(Automatic transcript - may present inaccuracies)

>> Good evening ladies and gentlemen. From the New York Academy of Medicine, we bring you a special program in commemoration of the 100th Anniversary of the birth of Paul Ehrlich, discoverer of Salvarsan, the magic bullet. Among our distinguished speakers this evening, will be Dr. Owsei Temkin of the Institute of the History of Medicine at Johns Hopkins University, Dr. Ernst Jokl of the Valley Forge Heart Research Institute, and Dr. Cornelius P. Rhoads of the New York Memorial Hospital. And to open the evening's program, here is the President of the New York Academy of Medicine, Dr. Alexander T. Martin.

>> Ladies and gentlemen, I'm very glad to welcome you here this evening to this very important meeting. It is in commemoration of the 100th Anniversary of the birth of Paul Ehrlich. It is being held under our section on Historical and Cultural Medicine, of which Dr. Curran is Chairman, and also the committee on medical information of the academy. In conjunction with these, we are very happy to greet two other groups who are cooperating with us in this meeting the [inaudible] Medical Society of New York and the Medical Circle Incorporated. We are very happy to have the presidents of each of these two groups here with us tonight. And in particular, I'd like to welcome a distinguished guest, the Consul General of Western Germany, Dr. [inaudible].

[ Applause ]

>> Mr. Chairman, ladies and gentlemen, it is a great honor and privilege for me to be invited to a night when you are celebrating the 100th Anniversary of Paul Ehrlich's birthday. I must tell you, quite frankly, though that I was somewhat embarrassed when I received your kind invitation. Here I'm speaking before distinguished group of outstanding physicians and scientists who knew much more about Paul Ehrlich and his work than I do. I personally, a Doctor of Civil Law only, I do not feel qualified to address this assembly on this subject of a medical gene just like Professor Ehrlich but I'm very, very proud that as a representative of the Federal Republic of Germany, I was asked to speak about this great gentleman. There's little I could tell you about his scientific achievement. You all know that Paul Ehrlich is a physician, chemist and biologist, devoted all his life to serum research work in the field of contagious diseases. My only personal experience with serum dates back to my early childhood when I had a serious attack of Scarlet fever. Five doctors, who my father summoned, give me up is hopeless. They asked permission to use a newly discovered serum. My father agreed and I was inoculated with the serum which was made from the blood of a horse. The horse died the following day and I survived.

[ Laughter ]

I still remember that I wept when I heard about the poor horse. A white one it was. The case was widely discussed in medical publications and there were some question whether my recovery was due to the serum or my having the constitution of a horse.

[ Laughter ]

But to get back to Paul Ehrlich, fortunately, I'm in the position to say something about his character, his personality, and his charm because members of my family knew him very well. I would like to mention my late brother, Atto [assumed spelling], a professor of pharmacology at Frankfurt University. And there is another relative of mine connected with Paul Ehrlich, my cousin, Professor Ferdinand Blum, himself, a great scientist was Paul Ehrlich's friend and doctor. Ferdinand Blum, who now lives in Tubingen is almost 90 years old still hard at work. He has been asked to speak at the Frankfurt celebration in honor of Ehrlich and von Behring. I wrote to him with the request for some details on Ehrlich's life. He replied immediately and I'm going to read you a part of his delightful letter. I quote. "Paul Ehrlich had a charming and truly funny nature. He needed that [inaudible] in his life [inaudible] quite. Yet he did not allow the difficulties and obstacles to deflect him from the target which he had set himself. People who knew him only slightly [inaudible] and a bit of [inaudible] may be that was due to the way he handle the conversation and perhaps to his desire to be left alone with pondering that problem. He greatly loved and was grateful for simply entertainment the distraction outside his scientific work. But he also was a man who was feeling the sharp and preside detriment on matters, political, social, and human. I do not think that Ehrlich ever made a decision unaware of what went on in the world around him, nor do I think that he ever gave anybody a wrong advice. He was probably reliable friend and I keep his friendship in grateful remembrance." End of quotation. Permit me to adjust a few words to Ferdinand Blum's appraisal of Ehrlich. As I speak to you tonight, Ehrlich's personality and achievements have a very special significance to me also in another direction. I hope you will not think need presumptuous if I compare his work to the job which we, especially in my service, have taken upon ourselves, all his strengths and all his heart, powered Ehrlich fought against diseases of the body. We too are fighting against a deadly dangerous disease of the mind emanating from the totalitarian school of sort. On this occasion, we pledge ourselves to carry on this fight, confident to succeed. Thank you.

[ Applause ]

>> I will now turn the meeting over to the Chairman of the section on Historical and Cultural Medicine, Dr. Gene A. Curran.

[ Applause ]

>> Dr. Martin, distinguished guests, ladies and gentlemen. It is a truly very great honor to be able to preside at this occasion where we are celebrating the 100th Anniversary of one of the really great man of all medical history, Paul Ehrlich who was born 100 years ago next Sunday, March 14th. I, of course, should not encroach at all upon the speakers who are to follow, who will talk to you about the era of Paul Ehrlich, Ehrlich as man scientist, as the man on contemporary science. But I would like to say just for about a minute, some of the things which Paul Ehrlich means to me. I think we might start in as follows, a great pioneer and the application of the aniline dye staining to blood cells, to bacteria, to tissue cells, and his side chain theory concept of immunity and of chemotherapy, and as prophet of the age of the magic bullets. I think we can actively describe him as indefatigable researcher with unvarying devotion to his ideals inexhaustible patients and uncomparable determination to follow his inspiration along the past, which is genius pointed out to him. Three of his models--I also like to quote, one was you see, you understand, you know. "In other words is certainly I find guide for any of us today trying to do scientific work, much testing, accuracy, and precision of experiment, no guess work or self deception, much work but few publications, no provisional or preliminary reports." Also, finally, one of Ehrlich's favorite models was what he called his 4 Gs. If I can announce the German first, Geduld, Fähigkeit, Geld, Gluck. Patience, ability, money, and good luck. I'm sure all of us were working within research institutions know we need a lot of all four, equally important today as it was 100 years ago. Our first speaker tonight is one of the fully distinguished professors and scholars in the field of medical history, Professor at Johns Hopkins University, Institute of the History of Medicine. Dr. Owsei Temkin, who is supremely qualified to portray to us the background and the era of Paul Ehrlich. Dr. Temkin.

[ Applause ]

