Schmiedeberg in Strassburg 1872–1918: The making of modern pharmacology

Life Sciences, vol . 22, pp . 1361-1372 Printed is the U .S .A .

Pergamon Press

SCHMIEDEBERG IN STRASSBURG 1872-1918 : THE MARING OF MODERN PHARMACOLOGY . Jan Roch-Weser and Paul J . Schechter Centre de Recherche Merrell International 67084 Strasbourg, France

One century ago pharmacology was an antiquated, denigrated and waning discipline content with transmitting impressionistic and largely erroneous dictums . In one generation one man in one city redefined its tasks, demonstrated its experimental methods and trained its work force . Virchow, Pasteur and Roch profoundly influenced their fields, but Schmiedeberg brought scientific pharmacology into being . Their names have become household words, his is rarely found even in medical dictionaries . Fortunately, he cared not about fame but about knowledge . Life and Times Oswald Schmiedeberg was born on 10 October 1838 as the son of a German forester in the rural environment of Laidsen in Rurland, a Baltic province of Russia (later Latvia) . He went to school in Dorpat, a 600 year old German town in next-door Livland (Estonia), and later studied medicine there . The University of Dorpat had been established in 1632 by King Gustavus II Adolphus of Sweden and revived with new funds and buildings by Emperor Alexander I of Russia in 1802 . In Schmiedeberg s time it was an Imperial Russian Univèrsity, but the language of instruction and almost the entire faculty were German (1) . Many outstanding scientists, including the chemist C . Schmidt and the physiologist F . Bidder, taught at Dorpat, but Rudolf Buchheim, the professor of pharmacology, was to have the greatest influence on Schmiedeberg . In 1847 Buchheim had organized in Dorpat the first institute of experimental pharmacology anywhere . For some years this was housed in the basement of his home, but in 1860 it moved into a large building specifically constructed for this purpose . Schmiedeberg worked with Buchheim in this institute and in 1866 received the Dr . med . degree for his thesis on the determination of chloroform in the blood . He remained with Buchheim at Dorpat thereafter and in 1868 was appointed a university lecturer in pharmacology . The importance for Schmiedeberg of his exposure to Buchheim's principles and practice of experimental pharmacology cannot be overestimated (1,2) . At the end of his own career, Schmiedeberg described Buchheim's decisive role in the birth of scientific pharmacology and perceptively analyzed the reasons why the solitary efforts of his mentor had been misunderstood and not 0300-9653/78/0410-1361$02 .00/0 Copyright © 1978 Pergamon Press

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supported by the medical profession (3) . In 1869 Buchheim left Dorpat for Giessen where he could not effect his ideas and died 10 years later . Before leaving Dorpat Buchheim succeeded in having Schmiedeberg, then only 31 years old, appointed as his One successor in the professorship of experimental pharmacology . does not diminish Buchheim's importance by concluding that his most consequential accomplishment was the training and support of Schmiedeberq . In 1871 he took Schmiedeberg did not long remain at Dorpat . a year's leave of absence to work in the physiologic institute of Carl Ludwig in Leipzig . Here he received further training in experimental methodology in the company of young researchers such as Rudolf Boehm who soon succeeded him in Dorpat and became his Henry P . life-long friend and fellow champion of pharmacology . Bowditch, later professor of physiology at Harvard Medical School, was another cotrainee . Schmiedeberg must have impressed Carl "Ach, der Schmiedeberg, Ludwig who exclaimed on a later occasion : das iat sin Genie" (4) . More importantly, when the University of Strassburg was looking for a professor of pharmacology in 1872, Ludwig recommended Schmiedeberg . He was appointed to the position and held it for 46 years . Strassburg, an ancient "Reichsstadt" of the German Empire which had become part of the France of Louis XIV in 1681, was incorporated into the new German Empire after the Franco-Prussian war of 1870/71 . Since the city was now the capital of the "Reichsland" of Elsass-Lothringen, it was thought appropriate to reestablish its German university which had been closed in 1794 as an aftermath of the French revolution . No funds or efforts were spared to make this new institution a leading university . Outstanding scientists were recruited by the university curator von Roggenbach from all German-speaking parts of Europe . The medical faculty of the University of Strassburg during the time of Schmiedeberg was certainly among the beat in the German Reich . Names such as Waldeyer (anatomy), v . Recklinghausen, Friedländer (pathology), Goltz (physiology), Hoppe-Seyler, Hofmeister (physiologic chemistry), Leyden, Russmaul, Naunyn, v . Mering, Minkowski (internal medicine) and v . Rrafft-Ebing (psychiatry) remain known even today . It was not a matter of course, however, that this faculty should have included a professor of pharmacology . The contribution that pharmacology had to make to medicine was being increas ingly questioned . Pharmacology had been dropped from the final Incipient physicians medical examinations in most German states . were being counseled to forget as soon as possbile what they might remember about drugs from their lectures or books (5) . In Giessen Buchheim was once again reduced to performing pharmacologic experPharmacologiste at almost all other Geriments in his own home . man universities did no experimental work, and no laboratories of experimental pharmacology existed in other countries . The development of pharmacology as a scientific discipline akin to physiology or pathology received little or no support from the medical establishment . The attitude of most clinicians was expressed by the famous Viennese surgeon T . Billroth : "Considering how little he has to teach and that half of what he teaches is superfluous, it is difficult to keep a professor of pharmacology busy in a full-time teaching position . What is needed is merely a short

