# Popular Science Monthly/Volume 78/March 1911/Ehrlich's Specific Therapeutics in Relation to Scientific Method

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THE
POPULAR SCIENCE
MONTHLY
MARCH, 1911
* EHRLICH'S SPECIFIC THERAPEUTICS IN RELATION TO SCIENTIFIC METHOD
By FIELDING H. GARRISON, M.D.
ARMY MEDICAL MUSEUM, WASHINGTON, D. C.
AN almost negligible mortality ratio of 12 deaths in 12,000 cases of syphilis treated by "606" is the record which Professor Ehrlich was able to produce at the Königsberg meeting of German scientists, and in these fatalities, accidental circumstances like shock, heart failure and extreme debility were coefficients of greater moment than the acid and toxic nature of the remedy itself. As compared with the high ratio of successful treatment—probably towards 90 per cent, or more—the result is significant and striking. As the administration of "606" by injection is exceedingly painful in the first stages, Ehrlich compares it with operative surgery in that it can never be given without a certain risk in desperate cases, yet is better worth trying than to leave the patient to suffer or die. Its use is interdicted in disease of the heart, blood vessels or kidneys or in advanced stages of nervous disease, and, with characteristic reserve and caution, its author declines to make any premature claims regarding the cure of the disease with a single dose, although this is the avowed and ultimate of his therapia sterilisans ​magna. Before any conclusions can be formulated, the after-effects of the remedy must be studied, he says, for some months running, possibly a year or more. Will "606" permanently abort or check an attack of syphilis, or will it, like a drastic silver nitrate treatment in gonorrhœa, cause some of the pathogenic organisms to burrow into the deep tissues, only to crop out as an embarrassing recrudescence later on? Will it have any effect upon the posterity of syphilitics or upon those strange parasyphilitic affections, locomotor ataxia and general paralysis? Will it produce a generation of paretics and ataxics as some think mercury does? These and similar questions that suggest themselves can only be resolved by a study of the treated cases over long periods of time. The fact that suckling infants are cured after their mothers have received the injection would argue, Ehrlich thinks, that something like antibodies are formed in the maternal milk, indicating that "606" acts like a true antitoxin. This would seem to be borne out by the disappearance of the Wassermann serodiagnostic reaction shortly after the injection is given. I am informed by Captain Charles F. Craig, of the Army Medical Department, that in 33 United States soldiers recently treated with "606" (medium doses of 0.6 gram), the syphilitic lesions and the Wassermann reaction disappeared in 28 cases during periods of time ranging from five days to about two months, the men being returned to duty as cured. Statistical results like these are now mounting up by the hundreds in the medical journals of the world, and if the effects of the drug are permanent it is probable that syphilis will become, in due course, a rare disease in civilized communities. There are some who have still enough of "odium theologicum" in their composition to think this disease a sort of divine punishment for the social evil, and that its suppression would imply an inevitable increase in immorality. But morality and immorality are too much the resultant of a conflict between innate disposition and social or ethical forces to be appreciably influenced by discoveries in therapeutics. These bigoted souls may take comfort in the fact that "606" is a simple chemical remedy, acting like quinine in malarial fever. It protects the innocent—the wives and children of the infected man—but, if it spares the sinner for the present, it holds out no alluring prospects for vicious indulgence in the future. "606" does not confer immunity from subsequent infection.
The scientific career of the remarkable man to whom medicine owes 80 much and who himself owes so little to university training is a striking example of the self-reliance and autodidactic tendencies that ​sometimes accompany ability of the highest order. As a student, Ehrlich bore out President Eliot's theory that any young man who has real capacity usually has a better inkling of its extent, if not of its limitations, than his elders can teach him. Age and experience may perhaps indicate what youth can't do, but they have no power of predicting what it can do. It is related that when Robert Koch was once visiting the Breslau laboratories, a young student working at a table covered with staining materials was pointed out to him, with the remark: "There is our little Ehrlich. He is a first-rate stainer of tissues, but he will never pass his examinations." The prediction was true. Ehrlich got his degree by courtesy, on the strength of his well-known discoveries in the histology of the blood; but doubtless his academic sponsors serenely followed the example of Kant, who, in lecturing, addressed himself to students of mean average intellect only, on the assumption that the blockheads were beyond human help, while the geniuses could take care of themselves. The young Ehrlich easily made himself recognized as a true-born scientific genius, but his example will scarcely save less careful or more luckless students from being plucked at their final examinations.
