Smallpox, Syphilis and Salvation

by Sheryl Persson

  Ehlich’s scientific output for such a young man was phenomenal but in the midst of this, in 1883, not long before he turned 30, Paul Ehrlich married nineteen-year-old Hedwig Pinkus. It was apparently a happy marriage during which the couple had two daughters, Stephanie and Marianne.[18] They were a close family, which no doubt helped Ehrlich in his frenetic and sometimes troubled and insecure career.

  The year after his marriage Ehrlich received an appointment to the University of Berlin as Titular Professor, later becoming Associate Professor. His doctoral thesis, ‘The Need of the Organism for Oxygen’, was published in 1887. In it he established that oxygen consumption varies with different types of tissue and that these variations constitute a measure of the intensity of vital cell processes.[19] In the course of ten years, Ehrlich had published more than 40 articles on various aspects of his work, but he considered this to be one of the most important.

  Ehrlich’s early interest was in dyes and how they had a selectivity for specific organs, tissues and cells. He had shown that dyes react specifically with various components of blood cells and the cells of other tissues. Considering the scientific climate of the 1880s and the feverish search for cures, it was probably a natural progression that Ehrlich would begin to test dyes for their therapeutic properties, to determine whether they could kill pathogenic, or disease-producing, microbes.

  The end of the first phase of Ehrlich’s frenzied scientific research coincided with a change in policy at the medical clinic at the Charité following the death of Frerichs in 1885. Ehrlich was a non-conformist and his position was in jeopardy because he did not enjoy the support of the new administration. He confided in Hedwig that he wanted to quit but this would put them in financial jeopardy.[20] When Ehrlich suddenly became ill with pulmonary tuberculosis, he tested himself with Robert Koch’s new diagnostic tuberculin. The test was positive and suddenly circumstances were out of his and Hedwig’s control and permanent work was no longer an option. Because of its mild climate Paul Ehrlich spent periods of time during 1888 and 1889 recuperating in Egypt in the hope that his lungs would heal. Hedwig went with him. It has been suggested that this brush with a deadly disease at such an early stage in his scientific career, and the knowledge that he carried the tuberculosis bacteria within him, may have prompted Ehrlich to turn to the study of immunity and to develop his unique chemical approach to the treatment of disease.[21]

  When Paul Ehrlich returned to Berlin in 1889 he was free of tuberculosis but was unable to get work. Undeterred, like Koch and Jenner before him, Ehrlich set up his own laboratory where, despite the primitive conditions, he worked out methods for assaying toxins and antitoxins and for determining their correct physiological doses.[22] In 1890 he was approached by Robert Koch, who was then directing the newly established Institute for Infectious Diseases, and Ehrlich was invited to work with him as an assistant.

  Ehrlich thus entered a new phase of his research and soon began his trademark immunological studies. It was while working on Blood Serum Therapy with Emil von Behring that Ehrlich solved the puzzle of why Behring was experiencing inconsistencies in the serum and then he devised the procedures for standardising the antitoxin content. Despite the success these two men enjoyed while working together, they were fundamentally different and the rift that developed between them was never breached.

  Paul Ehrlich’s skill as a researcher at the Berlin institute was acknowledged when, in 1896, he was asked to head the new Royal Institute for Serum Research and Testing, which was established in Steglitz, a suburb in Berlin. Behring could not help but feel resentful, even though the building where Ehrlich was to carry out his work was small and run down and the facilities quite basic compared to what Ehrlich had been used to at the Berlin institute. Such conditions did not phase Ehrlich, who plunged headlong into his work on immunology. He was heard to say that he could work in a barn as long as he had a water tap, a flame and some blotting paper.[23]

  Through the efforts of the Lord Mayor of Frankfurt am Main, the Royal Institute for Serum Research and Testing was transferred there in 1899 and Ehrlich accepted an invitation to become its director. For the first time, he was in control of modern, well-equipped laboratories. In Frankfurt, Ehrlich was required to conduct cancer research and evaluate serums for the government, but this was his opportunity to follow his heart. His mind was already investigating chemical therapies.

  Ehrlich was indefatigable in his laboratory work, but was surrounded by what appeared to be disorder. He now had his own team of capable assistants and, almost fanatical in the way he ran the laboratory, he assigned daily tasks scrawled on small coloured cards to each person. His instructions were to be carried out to the letter and every team member was required to give a daily progress report. Although described as kindly and verging on shy, Ehrlich was capable of flying into a rage if his directions were not adhered to. Researchers who did not comply soon left the institute. To many Ehrlich was an enigma but no one doubted his genius; a person with the capacity to visualise chemical structures in his mind, even before they had been synthesised, is unlikely to be pedestrian.[24] Those who worked closely with Ehrlich saw him as original and daring in his approach to science.