>> Dr. Curran. Ladies and gentlemen, the era of Paul Ehrlich is the period in which Germany exerted a preponderant influence in the affairs of the world. Ehrlich was about 17 years old when France was defeated by Prussia and the German states which Bismarck welded into a new Empire. When Ehrlich died, the First World War had just entered into its second year. Thus his manhood extends over the era of Bismarck and Wilhelm II, when Germany played the role of a world power, proud of her army and her "Kultur." In the wake of the Franco-Prussian War, the German university of Strasbourg was founded, largely with the aim of counterbalancing the French influence in Alsace. University professors were esteemed as perhaps never before, and the Geheimrat was almost a minor deity. It was a time of great achievements in all the sciences. All over the world, German had to be studied by scientists no less than by students of the humanities who wanted to keep abreast of new methods and results. If the professor was well aware of what others owed to his rank, he also remembered what he owed to his position, never ceasing hard work, thoroughness and self-criticism in his investigations, objectivity in viewing the results of others. It was the devotion to his calling that had raised the German professor to a pinnacle, not the mere worship of a title, widespread as such worship might be. Yet achievement is not always identical with inner strength and greatness. The time of classical German philosophy and literature was a matter of the past. With some very notable exceptions, the greatest names in the history of German sciences of the 19th century had made their debut prior to 1870. Among historians, Ranke was a very old man, and of Mommsen's Roman History the first three volumes had appeared in the late '50s. Liebig, the great chemist, died in I873. Henle the anatomist, Virchow the pathologist, Helmholtz and Carl Ludwig the physiologists, the clinicians Frerichs, Traube and Wunderlich had long occupied chairs of their own. Altogether, the debates over fundamental philosophical and scientific issues had lost vigor because of lack of opposing factions. To be sure, Darwinism was a lively topic, but its radical defense by Haeckel dated back to i868. In 1872, Du Bois-Reymond, the physiologist at the University of Berlin, read a paper, "On the Boundaries of the Knowledge of Nature" which he concluded with the words, "Yet, when the Scientist finds himself confronted by the riddle of matter and force, and their ability to think, he is obliged once and for all to pronounce the most difficult of judgments "Ignorabimus", we shall never know. Now what is left for the scientist in the face of such philosophical resignation? Research that will lead to positive results, especially those useful in human life. Science and learning in the Germany of that period were not private affairs. Unless the individual found a position in a public institution, he remained an outsider. And public institutions were integrated into the state. Plans to establish a university in Frankfurt, the seat of Ehrlich's Institute, dependent solely upon the plans of its private founders, came to naught when the Mayor opened a meeting with a copy of the Statutes of the Prussian State in his hand and read, "The universities are creations of the State." This state made itself felt in many respects as a protector as well as a supervisor. Virchow might defy Bismarck, among his younger colleagues a certain aloofness from politics, leaving this field to the ordained rulers, became widespread. The political events found a relatively weak echo at the universities. Professors and students alike mostly came from well-to-do homes. Students did not work their way through college and aspirants to an academic career needed private means while waiting for an appointment. Arbitrariness at the helm of the state bred arbitrariness lower down. In the Prussian cabinet for cultural affairs, Friedrich Althoff came to rule as a veritable autocrat. As Ehrlich's example shows, he could be of the greatest help in furthering talented men. But his treatment of some professors dependent upon his approval did not help to strengthen their moral backbone. Moreover, the official policy of the state, Prussia as well as Germany, became anti-Semitic under the influence of Adolf Stoecker, the court chaplain in Berlin. It was an anti-Semitism that did not allow a Jew to become a full professor unless he was baptized, again, with very few notable exceptions. In medicine, particularly, the influence of the state went further than in many other European countries, let alone the United States. Public health found a central body in the Reichsgesundheitsamt, established in 1876. In 1880 Robert Koch was appointed to this organization which combined the functions of an institute for bacteriological and epidemiological research with a public health agency. That the state should have a hand in controlling drugs, especially vaccines that needed standardization and careful preparation, was almost a matter of course, as was the inspection of meat, isolation and disinfection in cases of infectious disease, compulsory smallpox vaccination of babies and school children, and the many other major and minor regulations where the paternalism of the state met with the national respect for administrative wisdom. When a scientific meeting was held at Konigsberg, Virchow and a colleague of his took a walk along the coast, stomping with difficulty through the sand at the bottom of the dunes. They were hailed by some ladies suggesting that on this special occasion they take the easier though prohibited path on top of the dunes. Virchow not only refused but got angry and excited and continued stomping through the sand, holding forth about the lack of understanding among ladies for laws that served the common good and had to be obeyed by everybody on all occasions . From 1881, this paternalism of the state took a new departure when Bismarck initiated a program of social insurance that was to include compulsory sickness insurance as well. It hardly needs saying that the government enforced its requirements for obtaining a license to practice medicine as a physician. This presupposed a secondary education with a strong classical note and a prescribed minimum of years of medical studies at a university. Certain courses, as well as two official examinations, were required before the license was issued which was then valid in all German states. The degree of MD was subject to the writing of a thesis and an additional oral examination. But it is the leeway that the German system of medical education allowed to the student which needs to be stressed in connection with Paul Ehrlich's development. Apart from the minimum requirements, the medical student was free to choose his courses, to change his universities, and to devote almost as much time to his studies as he desired. Anatomy, physiology, pathology, and so on, were presented to him as sciences, each in its own right. If he felt attracted by any of them he was not only free to concentrate his energies upon it, but almost from the beginning it was made possible for him to engage in investigative work of his own. To the mediocre student, the absence of a rigid curriculum was a danger, often a temptation to waste years in idleness and an excessive consumption of beer. To the good student it was an opportunity to find his own way, free from spoon feeding. Above all, it was an ideal training ground for future scientists. The system was based upon the identity of teaching and research and fostered a veneration for research which hardly found its equal anywhere else. We characterized the time of Paul Ehrlich as the period of preponderant German influence, on a scene, we now have to add, where medicine became increasingly international. The formation of international societies and congresses falls largely within these years. The problems to be attacked and the methods to be used for their solution tended to become the same in all countries. This increasing uniformity was necessitated by the intrusion of exact scientific research into all fields of the healing art, including its practice. Around 1860, there were as yet few skills which a good doctor could not have acquired from a practical course in gross anatomy, the example of a good preceptor, and books. The ophthalmoscope introduced by Helmholtz in 1851, and the laryngoscope invented by Manuel Garcia in 1855 were just coming into their own and their use might require additional training. As to the progress in pathology and experimental physiology up to that time, what was there that could not be followed by reading the literature? Changing concepts of disease were interesting but not of vital importance as long as they had little practical bearing. The first sweeping change, I think, came in the wake of Virchow's cellular pathology of 1858, with its transition from gross anatomical description to microscopic study. To anybody, untrained in the use of the microscope and not acquainted with normal histology, these new doctrines must largely remain ununderstandable. More important, perhaps, were the practical applications of microscopy which extended all the way from a reliable postmortem diagnosis to the examination of urine sediment. Here then was a need to learn a whole new branch of science, not only an isolated technique as, for instance, cystoscopy. The experience of William Welch who went to Strasbourg to study pathology and had first to take a course in normal histology with Waldeyer illustrates our point. Microscopy owed a good deal of its progress to improvements in staining of specimens. In the '50s, Gerlach had popularized the use of carmine as a nuclear stain. Julius Cohnheim under whom Carl Weigert spent many years in Breslau and in Leipzig, and who for some time was Ehrlich's teacher, was one of the masters in the development of staining methods. Cohnheim used gold chloride and aniline blue in his famous studies on inflammation of 1867. Leukocytes ingested aniline blue which had been injected into the blood stream, they were thus tagged and their appearance in inflamed tissue proved that they had found their way through the walls of the blood vessels and were identical with the pus corpuscles. This epoch-making paper of Cohnheim's is worth mentioning not only as an example of the early interest in staining methods but also because it played a part in the controversy between the two leading pathological schools in Germany. Cohnheim's investigation centers around keratitis and demonstrated that here too the changes in the blood vessels at the periphery of the cornea, are the first phase of inflammation. Thereby he contradicted Virchow on a point of great theoretical importance. Without personal animosity, the differences between the two were yet to develop into an opposition between the morphological and experimental schools. To Virchow and his pupils pathology, the study of disease, was becoming more and more pathological anatomy, to the adherents of Cohnheim it meant, above all, physiology and experimentation. The difference was really one of emphasis rather than excluding principles. However, it seems that Cohnheim and his circle stood closer to the rise of bacteriology. And the emergence of this new science, more even than pathology, forced the practitioner to abandon the old ways and to keep step with scientific progress. The debt which