PAUL EHRLICH' PAUL KARRER University of Zurich, Zurich, Switzerland (Translated by Ralph E. O e s p e ~University ,~ of Cincinnati)
AN INSIOAT into the personality of a scientist is often better obtained by visiting the site of his labors and getting a closer view of his daily surroundings. What do these reveal about Paul Ehrlich? At 45 he had assumed, in 1899, the directorship of the Institut fiir experimentelle Tberapie a t Frankfurt am Main, and in 1906 he was also made head of the adjoining Georg Speyer Haus, which had recently been established as a private foundation t o serve the cause of chemotherapeutic research. He worked in these two research institutions until his too early death in August, 1915. This was the most successful and decisive period of his life. The two rooms in which he carried on his personal activities were in the older Institut. The laboratory had about 20 square meters of floor space, and the adjoining ofice was about half as large. A large working bench, with gas and water connections, was in the center of the laboratory. Its top was crowded t o the very edges with hundreds of bottles, flasks, etc. containing all kinds of substances (Figure 1). There was no real working space except above the two Bunsen burners, which were the actual centers of his experimental activities. Here he frequently spent hours searching for color reactions and suitable coloring agents and making many remarkable observations in a purely trial and error fashion. The office or writing room contained a small writing desk and a sofa. However, both had long lost their true functions; they were piled high with books, periodical~and reprints, towering almost t o the ceiling (Figure 2). Since it was no longer possible to write here, and still less t o stretch out and rest, a small writing table had t o be used for signing letters. It stood in the laboratory, hut of course it too had only enough free space t o allow a letter t o be placed on it. At times, even this last remnant of table top was occupied and then two saw horses were brought in and a rough board laid across them, and the signatures made on this improvised table. Only two ordinary wooden chairs were provided. The visitors, of whom there were many and often important men, had to be content with these rather primiThia lecture was delivered a t Luzerne in June, 1954, before the Sohweizerische Mikrobiologische Gesellschaft on the occasion of the commemor~tionof the centenary of Ehrlich's birth. ' T o the readers of THIS JOURNAL who may wish to know more about Ehrlich, the translator heartily recommends the charming and very human account given hy Ehrlich's secretary, Miss Martha Marquardt, in her "Paul Ehrlich" published by Sehumsnn, New York, 1951. 392
Paul Ehrlich
tive seating facilities and, if not, as was usually the case, they were received standing. Ehrlich ordinarily arrived in the Institut at 10:OO in the morning. First of all, he was brought up t o date on the activities of the various sections; he then visited all of the laboratories and talked with his collaborators. At intervals he dictated letters while standing, or a t least roughed out several ideas which his secretary later put into proper letter form. By this time it, was 1:00 o'clock. Without stopping his work, he drank a cup of soup. Many of the afternoous were spent in the laboratory, making one test-tube experiment after the other. If he thought that he had made a worth-while finding, he noted it on paper at once and sent the slip t o an associate so that the latter could look into the matter in more detail. This writer often received two, three, or even four such yellow slips a day (Figure 3). At 5:00 or 5:30, the indefatigable man, for whom time seemingly did not exist, was notified by telephone by his wife that it was time t o come home. He suent the long eveninp. wreathed in clouds of smokeA(hesmoked c e s s a n t l ; and was said t o have lived principally on cigars and mineral water), in his large library, where be read, wrote scientific papers, and above all gave free rein t o his lively imagination, furnished him with happy and significant ideas, This rather detailed picture of the daily routine of Ehrlich's life shows that externals and comfort counted JOURNAL O F CHEMICAL EDUCATION
for little with this great scientist and infinitely modest, man, no more than did money, which t o him was merely a means of advancing his science. Intrigued by every avenue of his field, he was interested solely in research and gladly sacrificed himself to this end. Paul Ehrlich mas born on March 14, 1854, at Strehlen in Silesia. He studied medicine a t Breslau, Strasbourg, Freiburg, Leipsic. His teachers included Waldeyer, Heidenhain, Cohnheim, and his cousin Carl Weigert. He later worked at the Charit6 Hospital in Berlin under the nominal direction of Frerichs and Gerhardt, and above all was associated with Robert Koch from 1890 to 1896. Even as a medical student he published a uumber of papers dealing with complet,ely new lines of thought. An episode during his student days was characteristic of the manner in which he derived important leads and conclusions from seemingly insignificant observations. He had read in Heuhel's hook on lead poisoning that the cells in which this met,al accumulates are able, even though dead, t o extract lead from its solutions and store it iuside themselves. From this statement Ehrlich concluded that these cells must have a selective anchoring ability for lead. He at once extended this idea and said to himself that probably not only lead but many other materials would exhibit such selective affinity toward certain cells of the organism. He tested this postulate with dyes and found confirmation. This undoubtedly was the impulse leading directly to his subsequent fundamental studies of the selective staining of cells, i.r., vital staining, which reached a certain peak in the discovery of a selective staining of tubercle bacilli. Working with dyes in a clinical laboratory was rather unusual at that time, and its accompanying feature, namely, the smudging of t,he table tops with traces of these coloring matters, aroused of course the ire of his fellow occupants of the laboratory. One of his older colleagues told him bluntly, "Wherever you work, you leave traces hehind," a remonstrance which in years to come was recalled with amusement and pride by Ehrlich. CORPORA NON AGUNT NISI FIXATA
Although the research fields tilled by Ehrlich may appear to be quite divergent, they were in fact dominated and tied together by a common idea, namely, that
Pigum 1.