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review of the most important drug groups and an experimental demonstration of the most intensive poisons . 'This can be done in 3 to 4 hours . The students should not be burdened with more lectures . How to use drugs one can only learn in the clinics anyway" (6) . Even when Buchheim convincingly defended pharmacology, he had to conclude : "What can a man who gives his whole strength to pharmacologic research achieve today under the best of circum~ stances? A professorship with a minimum salary and an empty auditorium" (7) . Nothing suggests that Schmiedeberg ever had any doubts about the essentiality and the potential of pharmacology . He knew that in most universities it was not a scientific discipline . But there was nothing wrong with pharmacology that could not be cured by diligent experimental investigations . Without scientific pharmacology rational pharmacotherapeutics were impossible . Upon his arrival in Strassburg he immediately began to create the pharmacological institute that was to become the world's most productive and most famous . His work in this institute during the next 5 decades was largely responsible for the rise of pharmacology to a respected scientific discipline and an indispensable foundation for medical practice . He accomplished this by his excellence as a researcher, teacher and writer .

Fig . 1 .

Oswald Schmiedeberg about 1905

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Schmiedeberg s institute and the German university of Strassburg did not survive the defeat of the German Empire in the First World War . After the return of Strasbourg to France in 1918, Schmiedeberg had to move across the Rhine to Baden-Baden . There he died on 14 July 1921 at the age of 82 . In the city where Schmiedeberg worked for almost half a century few have ever heard of him. No plaque marks the building that housed his institute when it was the Mecca of Pharmacology . A bust of Schmiedeberg stands in the pharmacologic institute of the University of Freiburg, but his real memorial is the scientific discipline of pharmacology . The Researcher Perhaps only in the Strasbourg of the last part of the 19th century could Schmiedeberg have accomplished as much as quickly for In this new, rapidly expanding, and well supported pharmacology . university with its young and enthusiastic faculty no established privileges or old rivalries cramped his purposeful energy . The' pharmacologic institute immediately moved into its own quarters, though these were initially modest and located in a building of the ôld French faculté de médecine . But planning of the new German university was under way and Schmiedeberg began to ponder the building which would best house his "Pharmakologisches Institut" . With the full support of the medical faculty and of the curator of the university its construction near the "Bürgerspital" between the institutes of anatomy and physiology was authorized in 1883 .

Fig . 2 . Main Wing of the Pharmacologic Institute of Strassburg University about 1895 .