bacteriology owes to Pasteur is so well known that we need not dwell upon his early work. Around 1876 the question was not so much whether microorganisms could cause disease; rather it was which diseases are caused by microorganisms and how can claims in this direction be proved. The answer to the latter question was given by Robert Koch's famous postulates. It took a longer time to survey the domain of infectious diseases; it is not quite surveyed even today. Nevertheless, by 1882, when Koch announced his discovery of the tubercle bacillus, the immediate value of bacteriological techniques could no longer seriously be doubted, where the diagnosis of relapsing fever, anthrax, actinomycosis, gonorrhea, leprosy, typhoid, malarial fever, and tuberculosis was concerned. It goes without saying that the correct diagnosis often had its immediate consequences for prognosis and prophylaxis. This meant that a physician could not be satisfied with reading in books about the progress of bacteriology, he had to be able to handle the new methods required or at least to be able to avail himself of expert services. The speed with which one new discovery followed another must have contributed to the growing sense of a changing time. Two years later, in 1884, diphtheria, cholera, tetanus had been added to the list and, at the same time, antiseptic surgery was constantly gaining new triumphs. Antiseptic surgery did not presuppose much bacteriological refinement. It rested on the simple assumption that surgical infection was carried to the wound by hostile microorganisms that could be destroyed by a chemical agent, carbolic acid. This assumption almost strikes us as too simple. But the many anecdotes about the surgeons who, after careful antiseptic preparation, continued to operate with a scalpel that had fallen to the floor, and similar stories indicate that to the generation of the '70s and '80s, a great effort was needed to grasp the underlying principle. That we think of Lister's teaching as simple merely goes to prove how different the outlook of younger men who, like Ehrlich, grew up with the changed views must have been from that of the generation before him. Antiseptic surgery, which in the '90s was to be succeeded by aseptic surgery, made the healing art more efficient in its cure of disease. For a number of years surgery seemed superior to internal medicine. Circumstare et verba facere, to stand around and talk, was all the internist seemed to be able to do while the surgeon snatched people away from imminent death by boldly removing an inflamed appendix or a cancer of the stomach. Therapeutic successes of internal medicine were relatively slow to come because they needed an elaboration of so many factors, immunology, experimental physiology, and pharmacology. Though many of the results were achieved later, the foundation nevertheless was established during the years under discussion. As with the rise of bacteriology, so with immunology the name of Pasteur is intimately connected. In 1879 he discovered the possibility of immunization against infectious disease by attenuating the culture of the responsible virus. This discovery led to great practical results, but the physiology of immunity remained dark. Two theories arose in short succession seemingly excluding each other. Metchnikoff made "phagocytosis" the main line of defense, harmful particles were removed by cells that acted the role of policemen. However, this theory was not adequate to explain protection against dissolved toxic substances; here a humoral theory looked more promising and the promise found an early practical fulfillment in von Behring's invention of antitoxic sera for tetanus and diphtheria. But this brings us so close to the borderline of Ehrlich's own contributions that we had better turn to another aspect of developments in internal medicine. In a paper of 1878, Julius Cohnheim, whom I mentioned before, made an attack directed, as I believe, against Claude Bernard, although he did not mention the great French physiologists by name. Cohnheim claimed that experimental pathology should be in the hands of clinicians who encountered disease at the bedside or pathological anatomists who studied its appearance on the postmortem table. The mere physiologist, because lacking the necessary contact with morbid phenomena, would tend to raise and answer physiological questions only. I do not know whether Cohnheim actually had in mind Claude Bernard's Introduction to Experimental Medicine that had appeared in 1865. But his attack is understandable from the point of view of German conditions. Much of what this book was fighting for had become reality in Germany. Not only pathologists like Cohnheim, but clinicians too combined the clinical, anatomical, and experimental approach. As examples we may choose Frerichs and Traube who represented internal medicine at Berlin, in disharmony we must say, for they were bitter personal enemies, the steps did even there to have friendly [inaudible] with the enemy camp. Now Traube is usually remembered as one of the founders of German experimental medicine. As far back as 1846 he had declared that, "It is the experiment, added to passive observation, which can make pathology too what it wishes to become, an exact science." But it is not always remembered that Frerichs also was an experimentalist. As a young professor he had become famous through his article on "Digestion", a purely physiological subject and shortly afterwards his work on kidney disease that utilized animal experiments. More than Traube, Frerichs was also versed in chemistry. One of his greatest pupils, Naunyn, tells us about Frerichs' attitude towards his assistants of whom Ehrlich later was to become one. I quote Naunyn's words. "He accepted each one from the very first day as a man who unquestionably could and would do everything the position required of him. So confident was he, unfortunately, of this that he never gave us any instructions as to how we should do anything; indeed, he scarcely said what he wanted done, and he actually managed to have everything done to his satisfaction without any such explanations. A little later on Naunyn adds, "It was just as much a matter of course that we should make scientific investigations and produce able pieces of work, as that we should perform our clinical duties to his satisfaction. What this work should be and how we did it was again entirely up to us, for he let us come and go and do whatever we wished, however we wished. "It is only necessary to point out that Naunyn in turn had as his pupil Minkowski whose work on the pancreas and diabetes was one of the preconditions for the later discovery of insulin, in order to perceive the clinical tradition of the Frerichs' school in which chemistry and animal experiment combined with pathology to render medicine scientific. We might expect that the search for exactness in medicine would lead such a school to therapeutic nihilism which had plagued medicine around the middle of the century. But this was hardly the case. Frerichs, a consultant with a very large clientele, was saved by his faith in proved" remedies from falling into the pitfall. The younger generation was saved by association with experimental pharmacology. Historically speaking the new pharmacology stemmed from the same root as experimental medicine, it really was a part of the latter. In 1873 there appeared the first issue of the "Archives for experimental pathology and pharmacology" edited by the clinician Naunyn, the pathologist Klebs, and Schmiedeberg, professor of pharmacology. The first three articles are characteristic, an investigation of blood coagulation in the living animal, a discussion of the effect of quinine on blood, and a contribution to the knowledge of micrococci, even the budding discipline of bacteriology was represented. The nature of the new pharmacology needs a word of explanation. Schmiedeberg, in his textbook, later on, defined it as "the science of the changes brought about in the living organism by chemically active substances, except foodstuffs, without regard as to whether such substances are used for curative purposes or not." In other words, the pharmacologist merely investigates "the living processes under the influence of drugs." He is a biologist. It is up to the physician then to choose those drugs he wishes to use in therapy. Pharmacology and materia medica stand in the relationship of a pure science and its application. The science exists regardless of its application, while application should not be made without the backing of science. We characterized the era of Ehrlich as one of achievement. We set out to trace its general features and then tried to sketch the situation in medicine during Ehrlich's formative years. It was a peaceful time that allowed a man to concentrate on the work at hand, sometimes without looking up and seeing wider horizons. To unravel the mechanism of things may have occupied the mind more than to know their interconnection. As has been pointed out by others, public health was submerged by bacteriological studies and medicine treated man as an organism with little soul inside. Yet the end of our survey showed a belief in the superiority of science over its applications, and in conclusion we may ask what this belief embodied. We shall try to solicit the answer from the Englishman, Thomas Huxley, who became something of a philosophical spokesman for many biologists of the late 19th century. In an address of 1866, Huxley18 looked back upon the great pestilence that had ravaged London about 200 years before. "Surely," he exclaimed, "it is true that our countrymen are less subject to fire, famine, pestilence, and all the evils which result from a want of command over and due anticipation of the course of Nature, than were the countrymen of Milton, and health, wealth, and well-being are more abundant with us than with them?" Remembering the repeated epidemics of Asiatic cholera and typhoid, the high incidence of tuberculosis and venereal disease which then prevailed we might not grant a positive answer with the assurance Huxley expected. However that may be, the speech goes on to say that in the eyes of many contemporaries, natural knowledge is nothing "but a sort of fairy godmother, ready to furnish her pets with shoes of swiftness, swords of sharpness, and omnipotent Aladdin's lamps, so that they may have telegraphs to Saturn, and see the other side of the moon, and thank God they are better than their benighted ancestors." To which Huxley contemptuously replied, "I think I would just as soon be quietly chipping my own flint ax after the manner of my forefathers a few thousand years back, as to be troubled with the endless malady of thought which now infests us all, for such reward." The "practical benefits" as he calls them are but incidental. "I say that natural knowledge, seeking to satisfy natural wants, has found the ideas which can alone still spiritual cravings. I say that natural knowledge, in desiring to ascertain the laws of comfort, has been driven to discover those of conduct, and to lay the foundations of a new morality. We may no longer share such a robust faith in the spiritual value of natural science. Nevertheless, we have to recognize it as an expression of the striving of many scientists in the time of Paul Ehrlich. It was the existence of such faith that made them value their work beyond the immediate results they achieved.