Although for practical use, Ehrlich's researches in synthetic chemistry rank near to those of Emil Fischer, he is a true Asclepiad, and his principal aim has always been to improve the diagnosis and treatment of disease. Nearly all his results are of fundamental importance for actual medicine and they are a long list. We can imagine some awarder of a Copley medal or Nobel prize recounting them: First, the improved methods of drying and fixing blood smears by heat and the staining methods which have become such a feature in recent diagnosis, notably the tri-acid stain, the fuchsine stain for tubercle bacilli and the method of intra-vital staining, the first step towards getting in touch with what is going on inside the living cell; then his discovery of five new constituents of the blood which have become basic principles in modern diagnosis; his important study of the oxygen requirements of a living organism; his diazo-test for the urine in typhoid fever; his demonstration that animals can be quantitatively immunized against the effects of vegetable poisons like abrin and ricin, as well as against the toxins of vegetable parasites; and conversely, that animal parasites have the power of immunizing themselves and their descendants against the action of drugs; his improvement of Behring's diphtheria antitoxin and his establishment of an international standard of purity for the same; his side chain theory of immunity, which led at once to such brilliant results as the Wassermann method of serodiagnosis and (in medical jurisprudence) to the precipitin tests for blood-stains (Bordet-Uhlenhuth) and the cobra-venom test for insanity (Much-Holtzmann); ​his studies in isolysins which inaugurate a physiology peculiar to the individual as opposed to the normal physiology of the species; his idea of a canonical study of the blood-serum in health and disease, so that a norm or "blood-canon" for the investigation of new or unknown conditions may be available; his demonstration that cancer may be changed into sarcoma by successive inoculations; that the growth of cancer in an animal body depends upon the presence of certain food-stuffs in that body; finally the gigantic labors involved in building up hundreds of new compounds and testing them as remedies for the two great groups of parasitic diseases, the spirilloses and the trypanosomioses, his prospective success being one of the greatest triumphs of the method of "trial and error" on record. Surely a career in scientific medicine only matched in recent times by those of Pasteur, Helmholtz, Koch and Lister.
To the orthodox chemist, who works by rule and formula, Ehrlich's experimental methods might seem mere haphazard "test-tubing," and he himself has jestingly referred to his laboratory procedure as "Spielchemie," an epithet which well describes the experimentation that results from the free play of a singularly acute mind. Some of his admirers have even gone so far as to say that he declines to work quantitatively. Although his own statement (in the Harben lectures) is just to the opposite effect—and all experiment that seeks the general law behind related facts is obviously quantitative in its intention—it is quite true that Ehrlich has steadfastly declined to follow Arrhenius in applying the quantitative methods of physical chemistry to the unknown entities of immunity reactions. "I have always emphasized the chemical nature of the reaction," he says, only "the formulas devised by Arrhenius and Madsen for the reactions of toxins and antitoxins explain absolutely nothing. Even in particularly favorable cases they can merely represent experimental results in the form of interpolation formulas." In Ehrlich's view, the mistake made by the distinguished Swedish physicist lies in the assumption that toxins and antitoxins can be treated mathematically as simple indivisible substances, whereas there is unimpeachable evidence of their dual and multiple nature—that they can be split up into labile components of such extreme complexity as to have, so far, defied ultimate analysis. Under these conditions assumed constants become inevitably dependent variables and the physical chemist is dealing with the shifting evanescent aspects of substance in the labile state. The careful quantitative work of such a competent experimenter as Dr. W. H. Manwaring has shown that, with the knowledge at present available, physico-chemical ​measurement of the constantly variable constants of immunity reactions is like computing the dynamics of ignes fatui. Even if the ultimate formulæ of toxins or protoplasm could be ascertained in the laboratory, as in the case of hemoglobin or urea, it would tell chemists nothing about what they are in the living body. The ultimate phenomena of life and death are still (in Spinoza's classic phrase) of a kind "quœ nullo numero explicari possunt," and Ehrlich's theory, as he predicted in his Baltimore lectures, has been deeply enough rooted in experimental fact to "withstand the Northern storms." In a most interesting paper in The Popular Science Monthly, Dr. A. F. A. King, of Washington, has thrown into relief the all-important point that the essential feature of a living organism is the limiting, peripheral, semiporous membrane, skin or sheath which, like the semipermeable membrane in physics, invests and insulates it, preventing it from dissipating its energy, except sparingly and under definite conditions. Detached from the investing semipermeable membrane. Dr. King holds that cellular protoplasm is "neither alive nor dead but between the two." The telling feature in Ehrlich's attack upon disease is the unique way in which he has visualized and dealt with those basic border-line substances which, in vitro, if not in vivo, are "neither alive nor dead, but between the two." He has clearly seen that the mathematical expressions for such labile complexes as protoplasm or toxins do not come under Sir William