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The institute was planned in all essential details by Schmiedeberg himself . It was constructed according to his specifications by professor Warth, a young architect from Karlsruhe who in 1878 had won a nationwide competition for the best design of the main building of the university . Construction costs totalled 262,000 Marks, more than was spent for the physiologic institute and about 58 of the total cost of construction for the medical faculty . The functionality and beauty of the building was universally admired The two main stories had a combined after its completion in 1887 . floor space of about 1500 square meters and housed well-equipped laboratories for animal experimentation and chemical work, offices, Schmiedeberg s detailed description an auditorium and a library . of the institute for Hausmann's 1897 book on the "Raiser Wilhelms Universität Strassburg" (8) shows his exact knowledge of all its features . Perhaps never before or since in the history of science has a fledgling discipline whose very raison d'~tre was still widely denied been provided with such superb facilities for its work . Given the favorable environment of Strassburg, Schmiedeberg s scientific vision, purposeful energy and inspiring leadership produced a veritable outburst of imaginative and successful experimentation that silenced those who had seen no substance in pharmacology . Many of these investigations were conducted by Schmiedeberg himself, others under his direction by the many young scientists who soon came to work with him . The high productivity of Schmiedeberg's institute flatly contradicts Parkinson's assertion that "perfection of planning is a symptom of decay" (9) . The many varied and pioneering investigations of Schmiedeberg and his group cannot be discussed here in any detail . They were reported in over 200 articles and books . A list of Schmiedeberg s publications appears in the "Festband" of the Archiv fttr experimentelle Pathologie and Pharmakologie published on the occasion of his 70th birthday in 1908 (10) . Later writings are listed in H .H . Meyer's appreciation of Schmiedeberg s achievements (11) . His last publication, a provocative hypothesis about the biochemical disturbances underlying diabetes mellitus, appeared in 1921, the year of his death . Schmiedeberg s doctoral thesis led to many later investigations by him and his students into the pharmacology of chloroform and related compounds . As a result of his studies on the pharma cologic actions of some carbamic acid esters, Schmiedeberg became interested in the relationship between chemical structure and narcotic effectiveness . Such considerations led to the experimental testing and later clinical introduction of amylene hydrate, paraldehyde, and, most importantly, urethane which in turn brought many hypnotically active urea compounds in its wake . Another early interest of Schmiedeberg concerned muscarine . His isolation of the alkaloid from the mushroom Amanita muscaria, its analysis, and the thorough experimental study of its actions remain a model of pharmacologic investigation of natural substances . Schmiedeberg s interest in muscarine led directly to investigations into the action of nicotine on the heart and to later studies on cardiac innervation and on the whole pharmacology of the autonomic nervous system .

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Of equal scientific and therapeutic importance were Schmiedeberg's chemical and pharmacologic investigations of the digitalis glycosides, including the isolation of digitoxin, during his first decade in Strassburg . His experimental analysis of the cardiac effects of these compounds demonstrated their favorable action on the performance of the heart which at that time was denied by most clinicians . Schmiedeberg also studied the actions of caffeine and related xanthines on striated muscles as well as their diuretic effects . The pharmacologic and toxicologic actions of heavy metals were systematically investigated . By using organic metal compounds, Schmiedeberg was able to define the systemic actions of heavy metals without interference by the local effects of inorganic metal salts . These subjects are merely examples of the far-ranging pharmacologic interests of Schmiedeberg and his Strassburg group of researchers and students . In fact, they performed the first exper imental studies on the pharmacology of most important drugs and In this way they succeeded in giving poisons known at that time . pharmacology a solid scientific foundation and assured its position alongside the other biomedical sciences at the universities . Schmiedeberg always saw himself as a protagonist of pharmacology and his life-task as its conversion into an experimental discipline . Nevertheless, some of his most original and memorable research and perhaps his most vivid interest focussed on questions of physiologic chemistry . Thus, he and his coworkers succeeded in demonstrating the formation of hippuric acid from benzoic acid and glycine in isolated, blood-perfused dog kidneys . They never observed production of hippuric acid by homogenates of renal tissue and thus were the first to conclude that some synthetic processes take place only in the "protoplasm of living cells" . They were also able to show the conversion of ammonium carbonate to urea and to establish its site and conditions . At the same time they elucidated and quantitated the ability of different animal species to neutralize administered acids throught the formation of ammonia . The limited capacity of man in this regard furnished the explanation for the acidosis due to hydroxybutyric acid characteristic of diabetic coma and for the serious acidotic states due to other endogenous acids in various diseases and intoxications . Soon after beginning work in Strassburg, Schmiedeberg observed that after oral administration camphor appeared in the urine in the hydroxylated form combined with a reducing substance . He isolated and analyzed this compound and named it glucuronic acid . Subsequently he demonstrated that glucuronic acid occurs in cartilage as a component of chondroitie which he showed to be the unit disaccharide of chondroitin sulfuric acid . Over many years Schmiedeberg worked on the chemistry of mucopolysaccharides and mucoproteins . He identified the components of hyaluronic acid and investigated its relation to chondroitin sulfate, collagen and amyloid . Last but not least, it was Schmiedeberg who first succeeded in purifying a nucleic acid . This brief list of Schmiedeberg's biochemical accomplishments omits many more isolated investigations which resulted in the Clearly his purification and analysis of natural substances . scientific curiosity was just as great in physiological chemistry as in pharmacology . He had no use for the compartmentalization of

