Reid89BehringEhrlich

Reid89BehringEhrlich - MlCROBES AND MEN 108 Roux a stranger...

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Unformatted text preview: MlCROBES AND MEN 108 Roux, a stranger for some time now to Pasteur's laboratory. When the attacks were strongest on Pasteur’s reputation, Roux came to the defence. He put an enormous amount of skill and energy into testing for the presence of rabies in dogs in order to quell the criticism that treat- ment was being given to uninfected patients. As it never failed to do throughout his life, Pasteur's pubiic image began to rise against the snapping of criticism. rifhe defence of this parti— cular work, however, was longer and more exhausting than most. Bit by bit events moved in his favour. Support for the Pasteur Institute mount- ed. At one theatre benefit, Gounod conducted his Ave Maria and, ‘in an impulse of heartfelt enthusiasm, kissed both his hands to the savorit’. At the Académie de Médecine opinion began to swing in Pasteur’s favour and he could now quote more favourabie statistics. From I 880 to 188 5 sixty cases of deaths from rabies had been reported in Paris hospi- tals. From November 1885 to August 1886, during which time rabies vaccination was in operation, there had been oniy three deaths, and two of these victims had not been vaccinated. The official reinstatement of Pasteur’s reputation came in July 1887 when he was elected Life Secretary of the Académie des Sciences. But this period had taken an enormous toll on him; physically and mentally it had been the most trying of his life. As well as having been deeply involved in more than two years of medical activity, with patients daily clamouring at the door of his laboratory, he had had to evaluate the pathetic claims of these same patients and, if his method was at fault, bear their deaths, when they occurred, on his conscience. In October I 887 he had his second paralytic attack. As he sat writing a letter in his room, he tried to speak to his wife, but she saw that he had lost the use of his tongue. He insisted on lunching with his daughter, as he had planned, and tried, as he had on the first occasion, to fight off the symptoms. But a week later he was struck down again. He was to five on for severe! years, but his life of phenomena! creativity was at an end. CHAPTER EIGHT ping about in his peripatetic fashion from laboratory to labora- tory, painfully bearing his breast to the many who had chosen to attack his theory of phagocytosis. At last he arrived in the Beriin labora— tory of Robert Koch where, anxious to please as always, iVIetchniIrofl' spread out some specimens for the great man to loolr at. But Koch, in spite of his experience as a young doctor trying to make his way in pure research, was as crushing to the Russian as others had once been to him. Metchnikoff was bitterly hurt, and was grieved even more by Koch’s assistants, who lined up behind the Master waiting to see on which side his axe would fali before they committed themselves to the rejection of Metchnikofl’s beloved phagocytes. Koch never knew it, but this was a critical visit which would deter— mine how Metehniltofi“ wouid spend the rest of his life. Metehnikofi had iust come from Paris. His reception by Pasteur there could not have been in greater contrast. Nervously he had sat in the laboratory looking at the 'old man, rather undersized, with a left hemiplegia . . . His pale and sickly complexion and tired look betokened a man who was not likely to live many more years’. Pasteur, nevertheiess, was not too decrepit to know that Metchnikoff desperately wanted to tail: about microbes, and in particular about microbes related to phagocytes. He sensed that, at the core of this ascetic and oddly mannered young Russian’s theory there was a visionary light. He was encouraging. It is scarcely surprising, therefore, that within a few months l‘l/Ietchnikoili~ was back in Paris working in Pasteur’s laboratory. Metchniltofi' established himself in Paris and became a fixture of the laboratory, much loved and admired in Spite of all his eccentricities. When the laboratory was in financial diffi- culties, Metchnikofi' refused his salary. He was never to leave the place except, as he himself wished it, when heading for Pete Lachaise Ceme- tery. One of Pasteur’s assistants who approved wholeheartedly of the Russian’s spartan life-style was Emile Roux. Metchnikoff found his personality attractive. Temperamentaily, however, the collected, handsome Roux was very different from the disorganised Metchniltofi: his attitude to women, for example. Said Roux, ‘Women are like drugs. When they no longer act, one must change’. (And one of his consider— abie number of female friendships was with Madame Metchniirofi', now no longer in her teens.) Their work too, though moving towards the same end, was based on fundamentally different ideas. Roux, along with Alexandre Yersin, had become deeply involved in Merchnikoff spent several weeks of 1887 in Western Europe, hop- iog MICROBES AND MEN NO the problem ofimmunity. Yersin had spent a short time in Berlin workw ing with Koch and had brought back to Paris a detailed knowledge of what the Germans were up to. Lbfiier, Koch’s assistant, had just sue- ceeded in isolating the bacillus responsible for diphtheria — small, needle-like rods. As the controversy over the rabies vaccine was raging, Roux and Yersin had been trying, without success, to find a similar vaccine for diphtheria. Roux tool: his microbe samples for his inquiry from children at two Paris hospitals, the Enfants Malades and the Hopital Trousseau. The death—rate from diphtheria in these places at that time was about 50 per cent. Still the only treatment for most of the children with throat mom-— branes affected by diphtheria was to have a tube pushed into the neck to allow them to breathe. The diphtheria bacillus, Lt‘afiler had shown, remained localised in the throat of its victim. Yet the whole body was affected as though it were poisoned. Roux had set himself the task of finding out why. Eventually he was able to cultivate microbes, let them incubate — as they did in a child’s throat — for several weeks, then filter off the liquid produced. He found that this liquid was a deadly poison, an ounce of which could dispatch 75,000 dogs. In diphtheria the mic- robes did not kill, but this substance which they secreted did. Roux believed that it should be possible to use this toxin as a vaccine. The theory was apparently in direct opposition to that of Metehniltoff, who believed that immunity to a disease could not be given by some inaniw mate poison in the blood, but by his lively cells, the battling phagocytes. But whatever else these differences of views revealed they showed no rift in the generally smooth relations between the workers in the Pasteur Institute. Apart from a tricky period of antagonism between Pasteur and Roux during the rabies worlt, this laboratory had all the appearances of being one where a common aim was shared. Here, whatever were the individual motives in the search for scientific truth, they produced remarkably few personal bitternesses and pettyjealousies. The same cannot be said of the other leading bacteriological labora— tory in Europe, led by Robert Koch. The achievements of the German school had been enormous. Pasteur’s success both with his rabies vac- cination and his public relations had temporarily redirected the lime- light to France. But the intense rivalry between the two laboratories remained, and the one in Berlin was poised to make some enormous advances in the understanding of the nature of diseases. The workers who were to make them, hoWever, were not to come out of the experi- ence unscarred by mutually inflicted wounds. In the few years before and after I 890 Koch’s