[ Applause ]

>> Thank you, Dr. Temkin. At the last meeting of our section on historical and cultural medicine, our subject was Harvey Cushing as we knew him. Although Dr. Ehrlich has been dead for nearly 40 years, we have with us tonight a distinguished scientist who did know, Dr. Ehrlich personally. Dr. Ernst Jokl, a distinguished scientist and a physiologist in his own right of the Valley Forge Heart Research Institute of Fairview Village, Pennsylvania, would tell us of Paul Ehrlich, man and scientist.

[ Applause ]

>> Mr. Chairman, ladies and gentlemen. May I open this discourse by reading to you a letter received from Sir Henry Dale in London. "I shall myself be attending, on March 14th and 15th, the celebration which has been organized in Frankfurt to commemorate the centenary of the births of Paul Ehrlich and Emil von Behring. I gladly accept your invitation to send to the Commemorative Meeting at The New York Academy of Medicine an expression of my veneration for the memory of Paul Ehrlich. More than any other man, I think, Ehrlich was responsible for the tremendous revolution in the medicinal treatment of disease which has taken place during the last half century. He had a large share of the responsibility for making immunology a progressive, experimental science. In retrospect, however, his immunological work appears to have been a diversion from, or an opportunist extension of, the main line of his researches. Even from his student days, his mind appears to have been permeated and his activities directed by the idea of therapeutics based upon specific chemical affinities; and the line of development appears to be direct, from Ehrlich's early work on the use of dyes as micro-chemical reagents, and on the oxygen-needs of the tissues, through salvarsan to the sulphonamides, the antibiotics, and all the great modern wealth of directly curative remedies. I myself have personal memories of Ehrlich's endearing personality, and I gladly join with you in celebrating the centenary of the birth of this great man of genius, and great benefactor of mankind." H. H. Dale. Ehrlich, during his lifetime had a great deal of success, was appreciated. Recently, then autobiography has appeared of Willstatter, the great chemist, and he gives a vivid description how Ehrlich persona grata it's [inaudible] in Germany and also strict ceremonial surrounding the Kaiser didn't apply to him at all. However, Ehrlich doesn't fully understood during his lifetime. I received a letter two days ago from Professor Aschheim, whom you know is the discoverer of the pregnancy test who writes, "I attended several lectures Ehrlich gave in Berlin. His discourses were always received with enthusiasm notwithstanding the fact that many among his audience were unable to follow his ideas. It was his custom to ask during his lectures, "Isn't everything perfectly clear?" And everybody shouted, "Yes, yes". Who indeed would have admitted to the kind professor that his theories were in fact quite difficult to grasp?" What I try to give you tonight a picture of Paul Ehrlich as a man and scientist. I'd like to make three points. The first point which is characteristic of Ehrlich that he thought in quantitative terms. The second is that Ehrlich possessed the gift of formulating dynamic, scientific hypotheses which he presented picturesquely as if he were to describe mechanical models. And the third is that the leitmotif of Ehrlich's research work was the theory of his teacher, Julius Cohnheim, that natural adaptations in pathological processes are unreliable. As to the first axiom, I like to quote to you a paragraph from James Clark Maxwell's "Theory of Heat" to which Ehrlich has repeated referred, "The most important step in the progress of every science is the measurement of quantities. Those whose curiosity is satisfied with observing what happens have occasionally done service by directing the attention of others to the phenomena they have seen. But it is to those who endeavored to find out how much there is of anything that we owe all the great advances in our knowledge. Every signs and some instrument of precision which may be taken as a material type of that signs which it has advanced by enabling of service to express the results is measured quantities. In astronomy we have to divide the circle. In chemistry is a balance. In heat a thermometer. While the whole system of civilized life may be fitly symbolized by a foot rule, a set of weights and a clock. If Ehrlich would have done nothing else but introduced quantitative measurement into experimental medicine, he would have made his mark. As a matter of fact, I like to stress that Ehrlich received a Nobel Prize in 1908 long before he had started his chemotherapeutic research that led to Salvarsan. His Nobel Prize was given, he got it half and half with Mechnikov together for introducing quantitative work into immunology. Actually the citation of the Nobel Prize in 1908 made that point. He stressed that he has defined the degree of immunity as a ratio between the largest amount of poison an immunized animal can stand and to those that would kill an untreated one. The Nobel Prize citation stressed that the method devised by Ehrlich to determine biologically the strength of diphtheria serum, in this case, the basic immunity unit is taken to be the amount of antitoxin which in a guinea pig weighing 250 grams is able to neutralize 100 times the amount that would ordinarily cause death. It was all before he had started his work with chemotherapy. And in 1908, the Stockholm committee said that Ehrlich had been nominated about 70 times from 13 different countries, while by some of his sponsors such achievements as his creation of modern clinical hematology and the discovery that a tubercle bacillus is acid fast had been cited as arguments for an award. A majority of nominations were based on his works on immunology. Shortly before his death, the "Festschrift", a volume celebrating his 60th birthday and his achievement came out in which a large number of first class scientists discussed and praised his achievements. On page 589 of the "Festschrift", there is a diagram by Hata and Shiga, two of Ehrlich's distinguished Japanese collaborators showing exactly the toxicity ranges of Salvarsan as against Neosalvarsan. It was the first diagram of its kind, but this diagram that presented a model for the conduct and presentation of experiments in chemotherapy, in pharmacology. And in conformably with the demands of Maxwell which had impressed Ehrlich as a young man, he had succeeded by now in creating a technique of precision which, if I quote Maxwell again, maybe taken as a material type of that signs which it had advanced by enabling of service to express the results as measured quantities. The second axiom to which I referred in the beginning was that of formulating scientific hypothesis as if it were mechanical models. Professor A.B. Hill of London, one of the great physiologists of our time, recently said that fact alone are apt to be dull things. They need to be tied together by theories or applied to practical problems if they are to be made reasonably palatable. And during the last quarter of the 19th century, Lord Kelvin told in Glasgow that you cannot have clarity on the scientific concept before you have presented it in form of a model. But Ehrlich had a great gift of constructing such models. I'll refer to you to the side chains, to the antigen antibody complement pattern, to the lock and key symbolism with which he explains the toxin-antitoxin interaction. And of course to the magic bullet that [inaudible] with which he shot with pathogenic microorganisms, so as to bring about what he called the "terapia sterilisans magna". His writings are full of picturesque phrases which I don't want to put in detail. And in preparing material for this lecture, I found something which is not very well-knowing. Professor Liljestrand who wrote a chapter on the Nobel Prize in Physiology and Medicine, it's the end of the first 50 years of Nobel Prize. The field that Ehrlich would have been--would probably have been given a second Nobel Prize if he would live--have lived a few years longer, and the citation or the tag of dealing with this event is long and I'll tell you only what Liljestrand writes at the end. He writes--although Ehrlich had already received a Nobel Prize in 1908, he was again nominated in 1912 and 1913. But his new achievements were not, however, submitted to a special investigation. Was only natural since practical experience was still too limited to determine the value of the