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scientific investigation and even suggested the eventual possibility of a unified bioscience . The Teacher As a researcher Schmiedeberg set the standards for scientific pharmacology, as a teacher he created its manpower . In actuality, His greatest his teaching cannot be separated from this research . impact as the preceptor of the next generation of pharmacologists was undoubtedly through the example of his creativity, conscientiousness and energy as a researcher . Schmiedeberg took a personal interest in his beginning students and gave much time to introduce them to the skills of experimentation (11,12) . He emphasized to them the dual need for original, critical thought and for painstaking experimental design and execution . Students who had become able to work independently were given a great deal of freedom, but Schmiedeberg was always completely familiar with the design, execution and critical analysis of all work in his institute . His interchanges with his students did not take the form of freewheeling discussions, it was not his intention to follow their trains of thought . Similarly, his lecturing was thoroughly and critically thought out, highly organized and concise, but dogmatically comprehensive rather than Socratic . Devoid of all rhetorical ornamentation or showmanship, his lectures were considered both impressive and effective by his students . Though never opinionated, Schmiedeberg clearly had complete confidence in his critical faculties and in his ability to make scientific judgements . Undoubtedly, Schmiedeberq would be called authoritarian today, but our standards are irrelevant to his time . His single-mindedness and inflexible insistence on critical thought and careful experimentation were central ingredients of his effectiveness as a maker of pharmacologists . In this task he succeeded almost beyond belief . More than 150 pharmacologists were trained in his Strassburg institute . Many were attracted to pharmacology only by the personality and work of Schmiedeberg . The 1908 "Schmiedeberg-Festband" of the Archiv für experimentelle Pathologie und Pharmakologie contains articles by 59 of his students (10) . His worldwide impact is shown by the surprising fact that 32 of these came from countries other than Germany . Among Schmiedebergs many outstanding pupils were J .J . Abel, J .T . Cash, V . Cervello, M. Cloetta, A .R . Cushny, H . Dreser, E .S . Faust, R . Gottlieb, J .T . Halsey, E . Harnack, W . Heubner, R . Kobert, H .H . Meyer, W . v . Schroeder, T . Solluran and H . Wieland . At the time of Schmiedeberg s death more than 40 chairs of pharmacology were held by his own students . Others were already occupied by their students . Indeed, most pharmacologists today are probably direct "scientific descendents" of Schmiedeberg . All others owe much of the scientific and experimental training which they received to the example set by Schmiedeberq in Strassburg .

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Fig . 3 . Schmiedeberg and his Students in Front of the Strassburg Pharmakologic Institute on his 70th Birthday (10 .10 .1908) . In the first row from left the professors of pharmacology Cloetta (Zürich), Heubner (Göttingen), Meyer (Wien), Cervello (Palermo), Schmiedeberg, Harnack (Halle), Cushny (London), Minkowski (Medicine, Strassburg), Gottlieb (Heidelberg) . The Writer Schmiedeberg communicated the results of his research in clearly formulated articles . His writing style was rigorous, at times even austere . Each word seems carefully chosen and no ver biage ever appears . The articles are packed with factual content and tight reasoning, they are not easy but rewarding to read . In writings that were partly directed at non-scientific readers, such as his treatises on chicory and on natural and artificial wine, Schmiedeberg can be entertaining and amusing . One of his last writings, at the age of 80, is a delightful analysis of the pharmacologic agents mentioned in the Iliad and the Odyssey . Schmiedeberg s popular writing deals with his main non-scientific interests, in all of which he became quite knowledgeable . These included history, classical languages, painting, architecture and wine, not necessarily in that order (13) . The usual forum for Schmiedebergs scientific publications was the Archiv für experimentelle Pathologie und Pharmakologie . Together with the internist B . Naunyn, a friend since Dorpat days, and E . Klebs, Schmiedeberg founded this journal in 1873 shortly after his arrival in Strassburg . He and Naunyn remained its edi-