pupils were to identify BEHRING the microbes that caused typhoid fever, diphtheria, erysipelas, tetanus, glanders and some forms of pneumonia and meningitis. And the identi— fication of the cause of a disease, as by now even the general public was aware, was the first step towards conquering it. Justifiably, this work gave Koch a phenomenal reputation. But in scientific circles the names of his assistants were also becoming well known: men such as Gafllry and Lather and, more recently, Emil Behring, the energetic ex- ?russian army doctor, Shibasaburo Kitasato, one of several Japanese taken on in German laboratories about this time since they added little to the laboratory’s budget, and Paul Ehrlich, an untidy chainasmoker of cigars who adored his laboratory work and was willing to Work without pay ifnecessary. When Behring arrived in Koch’s laboratory the wall of protective secrecy which Koch had built up in order to safeguard the priority of his Work was securely established. The spirit of competition worried Behring not at all. He enjoyed a race just as he enjoyed a good row; his military career had given him the stamina for some of the infighting that he was to take part in during the next few years. He was ruthless and he knew how to use his friends to his own advantage: characteristics which did not endear him to all his co—workers. Behring, like Koch, was one of thirteen in a poor family. But in his youth he was less of a dreamer than his profesaor had been. Behring was a pragmatist. He prepared himself for a priesthood since this was a means by which he could have free university training, transferring later to the army medical school. Once in the army, and with theological thoughts behind him, the young Behring ran up enough gambling debts to cause a minor scandal before, by contrast, he developed a more consuming interest in infectious diseases. He was 35 when he joined Koch at the Institute of Hygiene in I 889. Within a short time Behring had become interested in the diphtheria problem and the method of producing toxin which Roux and Yersin had turned into public knowledge. However, it was regrettably typical of the laboratory in which Behring was now working that, at that time, there was at least one other man occupying a nearby bench trying to turn up a diphtheria vaccine. The spirit of the place was such that each was moving entirely independently of the other. If he consulted this other man, Karl Frankel, Behring recorded no debt owing to him. Behring’s approach to his new problem was guided by his army ex- perience. There he had become very familiar with the use of iodoform as an antiseptic wound dressing; the efficient way in which it acted prompted him to try out iodoform on some of the toxic products of H! MICROBES AND MEN IIZ certain bacteria. He found it very effective as a way of reducing their toxicity. He now began to investigate the effect of treating cultures of dipl’xw theria bacilli with another iodine compound, iodine trichloride, with which he then inoculated a number of guineaupigs. Some survived and, significantly, he found that they were now immune to diphtheria. He was also able to show that minute amounts of diphtheria toxin immun- ised the animals. By taking blood serum from an immunised guinea-pig and injecting it into another animal he now found he was able to transfer the protection to the second guinea-pig. Not only that, an animal already suffering from diphtheria toxin could sometimes actually be cured. Alw though the serum did not affect diphtheria bacilli, it neutralised the toxin they produced. This was the discovery of an antitoxz'u. It was an epochal piece of research. For Behring it was worth a permanent and deserved place in the history of medicine. Behring would make good use ' of the place. If interpersonal relationships in general were bad in Koch’s labora— tory, nevertheless one fruitful, if unlikely, union had been made: that between the extravert ex-army officer, Behring, and the polite little Japanese, Kitasato. Only the year before they met in Koch’s laboratory, Kitasato had identified the microbe which caused tetanus and shown how, like the diphtheria bacillus, its danger to man lay in the toxin it produced. Together he and Behring were able to show that a rabbit could be immunised against tetanus in the same way as it could against diphtheria. The use of the rabbit meant that Behring and Kitasato were able to collect relatively large amounts of immune rabbit blood serum. Enough, at least, not only to protect a mouse from a lethal dose of tetanus toxin, but to cure one already suffering from tetanus. Antitoxin was a wonderful discovery since immediately it opened up the possibility of finding a vaccine for diseases such as diphtheria, which took so many children’s lives. Behring consulted others in the labora— tory besides Kitasato, who clearly deserved whatever acknowledgement he got for his contribution to thejoint work. The young Paul Ehrlich was undoubtedly one who made suggestions to which Behring not only listened with attention but was more than glad to adopt. Naturally, Behring would, in his situation, be expected to consult Koch. He did and, it seems, Koch counselled caution before publication. Behring, after all, had no idea what this antitoxin was. It was a mystery substance. The name antitoxin was convenient, but it explained nothing. Behring, however, had caught on to Koch’s idea that a publishable piece of scientific work was a property to be safeguarded. On 4 Decem— DOMES'I‘IC CRISES her 1890 Behring and Kitasato published their results for tetanus. A week later Behring published a second paper, which carried his name alone, and which deacribed his experiments with diphtheria. Behring had made his mark. he had produced nothing that could match the originality of his early scientific successes. Inevitably, as he grew older, his habit of working in secrecy was turning him into a nervously suspicious indivi— dual who saw a conspiracy behind every polite question. Soon he was to complain to a friend, ‘Whenever I start something new, a swarm of ill-— wishers and selfwseekers batten on to me’. Domestically, too, he was not a happy man. Twenty years and more of marriage to Emmy had not strengthened their bonds; the financial worries that tied them together had disappeared with Koch’s increasing fame. At the age of 45, bespectacled, bearded and with thinning hair, Koch began to look around him for something Emmy could not offer. His eyes lighted on a surprising subject. He was sitting in an artist's studio at the time having an official portrait painted. On one of the can- vases in front of him rested the portrait of a seventeen-year—old girl. A few enquiries told Koch that she was a student of the artist, she had played small parts at the local Schiller theatre and she was the illegitiw mate daughter of 21 Berlin workman; she was also, as Koch could see, unquestionably pretty. A meeting was arranged, and before long the Koch himself was going through a difficult period. For six years now _ girl, Hedwig Freiburg, was the centre of Koch's life and thought outside the laboratory. This crisis in Koch‘s domestic situation also happened at a critical time in his scientific affairs. How much one predicament influenced the other is difficult to guess. Although it was well known that he was work-- ing on tuberculosis he hid the details of what was going on behind his laboratory doors with even more caution than usual. The German Government too was well informed of Koch's preoccupation. His sue— cesses in the past had brought nothing but honour to Germany, and now his fame was a commodity that would be exploited in the cause of national prestige. It so happened that the Tenth International Medical Congress was to be held in