Hamilton's category of "real numbers." They may be vectorial quantities or relations like those of electrical science, and might be represented specially, graphically, vectorially or stereochemically to the mind's eye as Ehrlich has succeeded in doing; or they might be vaguely formulated as qualitative relations by the differential calculus. Quantities in the fixed arithmetical sense they are surely not. Ehrlich's method might be called a qualitative way of approaching apparently quantitative problems of extreme complexity, a sort of rough calculus of variations carried out in the laboratory under conditions in which the variables are well-nigh legion. His success has been due to his unrivaled knowledge of the intravital and distributive relations of different drugs, particularly of dye-stuffs and, on the theoretical side, to what he calls his "chemicoplastic imagination." Such a feat of fantasy as his sidechain theory is not only solidly built up on experimental fact, but is intimately concerned with the architectonics of stereochemical formulae and with certain space-intuitions which are coming to be pretty generally accepted by organic chemists to-day. So we find Professor H. E. Armstrong, of London, stating at the Winnipeg meeting of the British Association (1910) that for the modern chemist "the tetrahedron is the symbol of the functional activities of carbon," that "even the paraffins are not to be visualized as so many ducks strung upon a ​ramrod Munchhausen fashion, but as forming curls, according to the natural set of affinities"; and that "protoplasm, in fact, may be pictured as made up of a large number of curls, like a judge's wig—all in intercommunication through some center, connected here and there, perhaps, by lateral bonds of union." Ehrlich's conception of the molecule of functionally active protoplasm as consisting of a fundamental nucleus plus a large number of different chemical receptors or side chains is obviously at one with this stereochemical picture and he began to apply it as far back as 1885, in his studies on the oxygen requirements of the organism. In this important work he makes it clear that what he terms "color-analytics" (farbenanalytische Studien) is the most accessible way of investigating the intimate mechanism of intracellular or protoplasmic chemistry. He was early impressed (or as he himself puts it "obsessed") with the idea of a selective and distributive relation between definite chemical substances and definite body-tissues of the kind which chemists are agreed to describe as special "affinity." Starting with Hoppe-Seyler's observation that the emission and absorption of light in chlorophyll is accomplished, not by the entire chlorophyll molecule, but by certain specialized groups of atoms in it, he proceeds to outline the germinal idea of his side-chain theory, viz., that in the living cell the peripheral nutritive and excretory processes are accomplished by specialized atom groups of the protoplasmic molecule—the chemoreceptors. Suppose some extraneous substance, e. g., a food, a drug, or a poison, to be brought in juxtaposition with these peripheral receptive side-chains. Expressed in terms of thermodynamic chemistry we have the familiar Gibbsian problem in chemical equilibrium which Roozeboom has so picturesquely described as "the sociology of chemical substances." If the chemical and thermal relation of the substances is such that they will immediately and definitely combine, we shall have chemical and thermodynamic equilibrium; but if the effect of the external substance is stimulative or catalytic, the living protoplasm, having greater chemical energy and higher chemical potentiality, will expel a certain portion of itself to combine with the latter. Expressed in terms of stereochemistry, equilibrium is accomplished by the chemical ​bonds of the receptor atom groups and the corresponding bonds of the external groups being so related structurally that they dovetail, or in Emil Fischer's well-known analogy, fit each other as lock and key. The extraneous substance is thus in Ehrlich's own terminology "fixed," anchored or bound by the special chemoreceptor groups or the products they throw out. Now what we know of the dynamics of cellular pathology is summed up in Carl Weigert's generalization that the amount of repair of an injured or diseased tissue is usually in excess of what is required, provided the original injury is not too great. When a cell is attacked by a toxin or poison the receptor atom groups will, unless immediately overwhelmed, gradually acquire the power of throwing into the blood detached portions or products of themselves—the antitoxins—and these new side-chains float in the neighborhood of the cell, like so many battleships to protect it from injury. Ehrlich compares these antibodies to lightning rods which draw away the destructive elements to themselves. When administered as therapeutic injections he compares them to "charmed bullets which strike only those objects for whose destruction they have been produced." This is the gist of Ehrlich's theory of immunity and its central idea of a special affinity between drugs and tissues has been the center of gravity of Ehrlich's life work. The unusual terminology which he employs—the various toxophores, toxoids, toxones, amboceptors, haptines, etc.