Ehrlish'a Laboratory at ths lnstitvt fur Expe~irnentelle Thorapi. at Frankfurt e m Main
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Figure 2.
P a d Ehrlich in His Offire
the biological effect of all materials is constitutionspecific,that the structure of an active compound must be precisely geared to the cell constituents, and that the biological action presupposes an anchoring of the chemical substance on the cell. He thus logically set up his postulate: corpora non agunt nisi jixata in opposition to the ancient doctrine: corpora non agunt nisi solula. He seemed to have found confirmation of this theory in his staining of cells and living organisms and in his chemotherapeutic researches. Thus in his usual clear fashion he once said: If we wish to conduct as it were specific therapy with s, particular clnsa of compounds, the arsenicals for instance, in the case of various infectious diseases, it is possible to do so only by discovering for every parasite certain anchoring "accessory groupings" which are to a certain extent peouliar to it, whioh posseas particular radicals and thus make possible a apeeifio anchoring.
On another occasion he coined the now famous phrase: We must therefore learn to tske aim, and learn to tske aim through chemical variation.
Paul Ehrlich's earlier research years were occupied with his studies of cell staining and vital staining, to which were joined fundamental investigations of the histology and physiology of the blood cells. With the aid of dyes he was able to show the existence of two types of white blood corpuscles, namely lymphocytes and leucocytes, and he was successful in differentiating sharply the elements from which they are constructed. His successes, both theoretical and practical, were still greater when he began to deal with the problems of the theory of immunity. He worked out methods for rendering animals highly immune and later he developed procedures for making quantitative measurements of antibodies and for standardizing sera. He thus became the first to make really possible the practical application of curative sera. These investigations were undoubtedly inspired by the discovery in 1888 of the diphtheria toxin by Roux and Yersin and by the discovery of the diphtheria antitoxin by Behring. However, Ehrlich proceeded in his own way. In ricin, the poisonous principle of the castor bean, he found a substance which, similar to the bacterial toxins, produced ant,ibodies in the animal
German Dermatological Society Ehrlich could justifiably declare: I certainly can claim credit for being the first to allow myself to be guided by the need for pursuing therapy from the distributive standpoint. This point of view also became the source of the side chain theory, far which even the opponents must concede to me that it has exerted a very considerable influence on the course of modern research in immunity.