the summer of 189:: in Berlin. If, as it was rumoured, Koch was on the point of making some phenomenal break— through in the understanding of tuberculosis, the timing would be magnificent. A cure for an unconquered scourge announced by the discoverer himself in the nation's capital before one of the most distin- 113 MICROBES AND MEN 3:4. guished international medical gatherings ever held would be a shining demonstration ofnational intellectual supremacy. The situation was made quite clear to Koch by Gustav von Gossler, the Minister of Culture. And Koch was led to believe that not just the nation, but the Kaiser himself, loolred forward to Koch using the Con— gress as a platform to. make some climactic announcement about the disease. There seems little doubt that Koch was temperamentally in fav- our of the patriotic and nationalistic motives urging him on, and wanted nothing more than to respond in the same spirit that the requests were made. Regrettably, as the Minister of Culture could not understand, but as Koch know too well, neither bacteriological research, nor natural scientific research of any kind, can be made to fit into a timetable. As the date of the Congress came closer Koch, billed to speak at the opening session, with an audience expecting a sensational announcement, was so sensitive to the dangers of the trap he had helped prepare for himseIf that he was considering abandoning his speech altogether. He did not, however. He stood that day in an auditorium decorated in the brash style which the Ministry of Culture had decided was appropri— ate to a major medical occasion. Surrounding the hesitant, physically insignificant middle—aged man, shuffling his specimens on the raised dais, were the ludicrous cardboard and plaster trimmings ofa simulated temple guarded by a statue of Aesculapius, the god of medicine. Present in the hall was the scientific cream of the 700:: delegates to the confer— ence, all of them primed to expect that the nub of Koch’s speech would be something ofenorrnous scientific and medical interest. His introductory words made it clear that he intended to use the oc— casion to review the latest developments in bacteriology, all very fami— liar to his audience. Not surprisingly, the murmurs of disappointment turned to impatience, and soon to boredom — until he finally arrived at the words, ‘I have tested a large number of substances to see what influ— ence they would exert on the tubercle bacilli. . .’ The hall was now in silence. This was the preamble to what they had come to hear. Koch went on. cautiously listing the difficulties and failures he had encountered in many trials, then added, ‘. . . and I have at last hit upon a substance that has the poWer of preventing the growth of tubercle bacilli not only in the test~tube, but in the body of an animal’. Koch had produced an enormous rabbit from his hat. The excitement and response in the Hall was overwhelming. Koch had done all that was expected of him as a scientist and patriot — or so it seemed. In the hub— bub of the reaction few could, or cared to, listen to the qualifications to his remarks which he now began to list. His researches were not yet TUBERCULIN completed. His work so far had been only on laboratory animals. He was only at the beginning of trials which one day might lead from guinea- pigs to humans. It was too late. By next day newspapers had announced a cure for tuberculosis and Koch was the scientific saviour whose skills, as pre— dicted, had risen to the magnificence of the occasion. The adulation, hOWever, did not stretch to the informed members of his audience, which included men of the calibre of Virchow, Ehrlich, Roux and Metchniltofi. What was it Koch had done? He had not actually dis- closed any details. The only information he had given was that in his possession there was a liquid capable of wiping out tubercle bacilli: a magic potion the sceptics might, and did, call it. Koch would disclose details in his own good time. And for many that was proof enough. Koch’s reputation was, after all, based on an unbroken series of specta- cular successes. He had never failed in the past. it was to be called tuberculin. Within a few months the pressure of the public reaction had forced Koch into human trials. To his credit, the first subject was himself. He survived several hours of unpleasant reaction to the injection, including pain in the limbs, difficulty in breathing and fever. At last, by November 1890, he was able to put in print the results of his eagerly awaited trials on tubercular patients. Again Koch couched his words in cautious phrases, but again the only message that was popularly extracted from his paper was that of success, no matter how limited. The response among tubercular patients and their families was devastating. The sick and their guardians swarmed into Berlin for treatment. Tuberculin could not be prepared nor administered fast enough to meet the pathetic demand. its price became inflated and, inevitably, a black—market in the stud" sprang up. It appeared to matter not in the least to some of the city’s most reputable practitioners of medicine that they did not know what the substance was they were ad- ministering. The name of Koch attached to it was the imprimatur which guaranteed its efficacy. it took a relatively short time to realise that the panacea was not all it seemed. All kinds of tubercular conditions were being treated with it, and some patients, it was true, at first showed startling improvements. Disaster, therefore, was all the more poignant when a relapse set in and the patient Went into rapid decline. Even Joseph Lister was prepared to adopt an unquestioning faith in the elixir. He turned up in Berlin with his suffering niece, watching over her daily after Koch had personally supervised the treatment. The girl went into decline like so many of the 125 inoculation against tuberculosis using Koch's treatment THIS TUBERCULIN TRAGEDY others, and neither Lister nor Koch were able to prevent the inevitable tragedy. The fiasco had along way to run. Hotels and hospitals in the city were crowded to overflowing and injections were being administered in hotel rooms. Racketeering in the elixir became so outrageous that von Goss~ ler, the Minister of Culture, was forced to intervene to fix the price of tuberculin. In America the aslting price for a gramme was one thousand dollars. As the crown for the achievement Koch accepted from his Kaiser the Order of the Red Eagle. By now, Koch himself was like some plaster Aesculapius, presiding impotently over premature success celebrations being played out before him. His fall was imminent, and the instrument that would destroy not only Koch's hopes, but those of many thousands upon thousands of tuberculosis sufferers, was held by Rudolf Virehow. The sceptical pathologist, by January I891, produced evidence to show that the corpses of twenty-one cases of patients, all of whom had been treated in recent months with tuberculin, were riddled with the worst form of the disease: miliary tuberculosis. Virchow was too distinguished in his field for his statements to be passed over lightly. He had made sure that his words were talten seriu ously by flatly stating that the cases he had seen were worse than any— thing he had ever come across in his career as a pathologist. Koch’s reputation was on the block. There was uproar in Berlin medical circles. There was new no alternative to Koch putting an end to the mystery he had created and telling the world what tuberculin was. When at last Koch broke the news to the scientific community there was a sense in many of not merely having been letdown, but of betrayal. His tuberculin was a simple thing which involved the discovery of no fundamentally new principle. He had merely