—are simply so many tags or labels affixed to designate complex protoplasmic products of unknown composition with the action of which he has become familiar through long process of experiment. The importance of these imaginative concepts, Ehrlich insists, is in their "heuristic value." How great this heuristic value is, how it has served as an inductive principle in seeking the essentials through the labyrinth of accidentals, is seen in such a triumph of synthesis as the Wassermann method for the serodiagnosis of specific infections. Concerning this discovery Wassermann says that although the side-chain theory was for years an apple of discord among bacteriologists, a thing to look upon askance, yet he could never have hit upon so special a test without Ehrlich's imaginative picture of the mechanism of disease as a guide in his experiments. Protected by parallel control tests with known syphilitic and non-syphilitic bloods, this mode of diagnosis is practically infallible, even in ataxia and paresis. As an important step forward, it changed the whole aspect of those puzzling cases of immunity from syphilis which are known as Colles's law and Profeta's law. By Colles's law a syphilitic ​child may result from a syphilitic father and an apparently healthy mother, the mother's immunity being shown by the speedy infection of a healthy wet-nurse from the child's lips, while she herself nurses with impunity. Conversely, Profeta's law asserts that an apparently healthy child may sometimes be born of a syphilitic mother (and father), in which case it may be suckled by either the mother or a syphilitic wet-nurse without danger of infection. In either case examination of the blood has demonstrated the existence of the parasites as well as the permanence of the Wassermann reaction, in the mother's blood in the first instance, in the child's in the second. It became evident, from facts of this kind, that immunity from protozoan infection (animal parasites) is not the same thing as immunity from bacterial infection (vegetable parasites). In the latter case the immunity is derived from the antitoxic products of the bacteria themselves. In the case of the animal parasites, we know nothing of the chemical sources of infection and immunity. As a matter of pure speculation, perhaps the immune mother in Colles's law and the immune child in Profeta's law may, like the bacillus carriers of typhoid fever, come under Ehrlich's immunity of the first order (natural immunity), in which the sensitive receptors have either become worn out and insensitive or no longer exist as such. Theorizing aside, the practical outcome of these details was the evident impossibility of curing parasitic diseases by special antitoxins or vaccines, and the practical necessity of finding chemical specifics which would destroy the parasites as quinine does the malarial plasmodium. The next step towards a rational chemotherapy was Ehrlich's discovery that when mice infected with trypanosomes are treated with specific dyes like trypan red in doses that fall short of complete sterilization by some assignable quantity, a race of trypanosomes can be gradually bred which will prove permanently "fast," or resistant to the effects of the drug. The power of parasites to immunize themselves and their descendants against the effect of destructive poisons led Ehrlich to his next move in attempting to checkmate them—the idea of sterilizing the patient's body uno ictu ("mit einem Schlag") by a single dose of medicine. It was "upon this hint that he spake" in formulating his therapia sterilisans magna and we are now in a position to appreciate the value of his discoveries in pharmacodynamics.
In his Harben lectures before the Royal Institute of Public Health in 1907 Ehrlich stated his conviction that pharmacology, toxicology and therapeutics are "the most important branches of medicine." In other words, he believes that the chief end of the physician is to get his patients well. Self-evident as this proposition is, it has a certain paradoxical novelty when we consider the dominance of setiological studies (pathology and bacteriology) through the last half of the nineteenth century and the apparent débâcle of drug therapy which attended the rise of experimental pharmacodynamics. In such natural remedies as ​heat, light, electricity, hydrotherapy, climate, dietetics, hypnotism and psychotherapy, out-door exercise and simple living, the physician has many strings to his bow, apart from the more special arms of treatment like operative surgery, ophthalmology, orthopædics, etc. In respect of drugs, it is perhaps no exaggeration to say that scarcely more than a double baker's dozen are strictly reliable. Even the average practitioner of to-day will admit that in regard to general treatment of disease with drugs we are almost where we were over 2,000 years ago. Among the greater Greeks, the divine Hippocrates created surgical diagnosis and taught physicians how to group symptoms and to describe different diseases; Theophrastus Eresius, the friend and pupil of Aristotle, was the founder of scientific botany; Dioscorides made the first materia medica and Galen, the father of the experimental idea, taught the Romans how to apply it. Of the two great founders of European medicine, Galen was the abler and keener therapist, but inclined to brag about his cures. Hippocrates, who told of his failures also, was the truer clinician. The complicated and elaborate polypharmacy which Galen imposed upon medicine was exaggerated into the most filthy extremes during the Byzantine period and was further enlarged by the superior chemical knowledge of the Saracens. To this day, what Osier calls "the heavy hand of the Arabian" is sensed in the enormous bulk of our pharmacopœias. After the Revival of Learning and during the Renaissance period, the chief concern of medicine was the development of anatomy and surgery, and while a few original spirits like Saliceto, Mondeville and John of Arderne were good healers, yet down through the eighteenth century, treatment was largely an affair of lengthy "gunshot prescriptions," compounded of multifarious ingredients on the hit-or-miss principle, well-deserving of Mark Twain's comment "serve with a shovel." The tendencies of this picturesque therapy, founded upon the "doctrine of signatures," have been very prettily rhymed in the envoy to Kipling's recent story about old Nicholas Culpeper, the most famous of the seventeenth century quacksalvers, herb-doctors and "judicial astrologers":