organism and which in addition was easy t o detect because of its ability t o cause red blood cells to clump and to make them break up when it was present in considerable quantity. With the aid of this handy toxin model he was then able t o clarify the qnantitative relations between the toxin and antitoxin. He thus laid the foundation for many other studies of bacterial poisons and the antibodies they produce, investigations carried out by him or by Behring and a number of other workers a t the laboratory of Robert Koch in Berlin. When it then became necessary t o organize a government laboratory for checking the newly introduced curative sera, Paul Ehrlich was put in charge. This establishment was a t Berlin-Steglita from 1896 until 1899 when it was moved to Frankfurt am Main, Here Ehrlich found the time and opportunity to study in detail, the relations between toxins and antitoxins, especially in the case of diphtheria toxin, and t o work out exact measuring methods, and to put the study of toxins and serology on a firm footing. The extent of these studies is indicated by the fact that they involved about 10,000 guinea pigs. THEORY OF IMMUNITY
The problems of the theory of immunity eventually led Ehrlich also t o set up his so-called side chain theory which though accepted enthusiastically by some was sharply rejected by others. Despite such opposition it nevertheless exerted a powerful influence on the thinking and the mode of considering the immunity theory so that in a lecture delivered in 1908 before the 394
This side chain theory is based, on one hand, on the view that a toxic material can act only when it is anchored by particular haptophoric groups of the cell. This is especially true also for the toxins. The side chain theory then explains the formation of the antitoxins (antibodies) by stating that the toxin initially combines with certain cell receptors. The latter, because of the irritating action of the toxin, are produced in excess by the cell, they break loose from the latter, and, still provided with haptophores, they arrive in the bloodstream where they are capable of capturing any of the toxin present and immobilizing it. Recent work has shown that plasma cells play the role of antibody-formers. During his lifetime, Ehrlich's side chain theory was attacked particularly by Metchnikoff and his school, who regarded the phagocytes as the structures which destroy the invading bacteria and other cells, which likewise produce protective ferments (enzymes). Whereas the macrophages consume red corpuscles and other cells, the microphages clear out the bacteria. I n the end, Metchnikoff conceded that his phagocyte theory was not unconditionally opposed t o the side chain theory and could be combined with it. I n the 40 or more years since the death of Ehrlich, various other theories have been advanced t o replace it with respect t o the interaction of the antigens and antibodies. For example, l'auling believes that the antigen attracts the free ends of a globnlin-polypeptide chain and in a very particular manner forms the latter into a specific structure, which is complementary t o the antigen structure. On the other hand, the remainder of the globulin molecule shapes and folds itself, according t o other habits peculiar t o itself, and in doing this tears itself loose from the antigen. Eventually there is present a free mobile antibody, whose structure was determined, on one hand, by the intervention of the antigen, on the other by the folding of the polypeptide chain which was accomplished iudependently of the former process. Accordingly, this theory assumesand in this it goes somewhat beyond the Ehrlich side chain theory-an active shaping of the antibody by the antigen. I n the molecule ends of the polypeptide chain specifically shaped by the antigen it is not difficult to recognize the haptophoric groups of the Ehrlich terminology. A so-called ferment theory has been advanced by Burnet and Fenner and by Savag as a further replacement for the side chain theory. It is postulated that the antigen specifically alters the ferments which serve t o produce globulin in such fashion that they acquire a new permanent condition which is specifically attuned t o the antigen. Accordingly, this hypothesis transfers the formation of a specific structure by the antigen from a globulin molecule t o a ferment (enzyme). The concept of the constitution-specific relation between antibody and antigen, which conJOURNAL OF CHEMICAL EDUCATION
stituted the keystone of the side chain theory, is t h e r e fore retained also here. Of course, 50 years of research in this field have brought certain modifications in the ideas, but they still embody structural elements which the creator of the side chain theory attempted t o express in his highly pictorial language, and from this it is clear that undoubtedly our present theories will some day also have to be deepened or recast or replaced by something better. Ehrlich himself said that "an advance in our understanding can come only from the theoretical standpoint and an unsuccessful theory is always more fruitful than pure empiricism, which merely registers facts with no attempt at explanation." This statement in its bold form may perhaps go too far, but it is characteristic for this scientist, whose imaginative powers knew no limits and to whom his effervescence of new ideas and thoughts always provided inspiration for new strictly scientific researches. THE CANCER PROBLEM
Ehrich was interested also in the cancer prohlem. He was able to increase the virulence of mouse tumors t o the point that they could be transplanted with certainty to other experimental animals. Only then did it become possible to conduct experiments to determine what procedures or conditions can raise the resistance of the animals to the tumors. Even a t this early date Ehrlich embraced the idea that cancer is due to some sort of parasite, comparable to the bacteria, a view that still survives in the idea that tumors result from a virus. EXPERIMENTAL CHEMOTHERAPY