followed the lead of Roux who had separated the poison secreted by diphtheria microbes from the microbe itself. In the same way Koch had taken tubercle bacilli, cul- tured them on a glycerine broth for several weeks, killed the bacilli by heat, and filtered off his fluid. He had then tried to use this to kill the tuberculosis germs in the body. He now stood exposed as the worst possible form of charlatan: the cost of human lives could be laid on his conscience, it was true, how- ever, that he had never done anything other than counsel caution in both the interpretation and the application of his Work. But this does not excuse Koch, nor even those who used tuberculin, from blame for the pitiful results. Had he not wrapped his experimental worlt in secrecy in order to safeguard his own priority, the shortcomings of tuberculin 1:7 118 MICROBES AND MEN would have been appreciated before the worst panic demands for treat— ment had set in. And had Koch not used his authority, as one of the most creative biologists of his age, to persuade others to accept his mystery medicine on trust, the scale of the disaster would not have been nearly so great. A lesser man would have been forced to unwrap his product for full inspection and would not have expected to hide behind his credentials. There were few places Koch could look for support. In his own laboratory he had excluded from his colieagues the work which most needed the help of sceptical minds. Behring could be forgiven if he saw hypocrisy in the advice not to publish the work which was now revealed as far less premature than Koch’s own. As for personal solace, there were few pieces for Koch to turn: he was poised unhappily in the middle of a breaking marriage, and his only daughter was now married off to a young doctor who had administered some of the first tuberculin injec— tions. In the spring of 1891 he took a hoiiday in Egypt and it was from there that he wrote, as if half expecting rejection, to the girl who was far younger than his own daughter, Hedwig Freiberg. The letter he wrote at 47 showed his feelings of vuinerability and inadequacy, just as did those in his passionate youth: ‘As long as you love me,’ he told Hedwig, ‘I cannot be beaten down by the vicissitudes of fate. Do not abandon me now for your love is my comfort and the star to which upward I gaze.’ Hedwig did not abandon him. She became his wife. And, when looking for the motive which made Koch put himself in the terrible position of appearing to dupe the world, it is necessary to aslt how much the founder of bacteriology was influenced by the need for cash from the sale of tuberculin licences to finance a breaking marriage and a mistress of :9. ‘You couidn’t blame Koch,’ said one American, ‘but what on earth did she see in him ?' hen the furore and the optimism surrounding tuberculin was Wbeing fanned to its climax, and Koch was swept up into the uncertain role ofpubiic hero, the question of State assistance for tuberculosis research was raised in the Prussian Parliament. Luckily for Koch the subsequent disillusionment could not stop the momentum of support for an institute to house his work, in spite of the fact that some, like Virchow, were ready to point out that the new establishment was being set up with what seemed to be indecent haste. By the autumn 051891 Koch had his Institute for Infectious Diseases. To help stall~ it he successfully recruited some of the young research DIPHTHERU‘. ANTITOXIN Workers who had already put themselves in the front rank of their subject, including Ehrlich, Kitasato, Wassermann and, inevitably if reluctantly, Emil Behring. The tragedy of a few months earlier, if it was not mentioned, was not forgotten. Koch continued his work on tuberculosis, but the centre of attention in the laboratory, and the work which now held out most promise for spectacular results, was that con- nectcd with Behring’s diphtheria antitoxin. Behring was extravert and aggressive. There is no doubt that he was accepted as the natural leader of the group working on the diphtheria problem, and there is no doubt too that he tool-t up the role as his due. Koch soon found that Behring’s laboratory had become virtually an autonomous institute within the Institute; there was little the Director Couid do about it. Koch felt that the place was becoming more like a farmyard than a laboratory as he watched larger and larger animals being assembled, for the diphtheria research. Behring had to get enough blood serum containing his diphtheria antitoxin to begin trials on human beings. Starting with an immunised guinea-pig he had got enough blood from it to inoculate more guinea— pigs. From there he had progressed to rabbits, and from rabbits to sheep. By Christmas night, 1891 , more than a year after publishing his work, he had enough antitoxin, and was sufficiently confident to take a needle and inject a smali child lying in :1 Berlin hospital. rl‘his, the first of a series of experiments with human beings, was a qualified success. In a careful assessment of the therapy at the Berlin Charité Hospital —— careful in the light of Koch’s experience with antitoxin w the survival rate in patients was found to be high provided the treatment could be given early in the disease's progress. Back in the Pasteur institute, from which Behring had originally stolen the initiative in diphtheria work, Emile Roux was now using still larger animals. He was inoculating a horse with diphtheria toxin which had been weakened with iodine. Gradually he accustomed the horse to stronger doses untii it was able to resist pure toxin. He then bled it from the jugular vein and was able to separate enough powerful antitoxin to begin treating children. At the Enfants Malades Hospital from 5890 to 1893 there had been over 2000 deaths from diphtheria: a mortality rate of 51 per cent. In four months of I894. Roux’ work brought this down to 24 per cent. At the Trousseau Hospital in the same period, where the serum was not used, mortality was ()0 per cent. This was success in the Pasteurian tradition. But in the publicity that followed, Roux was careful to see that Behring got his share of the credit. The French, by now very familiar with the 119 MiCROBES AND MEN 120 unseemly rows over scientific ownership which the walis of Koch’s Institute had not managed to contain, were cautiously avoiding conta- mination by the same unpleasantness. Querelle: d’ffllemand the French cailed the squabhies, much as the English prefer to dub a foreign origin on anything they find vaguely distasteful, such as Asian flu, Dutch courage or French leave. ‘ Roux had scrupuiously followed the French pure scientific tradition, well demonstrated in Pasteur, of refusing any opportunity of personal financial gain by expioiting his discovery. Behring was tied by no such tradition. In his experience, custom, such as it was, was to take the cash while the going was good: and Behring of all people needed no urging. Already, he had patented his diphtheria antitoxin. In addition to Kitasato, without whom the serum might never have come into being, Paul Ehrlich was the other man who had helped Behring’s work into a useful medical tool. This untidy but brilliant ex- perimentaiist had spent several years in and around Koch’s laboratory. His habits and his method of work, relying almost entirely on test—tube experiments, used both to infuriate and amuse his co—workers. He wore detachahie cuffs on which he made copious notes, smothering his waist- coat with the droppings from his thick Havanas as he agitatedly moved about the laboratory, His simplicity in his styie of work helped him achieve some of his best resuits; his simplicity in his human reiations was frequently childlike. Amiahie and contented when engrossed in his work, he was capable of