remedy that was Salvarsan in the treatment of syphilis, which of course were the most important consideration. Because of Ehrlich's death in 1915, the subject was not taken up again. It is now generally admitted, however, that this contribution must be regarded as a landmark in the development of chemotherapy. The third axiom of which I've spoken matured early in Ehrlich's career while he was a student in Breslau. At that time, he was profoundly impressed with the teaching of Cohnheim. And before I elaborate this point, I like to refer to the richness of scientific life in Breslau in the '70s and '80s, the '70s and '80s. Because it was this period this formed and formulated ideas in Ehrlich's mind. There were three persons which Ehrlich can really--could consider his teacher. So first was Ferdinand Cohn, next to Linnaeus, the greatest botanist of all times. A brilliant and a very kind man, the first biologist to understand the categorical significance of the then newly discovered world of microorganisms, the last encyclopedist of his scientific discipline, and I must mention that Ferdinand Cohn was the discoverer and sponsor of Robert Koch. The second great man of the Breslau period of Ehrlich was Heidenhain, successor to the chair of physiology of Purkinje, and at the time then Ehrlich came to Breslau, a young man wrote his first paper under Heidenhain, that young man was Pavlov. And thirdly as I said, there was Julius Cohnheim. Julius Cohnheim whom Simon Flexner has rightly described as the greatest pathologist of all times. And Carl Weigert was assistant to Cohnheim. Carl Weigert was a cousin of Ehrlich's and Ehrlich therefore was very close to Cohnheim's idea. Ehrlich was really privileged to be taught by those great three men. From Ferdinand Cohn, he learned how to formulate lively scientific hypotheses and to think in terms of models. From Heidenhain, he learned how to measure quantities in biology. And Cohnheim convinced him that in his--in its adaptive reactions to pathological impacts, nature is unreliable. This last theory, Cohnheim's great theory is in my view the greatest idea, the greatest single idea ever contributed to medicine. And Henry Sigerist, teacher of my distinguished predecessor here, published in 1939 or republished 1939 a lecture by William Henry Welch with the name "Adaptation in Pathologic Processes". Welch had come back from Breslau and there he had studied under Cohnheim. And he repeated with very great intelligence and with its fine gifts of teaching what Cohnheim had bought him. Cohnheim said, "You cannot rely on the adaptive reactions of the body in illness." You can rely, as we now know, on the adaptations of the body in physiology. As a matter of fact one of the great general books on physiological theory of our time has the name "The Wisdom of the Body". It's written by the late Walter Cannon. But Cohnheim was the first man who said pathological reactions in medicine, the way in which the body reacts to disease is unreliable. He gave three instances. He spoke of the hypertrophy of the heart. The hypertrophy of the heart is a reaction which you find very frequently in response to a high blood pressure to a variety of changes. But it isn't adaptation which in itself is a damaging adaptation. Actually what happens is as the oxygen supply of the heart is decreased and that the body damages itself by its adaptation. The second is the inflammation. He writes, the more severe and extensive the inflammatory effects--this is Welch writing--the more serious, as a rule, is a condition of the patient. The surgeon sees his wounds do well or ill according to the character and extent of inflammatory complication. Measures directed to the removal of inflammatory exudation, such as evacuation of pus from an abscess, on empyema, are the most successful methods of treatment, and these rules are embodied in ancient surgical maxims. How can one conceive of any purpose useful to the patient served by filling the air cells of his lung with pus, fibrin and red corpuscles in pneumonia, or bathing the brain and spinal cord in serum and pus in meningitis? And the third example, which Welch quoted from his great teacher Cohnheim, was the formation of scars. He says the closure of pathological defects by new growth of tissue is a process which must be regarded as adaptive. But one would hardly describe it as advantageous, the scar in the brain which causes epilepsy. Up to the time of his Nobel Prize, in 1908, Ehrlich tried to make use of natural reactions. He tried to adjust, manipulate, improve the very weapons which nature uses itself. When von Behring came with the diphtheria antitoxin, it was Ehrlich who realized that he had to use concentrations of toxin which are greater than the ones that nature itself uses. But his great success, the aim of his career came when Ehrlich used non-physiological substances, non-natural substances. It was when Ehrlich used aniline dyes, metals, chemicals of all sorts, that he formed his magic bullets. The direct line of development from Ehrlich's early work on the use of dyes as microchemical reagents, of which Henry Dale writes, and on the oxygen needs of tissues, with Salvarsan to the sulfanilamides. This line represents the ultimate application of Cohnheim's thoughts. Of course, Cohnheim himself had been influenced by Virchow, and Virchow by Rokitansky. But the [inaudible] belongs to Ehrlich. I like to refer to an analogous situation in the world of music to which Sigmund Spaeth has drawn attention a situation in which a great master chose to devote his genius to the perfection of an idea which had matured before his time. I quote Spaeth. In the St. Matthew Passion, written for a Good Friday service in Leipzig, Johann Sebastian Bach made striking use of the chorale "O Haupt voll Blut und Wunden" which occurs five times in the course of the work. This seems to have been his favorite of all the Lutheran hymn tunes that came out of the old German folk music, for he used it again in his Christmas Oratorio, with the words "Wie soll ich dich empfangen", a regular advent hymn, to which he evidently wished to give a touch of Lenten prophecy. It also appears in four of Bach's cantatas and in his Choral Gesange. Cohnheim's ideas were in Ehrlich's heart. It was the core of his thoughts, and his great achievement would be unthinkable without the influence of his teachers. Ehrlich was a very impressive personality, notwithstanding the fact that he was modest and certainly did not set out to impress. A great number of his contemporaries have dealt at length with the reminiscences of Ehrlich. I've quoted to you Sir Henry Dale and Professor Aschheim [assumed spelling]. I received a delightful appreciation of Ehrlich from his distinguished publisher, Dr. Ferdinand Springer Heidelberg who earned Ehrlich special gratitude by sponsoring the fine biography of Carl Weigert, his cousin, whose scientific excellence, was to Ehrlich's sorrow, not reflected in his academic advancement. Dr. Chaim Weizmann in his book "Trial and Error" writes at length of his meeting with Ehrlich. Friedrich von Muller, the celebrated Munich internist, devotes a warm personal reference to him. Many valuable links exist between Ehrlich and this country. Landsteiner and Michaelis, his master pupils, worked for many years in New York. Ehrlich's daughters and his gifted grandchildren, Dr. Hans Wolfgang Schwerin and Mr. Gunther Schwerin live in New York. I have enjoyed the friendship of the Schwerin family since my childhood and I remember with pride, that I met Ehrlich shortly before his death in their hospitable home in Breslau. Ehrlich's cousin and devoted co-worker, the great dermatologist, Professor Felix Pinkus, came to this country in 1940. He died in Detroit where his son Herman continues in the footsteps of his father. The nephew of Professor Edinger, one of Ehrlich's closest friends of his Frankfurt period is today with us. I refer to Dr. Riesser. When Ehrlich died in 1915, Professor Arnold Berliner wrote a memorable obituary in the "Naturwissenschaften" of September 3rd which concluded as follows. "At dawn of history," Goethe tells us, "men held to solemn and sometimes terrifying belief. They imagined their ancestors seated in silent communion in great caves in a circle of thrones. When a new soul entered this company, they would stand and bow to welcome him if he was worthy enough. The ancestors are the great men whose services to humanity are recorded in the "Book of Eternity". We can be sure that they will bow deeply in profound veneration to the man now entering their presence."