The last major field of study t o which Ehrlich turned his attention was experimental chemotherapy. These researches brought him the highest scientific and practical successes and also a tremendous amount of publicity and popularity. I n these investigations he was once more guided by his theory that among the thousands of compounds it is necessary t o search for those that can anchor themselves t o the cells of the parasite by means of certain groups. However, the solution of this problem is encumbered by the necessity that the active chemical substance must be less toxic to the host, man for instance, than t o the parasite. I n dealing with the foundations of experimental chemctherapy, Ehrlich said: "Actually only those materials can be used as remedies which are so constituted that the damage t o the parasite is maximal and t o the body organs minimal." I n other terms, the parasitotropy must be much greater by far than the organotropy. The first chemical compounds studied under his direction as chemotherapeutic agents were dyestuffs of (a) the benzidine series (trypan red, trypan blue) and (b) the triphenylmethane series (e.g., tryparosan, a halogenated parafuchsin). Although they showed some healing action when administered to mice infected with trypanosomes, their effect was relatively slight. The hoped-for distinct progress was obtained only when trials were made with organic arsenic compounds. Some success against sleeping sickness had been secured by Robert Koch with atoxyl, which was first prepared by BBchamp in 1863, and Paul Uhlenhuth had shown that syphilitic rabbits could be cured by means of this VOLUME 35, NO. 8, AUGUST, 1958
arsenical. When Ehrlich turned t o this compound, he first of all cleared up its structure and then improved its characteristics by preparing various derivatives, such as arsacetin and arsenophenylglycine. But it was only after more years of research that the great success came in salvarsan (arsphenamine) which ushered in a new era in the struggle against infectious diseases. It is difficult today to realbe fully the great sensation this triumph aroused and to appreciate the enthusiasm that spread over the entire world when not only the medical journals but the daily press announced: syphilis is no longer an incurable disease, the trypanosomiases of the tropics (sleeping sickness, tsetse, donrine, Aleppo boils) can he combatted with success, framboesia (yaws) and relapsing fever can be eliminated, glanders, erysipelas and tertian malaria can be favorably affected. To Paul Ehrlich this success was no reason for standing still. On the contrary he continued his efforts with his customary energy and enthusiasm, hoping for further progress. The new chemotherapeutic agents were not ideal; they were toxic t o a degree that could not be disregarded. Moreover, some strains of parasites became resistant t o these compounds. These findings led Ehrlich to make extensive studies of the dmg resistance of the parasites and to search for new, still more effective chemotherapeutic agents. The fact of drug resistance is now well established in medicine and biology. But who remembers that the knowledge of its existence is hardly a half-century old and that this biological phenomenon was discovered by Paul Ehrlich as a consequence of deep-reaching experimental studies? While testing the action of arsenic compounds on trypanocidal effects, he found that relapses occurred when insufficient doses of the arsenical were administered and the trypanosomes which then reappeared in the blood had become more resistant t o the remedy. After further treatment of the pathogenic organisms with the same arsenic compound, the resistance increased still more until eventually the organisms had become "arsenic tolerant." This resistance was retained by the particular strain' of trypanosome, i.e., a permanent modification of the pathogen had developed which could be transmitted to the offspring. This fact was of prime importance in treating infectious diseases, and Ehrlich himself pointed out that the way t o avoid such drug resistance was t o employ a procedure which he called: therapia slerilans magna. He was indefatigable in his efforts t o have physicians adopt this method of treatment involving the maximum feasible initial dose. He explained drug resistance by assuming that in the microorganism certain "chemoceptors," which are specific groups that can bind the chemotherapeutic agent, are so altered when drug resistance occurs that they have less and less and eventually no affinity for the medicament. He further recognized that the acquired drug resistance of a microorganism toward chemotherapeutic agents is very constitution-specific i.e., it is dependent on the constitution of the particular substance. However, exceptions are known. Ehrlich himself showed that arsenic tolerant trypanosome strains had become resistant also t o certain acridine dyestuffs (and several related pigments). After his death, there was a lull in the field of chemo-
therapy; then gradually systematic chemotherapeutic researches were instituted especially in the works laboratories. They led eventually t o great triumphs. One of these was the discovery of Germanin (Bayer 205) and a still greater was the discovery of the sulfonamides (Domagk, TrBfouel, Nitti, Bovet, 1935). And then during the war years there began, with the discovery and introduction of penicillin by Fleming and Florey, the new era of the antibiotics, which made a large number of other infectious diseases accessible to successful treatment and which, in comparison with the earlier remedies, have an extraordinarily lower organotropy, i.e., toxicity toward the host. Only in this one point did the optimism of Ehrlich not suffice t o anticipate correctly the later research. In a lecture given in 1910, he said: The curative sera have no affinity for the bodily substances. Consequently, in this case the organotropy is reduced to null, the parasitotropy is absolute, and thus the antibodies represent magic bullets, which seek out their targets of their own accord. Hence the wonderful specific action and hence the advantage which the serum therapy and active immunization have over m y chemotherapy. We e m never expect any such successes with chematherapy and wxordingly we must bend all our effort to aim its sharply as possible, so that the parasites will be hit as fully as possible, and the body as little as possible.