infantile outbursts, which added another up- setting ingredient to the charged emotionai atmosphere of Koch’s laboratory. In Ehrlich's case personal financiai gain was not‘a motivating force in any of his actions; he was too fascinated by the process of scientific dis- covery to think that there were delights to be bought from its profits. However, he was well attuned to the iahoratory's custom of establishing scientific priority. There were many pieces of work to which he had made significant contributions of which he could fee! proud and for which he couid expect recognition. He had done pioneering work on the staining of bacteria and on immunity. In the diphtheria work he had used goats and horses to obtain antitoxin many times more powerful than Behring had succeeded in separating and, after a meticulous and long series of experiments, had discovered a method of measuring the amounts of antitoxin in biood, and calculating how much of it was needed to effect a safe cure in humans. Ehrlich, then, could rightfully expect some sort of share, if rewards for contributions to the discovery of an efi'ective diphtheria antitoxin Roux administering diphtheria antitoxin in 1894. 12] 122 MICROBES AND MEN were being doled out. In the passage of antitoxin from laboratory bench to hospital therapy events moved with extraordinary speed and the early optimism was not misplaced. Commercialisation of the antitoxin began in l 892 when Behring was approached by representatives of the Lucius and Bruning dye works, at Htichst near Frankfurt. Behring agreed to have his product developed and marketed by the Héchst firm, though Ehrlich's rightful share of the profits needed to be settled. Behring had a solution, of sorts. By this time he had already cultivated useful con- tacts in the Ministry of Culture and he and the manufacturers were able to persuade Ehrlich to renounce his patent claim, in exchange for which Behring would engineer a salaried government post for Ehrlich, and one commensurate with his undoubted abilities, though being a government post, one in which he would be unable to accept royalties on patents. With naive trust Ehrlich agreed. Behring, for whatever reason, was never able to use his charm with sufficient effect to fulfil his promise. Ehrlich had to suffer, not altogether silently, and watch a vastly profitable enterprise develop, from which he benefited by not so much as a pfennig. Ehrlich hid his bitterness from no one. He tool: the matter to Prussian ministerial level and had no compunction in displaying Behring’s in~ adequacies as a scientist. Intellectually Behring was Ehrlich’s inferior, and the incident provoked Ehrlich into saying so in no uncertain terms. ‘He wanted to be a Superman,’ he wrote of Behring, ‘but — thank God — - he did not have the necessary super—brain.’ The two never spoke to each other again. Nevertheless, from what he had achieved so far with what Ehrlich considered limited scientific abilities, Behring reaped a very satisfactory harvest. The success of diphtheria antitoxin gave him both fame and fortune. For a time the fame overshadowed that of Koch. His ability to be influential at ministerial level served his own cause better than it had Ehrlich’s, winning a professorship as well as ennobiement, with the right—- which he exercised with pleasure— to call himself'uon Behring. His gambling streak never deserted him, nor did his luclt. On one occasion be swept the boards at Monte Carlo and he bought himself a villa on Capri with the profits. There he entertained lavishly, as he did at his home in Marburg: a castle overlooking the town, in which he built his own laboratory - and mausoleum. Nearby he established his own chemical factory: the Behring Worlrs. And to help him share in the material success which, still only in early middle age, he so patently err- joyed, he married the daughter of the director of the Berlin Charité HOSpital, who was thenjust twenty. asunmo’s WORLDLY success Ehrlich’s view of Behring was, not unnaturally, coloured by events. Behring’s style was personal, acquisitive and aggressive, but it was not vindictive. When old and crippled, leaning heavily on his cane, he was to he one of the scientists who walked behind Ehrlich’s coffin to his grave where he said, ‘If we have hurt you, forgive us'. In spite of Ehrlich’s assessment, the contribution made by Behring to the signal triumph of conquering a terrible disease was great. And before he too died he was to make more contributions to the improvement of diph~ theria immunisation techniques, and to work for many years attempting to find a solution to the tuberculosis problem. But even here there were disputes among former colleagues of the Koch camp. Still racing to be first, Behring applied for a patent for a tuberculosis immunising agent, only to see it disallowed in favour of application for a difierent agent made by Koch himself. Ehrlich tool: the trouble to write to the Prussian Minister of Education to malce sure that it was realised at Governmental level that Behring’s work was unoriginal. In the event neither method worked and a satisfactory treatment for tuberculosis never came from a German laboratory, in spite of the years of creative talent, sheer hard work, tragedy and bitterness that had been associated with it. Yet again, the pendulum of success swung to France when Albert Calmette (who eventually became director of the Pasteur institute), and Camille Guérin, after years of work together, success~ fully tried their BCG vaccine (bacille de Calmette et Guérin) on a baby delivered of a mother suflering from tuberculosis. The vaccine was developed using the microbe attenuation methods so brilliantly devel- oped in Pasteur’s laboratory. In :92: the first successful trials began, having been delayed many months by the war. It was a war in which Calmette’s wife was taken prisoner and held as a hostage, and in which Behring was again rewarded, this time by a decoration from a grateful German government which had used his tetanus antitoxin with sweep- ing success on its wounded soldiers. m3 Paul Ehrlich CHAPTER NINE o matter what viewe Paul Ehrlich held about the intellectual in- adequacies of some of his colleagues, their views of him were united: behind the eccentric facade of ‘Dr Fantasy’, as they called him, there was an exceptionally able mind capable of working brilliant pieces of practical, creative chemistry. As a young research worker he had become fascinated by the preparation of dyes, and spent hours using them to stain animal tissues so that he could see them as they had never been seen. He wrote, for example, of his enchantment at being able to look at the fine twigs of the nerves of a piece of frog's tongue after it had been stained to a magnificent dark blue by the dye, methylene blue. His dyes became the centre of his life: his work and his hobby. Even when, in the evening, his wife played selections from popular operettas on the piano he, being tone—deaf, used the moment of relaxation to conjure up new thoughts about the use to which he could put his chemical compounds. Ehrlich had been one of the first clinicians invited by Robert Koch to try out tuberculin on patients; together they had seen the severe limits-u tions of the serum. Koch had quickly recognised the younger man’s sltilful techniques, and it was Ehrlich who perfected methods of staining the tubercle bacillus. During this period he contracted the tuberculosis that forced him into twa years’ convalescence in Egypt. On Ehrlich’s return, Koch offered him a place in his Institute for Infectious Diseases, and there he began his work with Behring on diphtheria antitoxin. Ehrlich’s part in Behring's success was as Ehrlich himself assessed it to be: crucial. For a time it diverted him from his all—consuming