g., Otto Loewi, “Salute to Henry Hallet Dale,” in British Medical Journal (1955), 1 , 1356-1357.

27. Van der Kloot to Geison (see note 20).

BIBLIOGRAPHY

I. Original Works. Lembeck and Giere (see below) give an apparently complete bibliography of more than 170 items by Loewi, arranged both topically and chronologically. In their topical bibliography, a summary is also given of the contents of most of his research papers. Appended to Henry Dale’s biographical memoir of Loewi (see below) is a bibliography of 150 items; Dale omits many of the essentially nonscientific papers included by Lembeck and Giere.

The most important of Loewi’s papers on metabolism is “Über Eiweisssynthese im Thierkörper,” in Archiv für experimentelle Pathologie und Pharmakologie, 48 (1902), 303-330. For the early series of five papers on the kidney, see “Untersuchungen zur Physiologie und Pharmakologie der Nierenfunction,” ibid., 48 (1902), 410-438; 50 (1903), 326-331; 53 (1905), 15-32, 33-48, 49-55. Loewi abandoned his earlier hypothesis of the mode of action of insulin in “Insulin und Glykämin,” in Klinische Wochenschrift, 8 (1929), 391-393. On the concept of the proprioceptive metabolic reflex, see “Über den Glykogenstoffwechsel des Muskels und seine nervöse Beeinflussung,” in Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, 233 (1933), 35-56. For Loewi and Frölich’s work on cocaine and adrenaline, see “Untersuchungen zur Physiologie and Pharmakologie des autonomen Nervensystems. II. Mitt. Über eine Steigerung der Adrenalinempfindlichkeit durch Cocain,” in Archiv für experimentelle Pathologie und Pharmakologie, 62 (1910), 159-169.

For Loewi’s work on the heart between 1912 and 1921, see “Untersuchungen zur Physiologie und Pharmakologie des Herzvagus,” ibid., 70 (1912), 323-343, 343-350, 351-368; “Über Beziehungen zwischen Herzmittel- und physiologischer Kationenwirkung,” ibid., 71 (1913), 251-260; 82 (1918), 131-158; 83 (1918), 366-380 ;Pflügers Archiv, 187 (1921), 105-122, 123-131; 188 (1921), 87-97; and “Über die Spontanerholung des Froschherzens bei unzureichender Kationenspeisung,” ibid., 157 (1914), 531; 170 (1918), 677-695; and 173 (1919), 152-157. For the celebrated series of fourteen papers on humoral transmission, see “Über homorale Übertragbarkeit der Herznervenwirkung,” ibid., 189 (1921), 239-242; 193 (1922), 201-213; 203 (1924), 408-412; 204 (1924), 361-367, 629-640; 206 (1924), 123-134, 135-140; 208 (1925), 694-704; 210 (1925), 550-556; 214 (1926), 678-688, 689-696; 217 (1927), 610-617; 225 (1930), 721-727; 237 (1936), 504-514. See also Otto Loewi, “Kritische Bemerkungen zu L. Ashers Mitteilungen,” ibid., 212 (1926), 695-706.

Loewi’s more general views on chemical transmission and his role as historian, reviewer, critic, and guide are best revealed in a number of his lectures given between about 1930 and 1945. Of these, the most important and valuable are “The Humoral Transmission of Nervous Impulse,” in Harvey Lectures, 28 (1934), 218-233; “The Ferrier Lecture on Problems Connected with the Principle of Humoral Transmission of Nervous Impulses,” in Proceedings of the Royal Society, 118B (1935), 299-316; “Die chemische Übertragung der Nerwirkung,” in Schweizerische medizinische Wochenschrift, 67 (1937), 850-855; “Die chemische Übertragung der Herznervenwirkung,” in Les Prix Nobel en 1936 (Stockholm, 1936), translated into English in Nobel Lectures Including Presentation Speeches and Laureates’ Biographies: Physiology or Medicine 1922-1941 (Amsterdam, 1965), pp. 416-429; and “The Edward Gamaliel Janeway Lectures: Aspects of the Transmission of Nervous Impulse,” in Journal of the Mount Sinai Hospital, 12 (1945), 803-816, 851-865. See also the lecture cited in note 24 above.