However, in a later (1912) lecture he was more confident: "I do not believe this to be entirely excluded." Modern chemotherapy has come very close t o this goal, a t least in the case of some antibiotics. It too is moving along the paths which Paul Ehrlich, far ahead of his times, cleared and himself traversed for the first time. His thought that an effectivechemotherapeutic agent must contain a haptophoric and a toxophoric group-in salvarsan the ortho-aminophenol group was assigned the haptophoric properties and the arsenic the toxophoric characteristics-was widely criticized. Some writers, such as Meyer and Overton, believed that much significance resided in the distribution of a material between the water and the lipoid phase in the organism with respect to the efficacy of the chemotherapeutic agent. Although the solubility characteristics of drugs obviously are of some importance, such factors can provide no basis for explaining the distinct constitutionspecificity of most chemotherapeutics. Furthermore, the action of the antagonists of many remedies, for example the antagonistic action of sulfonamides against the vitamin p-aminohenzoic acid or folic acid can be nnderstood-if at all--only on constitutional-chemical grounds. The more recent investigations of antibiotics, chemotherapeutics, and vitamins have, however, led to the discovery that the action of such substances on microorganisms is frequently not direct but indirect, in that they block or exclude certain materials which are of vital importance to the microorganisms and hence they indirectly aid in the destruction of these microorganisms. I t has been shown in numerous instances that enzymes are the primary point of attack of many drugs.
I n almost a11 of the fields explored by Ehrlich he opened new ground and made discoveries that had hitherto been completely unknown. These novelties, often far ahead of the time, which often were embellished with richly imaginative metaphors and espoused with ardor, frequently aroused the criticism and opposition of his professional colleagues. He had many scientific opponents and carried on impassioned discussions with men such as Bordet and Metchnikoff. For the most part, he has been upheld by the further development of the field. Scientific criticism never offended him, rather it inspired him t o new experimental activity. Many of his happy thoughts and brilliant inspirations, however, remained unrealized because other researches were given precedence. For example, he told this writer as early as 1913 that attempts should be made t o cure some diseases by infecting the patient with certain other diseases, and he expressly proposed malaria. This was four years before Wagner-Jauregg treated syphilis successfully with malaria. Paul Ehrlich received all of the honors that the world can confer on a great scientist. His own country and those abroad heaped him with lavish expressions of gratitude. The Nobel Prize for medicine was divided between him and Metchnikoff in 1908. None of these honors changed the simple modest man in the least. He went on as before, completely devoted t o his work. One characteristic was known only t o those who were privileged to become intimately acquainted with h i . This was his great human kindness; it was bestowed on many patients, on the numerous persons who came to him for aid and assistance, and on many of his closer associates and collaborators. The author worked with Paul Ehrlich for only three years, his last years on this earth. That period is among the happiest times of the author's life. Every day we had long conversations, often hours long, when we d i e cussed scientific problems. His secretary, Miss Martha Marquardt, in her biography of Ehrlich states that he and the author quickly became friends. The author prefers to say rather that Ehrlich was a fatherly friend to this young man who has always felt deeply indebted t o him. The name Paul Ehrlich will always be written in letters of gold in the history of medicine and science. His rich powers of imagination and his keen critical judgment produced a combination of talents with which he was able to open paths and successfully attack problems that had previously not been touched a t all. He had followed the counsel that had once been given t o research workers by another great hero of the physical sciences, August Kekul6: Let us learn to dream, then perhaps we shall find the truth: And to those who do not think, The truth shall he given, They will harvest without effort. But let us take care not to tell others of our dreams before they have been tested by the waking mind.
JOURNAL OF CHEMICAL EDUCATION