love- affair with his chemical compounds but, in 1896, his abilities by now widely recognised, he was invited to direct the new Institute for the investigation and Control of Sera in Berlin. At last, and without Behring’s help, he had the control of his own Institute. As his own master, he could push his work along whatever channels his peculiar fancy took him. Not that the new Institute was a model establishment with unlimited facilities: the laboratories were a converted bakery. For his techniques, however, Ehrlich needed little more than rows of empty shelves where he could store his botties of chemical compounds; test tubes, water, a tap, a flame and some blotting paper were all the other equipment he required. it amused him to be known as ‘the virtuoso of the test tube experiment’. His methods were highly refined, and he carried out these experiments with enormous care and with all the obsessive concentra- tion required of a good chemist, being willing to spend hour after hour :25 MICROBES AND MEN r26 in repeating the same process. He lmew the characteristics of the dyes in the bottles on his shelves as others might know the strengths and the weaknesses of human beings. And when he was depressed or in the middle of one of his feuds he would go and loolt at his bottles and say, ‘These are my friends who will never leave me in the lurch.’ Ehrlich attributed much of his success to being able to store away information about these compounds in the recesses of his mind and bring it out at the appropriate moment. He had mixed views about the reasons for his creative triumphs and he was fond of quoting ‘the four big Gs’ as the essential constituents of anysubstantial scientific achievement: ‘Geduld, Geschiclr, Geld und GIiick,‘ (patience, ability, money and luck). All who worked with him saw the first of these two qualities in operation} As for money, he had no wish for it for its own sake, but he had seen at close quarters how impor- tant it was to Koch and Behring in furthering their careers and their laboratories’ output. When the widow of a Wealthy banker, Georg Speyer, financed a second institute for him to direct, to be built next to his existing one, any problems arising from want of simple equipment or stafi'were efl'ectively removed. As and when it suited him Ehrlich acknowledged the importance of luck in his discoveries. For example, he was fond of describing how once during his researches on tuberculosis he had tried unsuccessfully to stain red blood corpuscles. One day he had prepared his materials and put them down on top of a stove: typically, his laboratory was so clut- tered with test tubes, bottles, journals and bundles of paper - he hated throwing anything away — that there was nowhere else he could see to put them. Next day, when he went into his laboratory he found that the woman cleaner had lit the stove. In a fury he retrieved his slides. But when he looked at them he found the most wonderful results; heating had brought about the staining process. But Ehrlich, even though he considered himself a lucky man, was ready to admit that the mere fact of a fortunate accident contributes little to scientific creativity; what gives it meaning is the store ofimowledge from a mind capable of build- ing on the fact; he, and he was never modest on the subject, had that store of knowledge. However, he had no suggestion to make as to how he ordered the knowledge in his mind, and the best he could do was to talre refuge in the new psychology of Sigmund Freud, and suggest that he possessed a useful ability to store information at an unconscious level. Knowledgeable chemists who watched Ehrlich at worlr, however, were not deceived by the Chaplinesque performance —- the detachable cuffs forever slipping over his wrists and the perpetual shoWer of cigar ash. annmcn’s WAY or wonumo They confirmed that, in spite of the indescribable mess of his laboratory, luck had only a small role in his successes; he proceeded only after the most careful planning, and then with infinite care and persistence. The laboratory atmosphere he created was, to say the least, singular. It was permeated by his cigar smoke, and by his voice ringing down the corridor, calling for a fresh box, or for mineral water with which to satisfy his apparently insatiable thirst. Aside from chemistry his intel— lectual stimuli were few, and these undemanding. Iust as he drew in- spiration from his wife’s piano renderings of Viennese light opera in the home, so too in the laboratory he found he could concentrate better with the encouragement from the street of an organ-grinder, whose art he financed by the generous supply of coins. Those who worked with him looked on many of his characteristics as those which could be expected of a child. His naive enthusiasm and his boundless energy inspired these same qualities in those who came to worlt with him. As one friend said, ‘Ehrlich is a man whom one can love as a child is loved'. On the other hand, his childlilce bad temper, his irrational rages and his convic- tion that all who were not friends were enemies figured strongly on the debit side of that same uncontrollable temperament. One of his habits was to scribble out his orders and his thoughts for the day onto small, differently coloured cards which he would have his assistant distribute to the different staff members in his laboratory. The cards were dupli- cated so that he could check that his orders had been carried out pre- cisely. These cards, often nearly illegible, enshrined some of his most original thoughts applying chemistry to medicine. But delivered, as they Were, as instructions to grown men, they were the cause of annoy— ance and, eventually, bitter resentment. Ehrlich was unconcerned by the effects of his emotional outbursts on those he worked with. When his work on diphtheria antitoxin was over, he was able to return to all that really mattered to him: the use of chem- istry to attack disease. He believed that chemical compounds could be used as real curatives, not, as they were then, as palliatives, acting on symptoms. He described his theory precisely when he gave his speech opening his new Institute, the Georg Speyer House, on 6 September 1906. rl’hat day he described the substances which would seek out and destroy the living microbes in the body as magic bullets. He spelled out the task of the new laboratory as being that of finding ‘substances which have had their origin in the chemist’s retort’ to cure infectious diseases. The method would be called chemotherapy. Looked at from today’s vantage point Ehrlich’s prediction that his Institute would give birth to a new way of treating disease is remarkable. 127 The original (and incorrect) formula for atoxyl. it supposed that the substance was a single side— chain attached to a benzene ring 128 NH -—As O; H; He had already made some progress with animals, but his work on human disease had not yet reached an advanced stage. Anybody with other than his immense foresight and intuition could not justifiably have made such a sweeping prophecy. A turning-point in Ehrlich’s work came when it was found possible to infect rats and mice'with trypanosome microbes. With what can certainly be described as intuition, but with what was in fact the result of a phenomenal knowledge of the behaviour of chemical compounds, Ehrlich had plucked a substance from his shelf and had bad one of his assistants use it on an infected mouse. A derivative of this substance, a dye he called trypan red, had killed the trypanosome and cured the mouse. Burns’ stanza beginning ‘The best laid schemes . . .’ might well be brought to mind by Ehrlich’s determination to extrapolate from mouse to man, but he was aware, more than most, of the formidable problems involved. There was immediate hope that trypan red might be of use in the treatment of the trypanosome which causes human sleep— ing sickness; but, when the dye was sent abroad for doctors working in the tropics to try on their patients, results were too variable for it to be used in treatment. However, whatever trypan red did not do, it also did not kill the patient. The results of his early work gave Ehrlich grounds for optimism and intense activity. He called the hypothesis on which he was basing his research his ride—chain theory. This was the controversial theory he had first introduced in his prodigious and painstaking work on immun- ity. Now applying it to microbial infections, Ehrlich believed that the chemical compounds he was using would only effect a cure if there was a particular relationship between the substance and the microbe in question. The one must fit the other as a key does a lock. He believed that, attached to the molecules of the microbial cell, there were groups of atoms which stuck out like arms, and that the problem of dealing with the microbe could be solved by finding a chemical compound of a suit— able shape to lock onto this arm. And to be of any value in therapy, the substance must not harm anything else in the human body. Ehrlich already knew that another substance called atoxyl, an arsenic derivative, had shown some promising results in trials on sleeping sick- ness. He also believed that the formula of atoxyl, which had been worked out and accepted several years earlier, was wrong (above left). But, again through his great store of knowledge w being familiar with the sort of chemical reactions atoxyl could, and could not undergo — Ehrlich guessed that the nitrogen atom was misplaced in this formula, and that the true formula had not one, but two, side-chains (above right). The true formula for utoxyl A5 03 H; HgN The original formula led chemists to believe that atoxyl could easily be decomposed and that its structure was not well suited to having new groups of atoms attached. Ehrlich’s formula, however, suggested it was a stable substance which could be manipulated, and that groups of atoms could be stuck on to it to give new side-chain derivatives. If he was correct, it should be possible to arrive at derivatives which, in the treatment of sleeping sickness and other diseases, might be more effec—- tive than the original atoxyl. Ehrlich responded to his own thought in the only fashion he knew. He scribbled instructions to his chemists on one of his coloured cards. The information it carried - that, for no particular reason, the formula of a chemical compound should be assumed to be something which they and establishment chemistry knew it not to be— reelted of scientific dogma. The incident soon took on the proportions of a first-class row, and Ehrlich found himself facing three angry senior chemists of his labora- tory, Drs von Braun, Schmitz and Bertheim, who were sufficiently in- censed to challenge the untidy man's dogma. But in a confrontation of this kind Ehrlich was unshiftable. By now in one of his fiercest moods he told them without any ado that, in his laboratory, they would do as they were told. ‘You,’ he shouted at the three well—qualified men in front of him, 'cannot judge whether this is right or wrong,’ and walked out on them. Von Braun and Schmitz resigned on the spot. Alfred Bertheim, counting discretion and uncertainty as the better part of vaiour, de- cided to wait and see. It was a decision he never regretted. He found that Ehrlich was utterly correct. Stable derivations of atoxyl could be pro- duced in the laboratory. The textbook formula was wrong. Just as Toscanini, more than a hundred years after the composition of a piece by Beethoven, as a result of his deep intuitive knowledge of the cams poser, could spot an acceptable and accepted copyist’s error in a single note; so by similar mental process could Ehrlich spot a flaw in the beauty 0er chemical formula. Bertheim’s star was to rise to success with that of the Master. His luck, however, did not have the consistency of Ehrlich’s. It fouled in an incident which would have been uproariously funny but for its pathetic outcome. When the Great War broke out, Bertheim joined the army. It was to be a short war for the poor chemist: the fish out of water. On his first day with his unit, sporting his dress uniform, he began to des- cend some stairs. Sadly, his spurs tangled with the carpet and he fell to his death with a broken crown. Now that atoxyl was properly identified Ehrlich showed how useful 129 MICROBES AND MEN :30 the money — which he had always seen as an essential condition of success— could be. In his new Institute, securely financed by the accom- modating Frau Speyer, there were ample stall" and resources for Ehrlich to embark on a long line of experiments with derivatives of atoxyl. The number of compounds they made went up by tens and hundreds and eventually approached a thousand. Each compound required rneticuw lous preparation and equally meticulous testing on animals. With the 41 8th substance came optimistic signs; it was effective on spirochetes, the spirally twisted microbes which caused syphilis. One of the problems of trying to find an effective cure for syphilis was that it had been found impossible to infect a laboratory animal with the disease. But in r909 a young Japanese scientist, Sahachiro Hata, came with a recommendation from Ehrlich’s old colleague, Kitasato, to worlt in Ehrlich’s laboratory. He was reputed to have discovered a method of giving syphilitic infections to rabbits. Outside microbiology ‘ the ability seems scarcely desirable; to the initiated it was a quite excep- tional achievement. In these years, at the beginning of the century, the disease was urn mentionable in most circles outside laboratories. There the thing could be looked on as a medical curiosity, rather than the ruin {which it was) of so many useful human lives. In cold statistical economic terms, its effects were startling enough. In every country in the West each year the number of man—years lost as a result of insanity, heart disease, paralysis and blindness caused by syphilis reached hundreds of thou“ sands. In Germany six per cent of all deaths were due to syphilis; in France, ten per cent. For the individual its effects were terrible. When Ehrlich’s chemists were looking for some clues to a treatment one doctor talked of wards full of soldiers, their faces rotting away from the tertiary stage of the disease. Only one in five ever recovered from it. it was not simply contagious: it was congenital. Moral attitudes to it Were peculiarly ambivalent. When children inherited it, some thought it right that the sins of the fathers should be visited on their sons; they considered that a cure would be open encouragement to immorality. When Hats arrived, bringing with him his special knowledge of the delicate corkscrew—shaped microbe, Ehrlich handed over two of the compounds from the long list he, Bertheim and others had over the years produced from atoxyl. They were 41 8 and 606. There were high hopes for 418, because of its action on some spirochetal infections, but 606 had been tried by one of Ehrlich’s assistants and found to be ineffective. It was therefore almost a disagreeable surprise to Ehrlich when Hats turned up in his office one day and, bowing low as usual, announced that rests err 606 606 was effective on the spirochete of syphilis that infected laboratory rabbits and chickens. Ehrlich was not the first, nor will he be the last director of research to be faced with entirely conflicting experimental results from two assistants, and not know which to mistrust most. But he allowed his iniuitive processes to act as they normally did. The stream of abuse he let out over the bowed head of Hate was aimed at