For useful autobiographical material, see Otto Loewi, “An Autobiographic Sketch,” in Perspectives in Biology and Medicine, 4 (1960), 1-25, reprinted in Lembeck and Giere, pp. 168-190; “Prefatory Chapter: Reflections on the Study of Physiology,” in Annual Review of Physiology, 16 (1954), 1-10, reprinted in The Excitement and Fascination of Science: A Collection of Autobiographical Essays (Palo Alto, Calif., 1965), pp. 269-278 ; and From the Workshop of Discoveries (Lawrence, Kans., 1953). Lembeck and Giere have also published two posthumous MSS by Loewi, “Meaning of Life” and “The Organism as a Unit” (pp. 191-203 and 204-217, respectively); as well as a dozen brief ceremonial addresses given by Loewi between 1942 and 1952 (pp. 218-241). Several of these sources emphasize Loewi’s organismic philosophy and approach; a few relate to the Jewish question and to more general political and humanitarian concerns.

According to Lembeck and Giere, Loewi’s MSS and papers are deposited in thirteen file drawers at the Royal Society of London. In the obituary files of the Medical-Historical Library, Yale University, is a letter from Loewi to Harvey Cushing (27 Nov. 1937) in which Loewi seeks aid for a victim of Nazi persecution. Coming just a few months before his own imprisonment by the Nazis, it is both a reminder of the horror of Nazism and a testimony to the solidarity of its victims.

II. Secondary Literature. The basic source for Loewi’s life and work is Fred Lembeck and Wolfgang Giere, Otto Loewi: Ein Lebensbild in Dokumenten (Berlin, 1968). Although not a scientific biography of Loewi, this remarkable book reprints or provides references to almost all the material that a biographer could conceivably use. Besides the reprinted material and bibliographies mentioned above, there is a brief biographical sketch (pp. 2-16), a list of his honors and the professional associations to which he belonged (pp. 19-21), a bibliography of more than fifty sketches and obituaries (pp. 22-24), and a lengthy section containing extensive and impressive documentation of his life (pp. 27-91).

Of the many biographical sketches of Loewi, the most valuable is that by his Nobel colaureate Henry Dale, “Otto Loewi,” in Biographical Memoirs of Fellows of the Royal Society, 8 (1962), 67-89, with portrait and bibliography. For short biographical sketches, brief attempts to place Loewi’s work in historical perspective, and excerpts in English from his writings, see Lloyd G. Stevenson, Nobel Prize Winners in Medicine and Physiology, 1901-1950 (New York, 1953), pp. 186-195; B. Holmstedt and G. Liljestrand, Readings in Pharmacology (New York, 1963), pp. 190-196; and Edwin Clarke and C. D.O’ Malley, The Human Brain and Spinal Cord: A Historical Study Illustrated by Writings from Antiquity to the Twentieth Century (Berkeley, Calif., 1968), pp. 250-255.

Gerald L. Geison

Otto Loewi

views updated May 23 2018

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). □

Loewi, Otto

views updated May 14 2018

LOEWI, OTTO

LOEWI, OTTO (1873–1961), pharmacologist and Nobel laureate in physiology and medicine. Loewi was born in Frankfurt on the Main but became a U.S. citizen in 1946. He graduated in medicine at the University of Strasbourg (then in Germany). After initial appointments in the universities of Marburg and Vienna he became professor of pharmacology at the University of Graz, Austria (1909–38). After the German invasion he was imprisoned, deprived of his possessions (including his Nobel Prize money), and allowed to leave. After working in Brussels and Oxford (1939–40), he was appointed research professor at New York University College of Medicine. Loewi's initial contributions concerned carbohydrate and nitrogen metabolism but his main research interest was in the sympathetic nervous system. He proved that nerve impulses in the parasympathetic nervous system are transmitted by acetylcholine and, with his collaborators, he established that nerve impulses in the sympathetic nervous system in general are mediated through chemical transmission. He was awarded the Nobel Prize (jointly with Sir Henry Dale) in 1936 for this work. His honors included foreign membership in the Royal Society (London). The Austrian government issued a stamp to commemorate the centenary of his birth.

[Michael Denman (2nd ed.)]

Otto Loewi

views updated Jun 08 2018

Otto Loewi

1873-1961

German-born American physiologist and pharmacologist who received the Noble Prize for Physiology or Medicine in 1936 with Henry Dale for their work regarding the chemical nature of nerve signals. Loewi primarily studied the physiological action of chemicals and is best known for his extensive work regarding the autonomic nervous system. One important discovery was that the neurotransmitter acetylcholine was released directly on to the heart by nerve endings where it exerted a physiological effect.

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