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tors until his death . The Archiv quickly became one of the most highly respected scientific journals, exemplary in its standards . For many years almost all pharmacologic research was reported in its pages and its contents were primarily pharmacological . After 4 name changes the Archiv is now called Naunyn-Schmiedeberg s Archives of Pharmacology . It has maintained the high standards of its founders and has just completed its 300th volume . Schmiedeberg s qualities as a writer are well exemplified by his textbook . The first edition of this "Grundriss der ArzneiThirty years later it had mittellehre" appeared in 1883 (14) . reached its seventh edition and had been translated into many languages . In the preface to the first edition Schmiedeberg circumscribes the province of the pharmacologist . "This outline presents only that part of drug teaching which can be judged by the pharmacologist, and is, therefore, not a compendium of therapy . The pharmacologist does not deal with ther apy, the practicing clinician does . The complexity of treatment in modern medicine on one side and the scope of pharmacology on the other no longer allow anybody to represent both disciplines if he is not to become a dilettante in one of them . Without pharmacologic knowledge the physician will stumble around in the dark whenever he employs drugs . Transmission of such knowledge is one of the tasks of the pharmacologist . Yet, he cannot tell physiRather, he must content himself cians how to treat illnesses . with describing the actions of important pharmacologic agents on man, with characterizing the consequences for the entire organism of the use of such agents under various conditions, and with deriving general rules for the use of drugs from pharmacologic facts . Whether the actions exerted by a drug on the organism can be therapeutically useful depends not only on the nature of the illness but most importantly on the features of each particular case" . In Schmiedeberg s introduction to his book we sense his great concern with the prevailing empiricism in pharmacology which had He argues forcefully that brought the discipline into disrepute . pharmacology must receive a rigorous experimental foundation if it is to gain its proper place as a biologic science alongside physiology and pathology . This experimental pharmacology should then study all substances which through their chemical properties cause changes in the living animal organism, regardless of whether or not they are employed in therapy . Schmiedeberg categorically rejects the notion that scientific concern of pharmacologists should be limited to substances of accepted therapeutic value . He points out that thorough experimental studies of a substance can disclose therapeutically useful properties which nobody could have suspected in advance . In any case, how can one be . guided by something as fickle as clinical acceptance of a drug? "Many drugs disappear from the scene after a brief period of use . Others take their place but sooner or later may meet the same fate . In some countries drugs are used whose names would not even be recognized in others . When all is said and done, each physician has his own drug trove" . Schmiedeberg knew very well how unscientifically and, therefore, unsatisfactorily drugs were being used by clinicians . He felt that the experimental underpinning of pharmacology would