the absent and incompetent assistant. Hata’s results, under repeated test— ing, stood firm. After Ehrlich was satisfied with his laboratory trials two of his col- leagues’ assistants volunteered to submit themselves to doses of 606 to test its safety. This was an anxious time, since blindness was ltnown to be one of the side-effects of some arsenical preparations. The young men survived unharmed. However, the first patient to be treated with salvat— san (as 606 was to be called), was suffering, not from syphilis, but from a disease caused by a different organism, relapsing fever. A St Petersburg doctor, Julius lverson, had shown that atoxyl was effective in the treat-— ment of this disease, and Ehrlich therefore sent him samples of 606 to try. Of 55 patients treated by lverson during the city’s relapsing fever epidemic of 1909, 5 I recovered totally after one injection. Equally dramatic efiects occurred with cases of syphilis, some of the hideous, disfiguring ulcers disappearing within hours of the first treatment. Ehrlich, however, was cautious. He had no intention of melting a pre— mature announcement in the light of Koch’s experiences with tuberu culin. Indeed, many relapses did occur in syphilis treatment when over— cautious doctors administered insufiicicnt doses. Loss of hearing was one frequently reported worrying side-effect. But by examining in detail the Work of all doctors who were using salvarsan, Ehrlich was able to reassure himself that the sometimes permanent injuries Were the con- sequence of the misuse ofsalvarsan, and not one of its unavoidable side— effects. By r 9 to he was sufficiently confident to announce his discovery. Recognising that he had achieved what he forecast could be achieved from chemistry, he ordered the whole of his chemical laboratory to do nothing else but prepare more of the yellow, crystalline powder of pure 606 until the time that the Hbchst chemical Worlts could begin large- scale production. Ehrlich himself ltept a record of the doses handed out each day on the baclr of the cupboard door in his cluttered olhce. They ran into many thousands and Ehrlich was often to be found on his hands and knees as the list lengthened towards the carpet. He allowed no doctor to be supplied with the compound unless he undertoolt to keep him, Ehrlich, informed of its clinical results. In spite of all his care there were more relapses, and some unpleasant 13! MICROBES AND MEN :32 side-effects which could not be prevented. Some of the problems arose from the way in which the yellow powder had to be administered. It had to be dissolved in a large amount of water literally at the bedside and then injected into a vein: a tricky procedure even when performed by a slcilled doctor. If much of the solution escaped into the tissues around the vein it could kill off'the living cells; the result might mean that the patient’s limb would have to be amputated. But by 1912 Ehrlich had introduced his 914th derivative of atoxyl, neomiuartmz, a more soluble substance and a more reliable cure. Ever since he had announced the discovery of salvarsan two years earlier, Ehrlich's life had taken on a different aspect. He had become famous. Salvarsan was ideal newspaper copy, and the mass—circulation papers were now enjoying their boom years. The new discovery and the disease it cured had almost every journalistic ingredient to make it qualify automatically for reportage under banner headlines; with sex, suffering, medical triumph and more than a loose connection with im— morality, Ehrlieh’s Work could not fail to have regular and frequent coverage. However, once the swell from the wave of public reaction to the first announcement had died down a little, the tragedies of chemotherapy now began to qualify for a substantial number of front—page column inches. Some of the early disasters associted with salvarsan w the amputated limbs, the permanent deafness — were given full publicity, and the clinical trials of the drug came in for harsh criticism. Ehrlich tool: every piece of criticism personally and seriously, and attempted to deal with it as best he could. But by this time his health was not good; the exposure to a public which was not always either rational or even modestly well informed about his work tool: its toll on both his temper and his energy. The longest period during which he had to put himself on public display in order to defend and explain his work was also the most bizarre. It began when Karl Wassmann, the eccentric publisher of a Frankfurt paper, Die Wahflzeit (The Truth), used his pages for a series of attacks on salvarsan and on the administrators of the Frankfurt Municipal Hospital. Wassmann claimed that not only were the local consultants using a dangerous drug, they were making entrepreneurial profit out of it. He also made the startling accusation that the city’s prostitutes were being dragged into the hospital, being forcefully treated with salvarsan and being used as human guinea-pigs in clinical trials. Eventually, in May 19:4, the city authorities tool; libel action against SALVARSAN 0N TRlAL Wassmann, and Ehrlich was called to the Frankfurt Court of Justice as an expert witness. The trial was long, unusual and, for Ehrlich, exhaust- ing. During the hearing Wassmann and some of the prostitutes made a habit of interrupting the evidence from their seats in the body of the court. Unconventional as their methods were, there was no doubt that there were some worrying aspects to the case. There was irrefutable evidence that salvarsan treatment had been made compulsory for syphi- litic prostitutes and forcibly given to some of them, and that over the years there had been four deaths in the prostitutes’ ward; however, the causes of the deaths were in dispute. Giving evidence, Ehrlich had to admit that during the early months of its trials the unskilled or careless use of salvarsan had led to disasters. In the end, however, no evidence was produced to show that any doctor had made money from the pro- motion of salvarsan, and Wassmann was sentenced to a year’s imprison- ment. But although the action left a considerable number of questions relating to the desirability of forcible treatment of patients unanswered, it left the reputations of Ehrlich and his salvarsan intact. However, being made to defend his work in this way -— in public, and in a bizarre setting — threw Ehrlich into a deep depression. It was a depression which began to afiect his health, and from which he never properly recovered. In truth, there was no rational reason for this great bout of introspec» tion. He had been as good as his word. He had devised and planned a research programme which, after thousands oflaboratory bench experi- ments and tests on animals, had been completed within six years. He had designed a chemical which could search out and destroy a microbe within the human body. His first success in this field had been to pro— vide a wonderful cure for a hideous disease. In what to the casual observer might seem a completely disorganised and messy fashion he had devised techniques which would give a new orientation to medical research and to twentieth-century medicine. Ultimately the lives saved and the economic and social effects of this man’s work are incalculable. Ehrlich himself, however, was not satisfied with what he had done. His dream was to produce a substance which, with one big dose, could effectively destroy all the microbes of a disease which had invaded the body. Until days before his death, he was still looking for his solution, still working on salvarsan and still the childlike, irascible old man hunting out his microbes with the unswerving fierceness he used on any human whose opinion differed from his own. 133 ...
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