[ Applause ]

>> We will now bring the influence of Paul Ehrlich down to the modern world. And I know of no one who was more eminently qualified to speak on his contributions to contemporary science but Dr. Cornelius P. Rhoads of the Memorial Hospital in New York. Dr. Rhoads.

[ Applause ]

>> Mr. Chairman, I think it is inevitable when poor individuals address themselves to the topic of the same individual, that there be a certain amount of repetition. Furthermore, the topic assigned to me requires some reference to the events of Ehrlich's life in order to make clear the impact upon it as far as modern science is concerned. I know of no better summary of this man's life than that of Neisser and his obituary. I translate this distinctly clearly, an effort to achieve clarity and simplicity of presentation. But Neisser said it is amazing that Ehrlich understood from the beginning of his career a broad and useful application of a simple principle of basic biology. This held inherently true for the work of his entire life and many, apparently, unrelated areas of science. And applied in the studies of the form and functions of cells and tissues in biochemistry and immunology and the study of neoplastic growth, and finally, in his most fruitful expression in the creation of chemotherapy. The principle was so simple and so basic that it is almost incredible today that it was fully revolutionary 75 years ago. This is my remark. To quote again, everything that Ehrlich did was based on the concept of specific relationships between the molecular configuration of substances acting on cells and the constitutional elements of the structures of those cells. The logical sequel to this principle was the possibility of penetrating the very secrets of life itself by the observation of the relationship, protoplasm to chemical units of known configuration, obviously the beginning of modern cytochemistry. The sentence of Ehrlich widely quoted "Corpora non agunt nisi fixate" express this principle as a law which govern not only the distribution of compounds according to their chemical constitution but also their biological effects. And from this law came inevitably the concept that a desired therapeutic effect could be obtained by virtue of the predetermined construction of a chemical compound. This in turn led to the conclusion that the constitution of such a candidate therapeutic compound could be so formulated as to be fixed only by certain types of cells and so, to affect them specifically. This might be either cells of the body, obviously, or invading cellular units such as bacteria. Chemistry formerly has simply provided an arsenal for the therapist. Filled with substances from which the physician with more or less luck might draw a more or less useful weapon. It was converted by Ehrlich from such an arsenal, into the servant of a therapist who knew the details of his target and could formulate his chemical weapon rationally and precisely to achieve a predetermined end result. Now, you will observe that this is directly opposed to the conventional concept of this individual, was popularly depicted as laboring obscurely in a murk of cigar smoke and a [inaudible] of mineral water in a musty Victorian laboratory, surrounded by two or three old family retainers. Quite the contrary. A, this man was not an empiricist but a rational worker. And B, he knew the principle of program research and followed it assiduously from his first studies to his death as far as one can ascertain. Now, it's quite impossible to go further in discussing the impact of this individual's observations on modern science without discussing in summary the progress of the events of his life, because they build up a sequence of observations which culminated in no less than 15 new basic principles which did not include Salvarsan, which I [inaudible] has only one important social contribution, to which but only one of many intellectual contributions that his life provided. Now, it should be recalled that if there'd be any single characteristic which can be connected nicely with his scientific career, it was this curious fascination which colors had for him and had for him apparently since his earliest childhood. Now, it's quite obvious that any child may have a curious and all pervading interest in color. But in this individual's case, he had a cousin referred to already Carl Weigert who had a use for colors. That is because of his work with Cohnheim. He was concerned with the application of colors to bring into relief those structures which were only dimly seen through the microscope until aniline dyes were available. And furthermore, Ehrlich was by inclination a chemist, with an extraordinarily keen interest in biological phenomena. Hence, an interest in color, the availability of colors from a growing outstanding German chemical dye industry, a cousin who was in pathology led very naturally to a coming together of concept to what these colors meant when they selectively stained different parts of tissues. And I recall [inaudible], first place recall while a student, he was always staining things, and it was a joke. And one day while staining things, Koch came through the laboratory and observed this interesting man with a desk covered with stains and I presume forgotten, until a number of years later, all about the visit. But during his period from '78 to '85 with [inaudible], he laid the foundation of modern hematology. And many have forgotten that he really gave us the first ability selectively to stain the various types of cells of the blood, to describe adequately leukemia, pernicious anemia, and aplastic anemia. And furthermore, he understood that whereas the last two were maturation defects, that they took place at a different level of maturation and were of a different type. It is quite surprising that we find so few references at this time to the staining of neoplastic tissue. And I presume this is true because the convention of the time was completely controlled by the bacterial etiology of disease. Now when Koch announced the discovery of the tubercle bacillus, it was very natural for Ehrlich to recall the curious forms he had observed when he fooled with his dyes, particularly methylene blue, in the staining of pathologic tissue derived from the autopsy room, frequently tuberculous tissue. And this led of course, as you all know, to the development of [inaudible] trypsin stain, use of aniline, the use of heat, the demonstration of acid fastness, which is today are procedure for staining tubercle bacilli. But it was far more important than a technical procedure for demonstrating better than had Koch done the presence of these organisms. It said something else. It said that these particular organisms differed in their receptivity and the retentiveness for particular dyes than any other organism then known to affect human tissue, and was the beginning of this conception of a specificity of binding power. You're all familiar with his move to vital staining, which of course made all modern neuroanatomy. But many have forgotten that from this observation, the vital staining of nervous tissue still employ. He proceeded immediately to consider the possibility of the use of this in therapy. And there are available curious old experiments in which methylene blue was employed in an effort to treat disorders regarded as due to the nervous system, notably the neurologist. And here is the--perhaps is one of our earliest indications of a trend toward the used of dyes for specifically therapeutic purposes. Then I've been utterly surprised to find this man turning his hand with his methylene blue to the treatment of malaria. Now as far as I can ascertain, malaria was not a particularly common chemical problem in the Germany of that time. But it is also true that this was a period of the awakening German empire, with a strong push toward colonial expansion. And one wonders to what extent he felt that perhaps this would configure in some social function throughout the welfare of his nation. Could he achieve a means for controlling the parasites so troublesome when his countrymen went out to new lands? All know again that in the course of his work, presumably because of exposure to the break in his tissue, he acquired the disease. And I suspect he was rather glad to be able to have a rational reason, a rational cause of giving up his work because at that time he was very unhappy with Gerhard [assumed spelling] and often wished that he could shift in some way his associations. We find remarkably few references to [inaudible] or to [inaudible] therapy as far as he himself was concerned. There are statements that he took a certain amount of [inaudible] and did from time to time ascribed his improvement to that therapeutic procedure. Certain it is that he became anonymously interested in tuberculosis as a therapeutic problem and this led--This plus the fact that he made a major contribution in terms of staining of a tubercle bacillus that of course Koch offered him a post when he returned from Egypt about 1889. Now the association with Koch I find rather fascinating. Recall that Dr. Koch really began his scientific life because of a deep interest in [inaudible] and in sterilization by coagulating chemicals, notably phenol. And Koch made a number of studies of other types of coagulating chemicals in an effort to achieve better sterilization and better antisepsis. Then as time went on, began to dream about internal sterilization which of course is chemotherapy. And he actually tried experiments employing mercury salts and various types of experimental bacterial infections, and of course failed. But I have no doubt that these early experiments in on internal disinfection, no doubt to Koch, had a profound influence upon a man who himself needed internal disinfection because of his tuberculosis, who lose the specificity of dyes, who had an awakening interest in therapeutic problems and was convinced that anything was possible to the scientist modern for that day joined with the chemical industry. Now recall that the next contribution of Ehrlich's was an exceedingly revolutionary principle. Diphtheria toxin have been described and active immunity was well-known. But for some reason which is hard to perceive at this distance, it seems that the notion or the ability to employ immune serum therapeutically was not well understood. Clearly the reason is that people could not make a dependable antiserum of high titer, as has been referred to. And here comes the first example of what my--What the previous speaker gave such emphasis to, that is the insistence upon a quantitative method. Because rather than trying to work out, the infinite and then unknown details of toxin production by bacteria and antitoxin production by inoculated animals, Ehrlich turned to a synthetic toxin, that's not a fair term, a pure toxin of nonbacterial origin, ricin, in order to give him something which could be measured absolutely in so far as its antigenic content was concerned. And by the use of such a non-bacterial antigen achieved high titer antitoxin, and then converted those principles to the production of high titer diphtheria antitoxin which was therapeutically active. And this is an enormous contribution because the idea of therapy when an antitoxin as far as I can learn was a new thought, and certainly a new experience.