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enable this science to generate the facts without which practicing physicians could never be extricated from the morass of their pharmacotherapeutic prejudices . A scientific approach to drug therapy could not possibly flourish before basic pharmacology was firmly established as a scientific discipline and had generated experimental findings about drugs that could explain their clinical actions . Some critics have suggested that Schmiedeberg had no interest in drug therapy and no concern for the problems of the practicing physician . They must have misunderstood his insistence that phar macologists can communicate facts about drugs only after these have been ascertained by experimentation and his caution that expertise in pharmacology is not a sufficient qualification for treating any particular patient . "Pharmacology is a guide-post for therapy, but the therapist must decide which road to take" . Any doubt about Schmiedeberg's concern for making therapy more rational is removed by reading the fourth section of the introduction to the "Grundriss der Arzneimittellehre" . Here Schmiedeberg considers "The Choice of Drugs on Rational Grounds" . He points out how difficult it is to determine the therapeutic effectiveness of drugs and compares the value of sub jective estimation, statistical comparison and what he calls the "rational method" . Most of this lucid discussion remains entirely valid one century later . Knowledge about the effects of drug therapy gained solely through observation and subjective estimates Schmiedeberg considers highly uncertain, because it rests on the assumption that the observer can predict the course which the illness would have taken without such therapy . He strongly deplores that after constant repetition such impressionistic opinions are often accepted as facts . Statistical comparisons between a treated group and a control group Schmiedeberg accepts as much more conclusive . He is concerned, however, about their methodological difficulties . In par ticular, he stresses the problem of obtaining sufficiently similar patient groups and of avoiding all differences in their treatment other than the administration of the drug in question . He also emphasizes that statistical comparisons only yield results of "general significance" which do not ipso facto apply to individual cases, each of which has its own features and course . In any case, to him both subjective evaluations and statistical comparisons are "purely empirical" and yield no insights into the mechanisms of therapeutic drug actions . Schmiedeberg's hope for better pharmacotherapy clearly lies with the "rational method" which consists of counteracting disease-induced disturbances in the various organs with specific drug effects . He admits that successful application of this method requires exact knowledge of all aspects of the illness as well as understanding of the actions of drugs . He appears strangely confident about the achievement of the former goal, or perhaps he was content to leave this task to clinicians and pathologists .

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In contrast, Schmiedeberg tells us exactly how the actions of drugs will be delineated : "experimentation is the only possible way" . There is no reason to believe that he had only animal ex perimentation in mind . Although he never used the term, Schmiedeberg would surely have welcomed the development of clinical pharmacology as a scientific discipline based on controlled experimentation with drugs in healthy human subjects and in patients . Certainly, however, he would have insisted that the clinical pharmacologist must remain an experimental scientist firmly based in pharmacology and should not become a pharmacotherapist delivering patient care . That would constitute the pharmacologic and clinical dilettantism he warned about . Would Schmiedeberg be disappointed to learn that the "rational method" of drug development and therapy has not yet been successfully applied to many important diseases? Would he be sur prised to find that today we often know far better what a drug will do to a patient than what that patient needs to have done to him? How would he react to our considerable understanding of the pharmacologic actions of such drugs as antithrombotics, hypoglycemics, hypolipidemics and antiarrhythmics and our great uncertainty about the therapeutic usefulness of their chronic administration? Most probably he would point out that it has proved easier to apply experimental methodology to the delineation of drug actions than to the elucidation of the genesis and mechanisms of diseases . Very likely he would be proud of the achievements of pharmacological science during the 57 years since his death . Certainly he would tell us to continue experimenting . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 12 13 14

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G . KUSCHINSKY, J . Hist . Med . 23 258-271 (1968) . E .R . HABERMANN, Annu . Rev . Phârmakol . 14 1-8 (1974) . 0 . SCHMIEDEBERG, Arch . Ex . Pathol . Pharmakol . 6 7 1-54 (1912) . J .J . ABEL, J . Pharmakol . Ex . Ther . 2 - 6 X926) . H .H . MEYER, Naturwissenschaften 1 1~-107 (1922) . T . BILLROTH, Ueber das Lehren undLernen der medizinischen Wissenschaften an den Universitäten deutscher Nation , p . 8, Wien (1876) . R . BUCHHEIM, Arch . Ex . Pathol . Pharmakol . 5 261-278 (1878) . S . HAUSMANN, Die Kaiser-Wilhelms-Univers tät, Strassburg, Ihre Entwicklung und Ihre Bauten , Heinrich, Leipzig (1897) . C .N . PARKINSON, ParkinsonTS Law , p . 61, Riverside Press, Cambridge (1957) . SCHMIEDEBERG FESTSCHRIFT, Arch . Exp . Pathol . Pharmakol . Supplementband 1-528 (1908) . H .H . MEYER, Arch . Ex . Pathol . Pharmakol . 92 I-XVII (1922) . R . GOTTLIEB, Munch . Med . Wochenschr . 6 1119-1121 (1921) . B . NAUNYN, Arch . Exp . Pathol . Pharmakol . 9 0 I-VII (1921) . 0 . SCHMIEDEBERG, Grundriss der Arzneimittéllehre , Vogel, Leipzig (1883) .