[ Pause ]

I want us to recall [inaudible] a great deal about the side chain theory. And from the evidence, Ehrlich thought that the reason dyes stain particular parts of tissues with particular affinity was because of [inaudible] receptors which hooked on to these dyes, which is very reasonable. But then he had to explain the action of the antitoxin, and of course he invoked the same mechanism. And then, we find that this was brought in to a curious concept of anti-nutritional effect of antitoxins on the one hand and the selectively binding dyes on the other, and this was the beginning of the thesis of antimetabolite action, as far as I can learn. Now we know when he went to the celebrated--On the celebrated trip to the Society for Internal Medicine, he have had his first expression of conviction about chemotherapy, because he said, "A systematic and extensive chemical and biological experiment should yield specific curative compounds." This is the conversion of immune serum therapy to chemical therapy based upon a specific binding of chemicals by a particular part for tissues. And furthermore at this time, we brought for the next principle, the chemotherapeutic index, organotropic as compared to parasitotropic binding of dyes. And then came a major move, the invocation of the chemical industry to his aid. When he had the celebrated struggle with Bertheim, his great friend from industry, in which he prevailed upon Bertheim to modify atoxyl, then a toxic compound, in order to give him something which would control trypanosomiasis. And I was very puzzled why this man became interested in trypanosomiasis. Here again, this was not an endemic disease in Germany of the time. And quite clearly, he had an idea once more that this was a problem of concern with the expanding German nation and its ability to settle its citizens in foreign lands. So [inaudible] in red the outcome of the struggle with the chemical industry was his first therapeutic prime. Now, I don't need to go further than to mention [inaudible]. The observations of the presence of spirochaetes in nervous tissue of the syphilitics, the suggestion that spirochaetes might be related to trypanosomes by some unknown observer or discusser. The picking up of this idea by Ehrlich, his rejection of it until Hata came to him from the Japanese laboratory with a quantitative method of inducing experimental syphilis in the rabbit and then, going full force toward the achievement of chemical control of this disease. Now, any individual and his activities is the product of his environment, the conventions of his time, his physical surroundings, and fully investigate all the total scientific picture of today, composed of all the available knowledge. And most important are the contributions of the individuals, who proceeded or were contemporary, to the one whose achievements we are concerned with. Now, we've mentioned Waldeyer, whose inspiration as far as microscopy was concerned undoubtedly swung Ehrlich into the field of the microscopic study of staining reactions. We know that at that time Virchow was a figure of profound influence. He had been the father of cytology of disease, the cytologic study of disease and recall as well, he was a great and strong political figure. But without Perkin, the aniline dyes, that Dr. Galdston here has so well-describe there would have been no staining for this group to work with. And the effect of Pasteur and of Koch also manifest has to need little further discussion. Finally, there was at his hand a developing German chemical industry of the most extraordinary energy and ability. He could turn it well to his friends there for essentially any compound he desire. We had the combination of a government interested in scientific advance of a community deeply concerned with medical topics and industry putting all aid at his disposal and a medical organization which emphasized clinical study and is doubtful, without these various factors, that the great successes would have been achieved. Now, what are these new concepts this man developed? The first one is that the fixation of dyes with biological units, cells or their parts provides an index of the constitution and function of those units. It is almost impossible to overestimate the importance of this point of view. We still provide the basis for much of modern medical investigation. The second outstanding principle was his insistence upon the quantitative method as already mentioned. First seen in the employment of ricin in his studies of anatoxin production. Later, and most notably seen in his work with Hata with experimental syphilis, very clear from his studies with experimental tumors and recall he had one failure to observe this when the effectiveness of trypan red was passed over by an assistant and he never forgot that lesson. From that day on, nothing would deviate him from the employment of the quantitative measure. The third concept was the one termed by him athrepsia. It's a term long forgotten now but, he believed that agents active in a pharmacological sense exerted their effects by blocking those structural units of the affected cells which are normally employed for the ingestion of nutrients. This is obviously the first understanding of what we know in modern terms as anti-metabolite action. It has taken almost 75 years for this principle to be recognized as a basic one capable of being employed to achieve the most outstanding therapeutic results. It is quite extraordinary in the field of which my associates and I are interested that the nitrogen mustards for the treatment of malignant neoplasms arrived during this last war. And in going over material on Ehrlich's life, we found to our utter astonishment that he first employed ethyleneamine which is the functional compound in which the mustards are converted when they direct their action in the 1880s. And not only did he described ethyleneamine but he described the acute papillitis of the kidney, pelvis induced by the action of that agent in excessive dose levels. Now, Side-Chain Theory was not a very accurate thesis. It was as you know that these substances--any substance affecting your cell were fixed by some anatomical part of the structure, a little arm. And in an effort to protect itself, the cell produced not only more of these parts, but actually an excess, which were then sent into the bloodstream as antibodies. And then these little arms to which the chemicals or immune body--or antigens hooked themselves, where some kind of digestive functioning units. Now, there are obvious flaws in this and many have derived in the theory and of course it has gone into--now into the limbo of quasi forgotten things. Nevertheless, it was a perfectly practical working thesis which people have paid more attention to, rather than objecting to as were done at that time. When this was a topic of major role dictation, it would have led to considering more progress than it occur. And furthermore, it led as a perfect good explanation of the acquisition of resistance to toxic compounds by affected cells. Now, all are familiar with the phenomenon of acquired resistance. It's as old as the history of poisoning, but it is the explanation of our more serious bacteriological problems and some of our very serious problems in the tumor field in the aspect of chemotherapy today. Now the 5th outstanding contribution was the employment of the principle of active immunity to the use of immune serum in active therapy. And, I find it very hard to overemphasize this conceptual contribution. The employment of specific dyes to measure these function of living tissue has been referred to. This is of course in his studies on the oxygen uptake of such tissues as studied by chemicals of the type of indophenol, what we now call redox system, a term unheard of about 50 years ago. And, yet nevertheless, essentially every biochemist has today indophenol upon his shell mostly ascorbic acid titrations were done with this agent and we hear almost daily of this or that experiment which goes straight back to these primary observations of Ehrlich so long ago. Vital staining I have mentioned, but here again recall this represented a concept more that just an experiment, a concept that the chemical reactivity of cells and tissues in life might and indeed did differ greatly from those manifested after death. And this stimulated the conversion of pathology, the study of disease from observations of the form of inert tissue, tissue manifesting the alterations of past events, to a study of the action of the agents themselves. Pathology is still undergoing of this conversion, begun entirely by Ehrlich. Now, modern biochemistry, with its extensive knowledge of essential factors in nutrition, vitamins or related materials, is obvious today and easily accepted. Anybody understands pernicious anemia as a deficiency disease, when it disappears overnight after somebody administered B12 or similarly acting agents. We fail to remember even the comparatively recent struggles over this concept. The struggle between those who regarded this as a hemolytic disease and those who regarded it as a maturation defect of unknown nature, until Dr. Peabody [assumed spelling] began to apply the consideration raised by Ehrlich 30 years before Dr. Peabody's time. We forget that Ehrlich almost 70 years ago described this disease as a maturation defect and caused me thinking me of the Side-Chain Theory and it's--and the way in which toxins blocked the availability of nutrients to cells, assumed that this defect of pernicious anemia was one due to the lack of some essential nutrient, and that turned out to be the case so many years later. The correlation of molecular configuration of biologic action, now a second nature to every pharmacologist and every chemotherapist is a cardinal principle of modern medical work. And it was the 9th of Ehrlich's contributions. A few investigators would question its importance now. But recall this was the final step in the swing. As Dr. Galdston has pointed out from Paracelsus--Paracelsian philosophy, from Galenical philosophy to the teachings of Paracelsus and the beginning of modern therapeutic biochemistry. Particularly, [inaudible] in the next contribution of Ehrlich, the appreciation that investigation is not an end in itself. He employed chemistry to accomplish predetermine ends which were obviously important to society and he was interested in trypanosomiasis and malaria, although they were not direct problems of his surroundings, they problems of his nation which required solution. All through his life he struggled with chemist, he struggled with Bertheim as only one example because he insisted that they could accomplish but was needed by the community if they would do so. And invariably he was correct, he finally wore down by sheer persistence, the doctrinary prejudices of the Erudite and there by achieve major therapeutic trials. Whereas the triumph was important in itself, even more so was the principle involved of the useful employment of knowledge, the foundation of modern pharmacology and his 10th contribution. Often forgotten, is his 11th, and this was knowledge of antibodies are distributed by maternal milk to nursing young. Now this is one cardinal tenants of modern immunology. If you recall or care about the enormous economic lost which affected almost every country imposed by diarrheal disease in newly born farm animals not permitted to nurse. And it's hard for us to realize here and I'm sure hard for you who are not brought up in the country, to realize that scours in calves taken from their mothers was enormously threatening matter to the agricultural individual. No one dreamed until Ehrlich's time that immunity was not inherited on a genic basis. No one believed that sucking played any role. And this observation so long forgotten now perhaps has had as great economic effect as any other of his studies. Now, the chemotherapeutic index is discussed everyday. We can go back and use his terms parasitotropic as compared to organotropic if we choose. It's his 12th contribution. And everyday I discuss problems with those engaged with chemotherapy, and everyday I find they forget the importance of the chemotherapeutic index. The differential between the effective of a compound upon normal tissue and upon the cell which one wishes to destroy and nothing is more useful than to recall the existence of Dr. Ehrlich on this exceedingly important and essential matter. You must have a differential if you expect to achieve any specific therapeutic effects. Now, the medical literature and conversation of scientist from then until now has contained endless examples of pessimistic remarks for the effect of this or that biologic action can not be exerted without to generally toxic in effect. It is said about trypanosomes until a therapeutic agent come to hand. About syphilis until Salvarsan was discovered. About bacterial infections until we have some sulfanilamide, penicillin and other compounds acting in the similarly specific fashion. About malaria, until the discovery of the 4- aminoquinolines. It is still said about neoplastic cells despite the availability today of compounds which will affect such cells in animals in a limited fashion. It was never said by Ehrlich, he was perfectly satisfied that if a particular issue would take a particular dye, that some modification of that dye could be add which would exert an adverse effect upon that cytologic unit and he was always right. Every pharmacologist guides his endeavors along the principle of rates of absorption and excretion of blood levels and the action of the metabolites produced from the administered drugs. As far as I can ascertain, these principles began with Ehrlich, and were his 13th great contribution. Certain it is that he knew them well and certain it is that he applied them well. It is interesting and impressive that even today, it must be constantly reiterated in any discussion of the usefulness of a therapeutic compound. In the case of drug resistance, it's hard to over emphasize the importance of the principle involved. He understood perfectly well that the ability of the individual biologic units, bacteria or parasites, which he wished to destroy. To immolate the accomplishment of the entire organism was the most single important factor in chemotherapy. Now, there was constant tendency today to overlook the fact that resistance can be overcome. And his principle of massive dose therapy was the means for overcoming bacterial resistance. And we hear nowadays an immense number of gloomy statements made upon, may concerning new drugs which are advanced in the treatment of this or that disorder which involves these specific injury to invading cells. The statement that all the cells one wishes to destroy and acquire resistance and of course they do. But what we often forget is the fact that Ehrlich never forgot which was that a simply one more hurdle to surmount but not a cause for stopping work. He said that cell resistance have not negate the possibility of effective chemotherapy, but is simply a minor obstacle to be overcome. Now it is in the cancer field that the last great fundamental concept, his 15th, nowadays originally requires application. It was he who end an era of bacteriology recognized the cancer cell as etiologic agent of the disease cancer. He saw this cell with crystal clarity as the analog of the invading bacteria. And the biological unit of which the destruction must be solved, it appears to be achieved. It's very interesting to observe at essentially every experiment we now do in the field of experimental cancer was done by Ehrlich and his coworkers Apolant, Cherney [assumed spelling] and others. He knew well a phenomenon of tumor resistance. He knew well how to break it down by exhausting the antibody capacity of the body. He employed attenuated suspensions of tumor cells. Quite the analog of what is being done today in other ways. He never worried about the possibility of cancer being caused by some other kind of invading organism for his case. He was satisfied with the destruction of the cancer cell or the induction of immunity to it. He saw clearly the role of the endocrine system in this immunity. He saw clearly the ability to achieve the selective destruction of such an invading biological unit. I feel sure that were he here today, he would be quite familiar with the experimental techniques presently in use. He would have solved the destruction of cancer cell by any means that came to his hand. It's removal by surgery, the destruction by radiology or if widely scattered, its destruction by some specific chemical means, selectively injuring yet to a greater extent that would injure a normal tissue. He would have sought to control its ability to multiply by bringing to bear upon it, those of adverse effects provided by immunology, by nature's own defense processes, by endocrinology and by those agents which could be created in the chemist laboratory. And further more I'm sure he would not stop work until he had achieved the desired goal.

[ Applause ]