  EHRLICH DEVELOPS A LANDMARK THEORY

  Along with the many other things he did, from very early in his career Ehrlich began to develop a chemical structure theory to explain the immune response. At a time when very little was understood about toxins and antitoxins he deduced that they were chemical substances. Chemical knowledge was limited even among scientists who were synthesising therapeutic agents, and very few hypotheses had been put forward about how the therapeutic agents that had been created actually interacted with living systems.[25]

  From around 1897, informed by his immunological work with Behring and other research he had undertaken at the Berlin institute, Ehrlich began to formulate his famous Side-chain Theory of Immunity, Seitenkettentheorie, in which he sought to explain immunity and how antibodies are formed. Although some of the concepts have since been proven to be incorrect, this theory allowed Ehrlich to achieve new breakthroughs while providing the groundwork for later researchers in the immunological field.

  When presenting his Side-chain Theory to the Royal Society in London in March 1900, Ehrlich summarised the science that had led him to his theory and acknowledged the work of those who had paved the way. A century had passed since Jenner had made his great discovery of the protective action of vaccinia against smallpox and, in that time, Ehrlich said, the ‘terrible scourge of mankind’ had been almost completely eradicated from the civilised world. However, Ehrlich lamented that Jenner’s discovery of inducing artificial immunity had stood almost alone in all that time.[26]

  Jenner had shown that by the use of an attenuated virus, which itself caused no injury, it was possible to ward off the disease caused by the virulent virus. Jenner had also established that vaccination with the weakened poison produced not only immediate, but also enduring protection. Ehrlich believed that Jenner’s discovery remained so isolated because the theoretical conceptions of the cause and nature of infectious diseases had not advanced in the decades after the introduction of the smallpox vaccine. And that was indeed the case.

  It was under Pasteur, Ehrlich claimed, that investigation into the cause of infectious disease reached its zenith. Ehrlich was referring to Pasteur’s Germ Theory of Disease and he saw the revolution in wound treatment that was led by Joseph Lister as the most significant outcome of Pasteur’s fundamental work. This was followed by what Erhlich called Koch’s profound investigations on anthrax and the pure cultivation of the most important pathogenic bacteria. Therefore, Ehrlich explained, it was the work of Pasteur and Koch that provided the basis on which the study of artificial immunity could again be undertaken. Because of their work the possibility existed for producing a number of the most important infectious diseases of men and animals, and of modifying pure cultivations of bacteria, either by Jenner’s method or in artificial culture media.[27] A
s a result further advances were at last possible.

  After Jenner, Pasteur had been the first to produce an artificial immunity by using an attenuated virus, but even so, asserted Ehrlich, theoretical explanations lagged far behind the practical effects. Behring’s remarkable discovery that the blood serum of animals that had been immunised against diphtheria and tetanus contained bodies which were able to specifically protect other animals against the toxins of these diseases, opened the door to new possibilities for protecting humankind against even more diseases.

  This, in fact, is what occurred as the twentieth century progressed, but in the short term Ehrlich was disappointed when the success of the diphtheria antitoxic serum that he had worked on with Behring did not lead to a rapid succession of similar achievements. Ehrlich believed that success would only come through an accurate knowledge of the theoretical considerations underlying the question of immunity. To find an answer to that question, he explained to the Royal Society, he had laboured for years trying to ‘shed some light into the darkness’ that shrouded the subject, and the result was his Side-chain Theory.[28]

  Ehrlich then went on to explain. His theory was that every cell has various special receptors, which he called side-chains, similar to the sidechains in dye molecules that he had studied. A side-chain in organic chemistry and biochemistry is a part of a molecule that is attached to a core structure. According to Ehrlich the side-chain receptors work like gatekeepers or locks for the cell, their primary function being to absorb nutrients for the cell.[29] However the receptors also allow many toxic substances to enter. When a cell is attacked by a toxin, it produces excess side-chains matching the toxin which are then released, flooding the body and neutralising toxins by attaching to them. The toxin is wiped out by these ‘magic bullets’ as Ehrlich called them, immunity is induced and the remaining healthy cells are protected.[30]

  Ehrlich’s concept was that Blood Serum Therapy was an excellent method of contending with infectious diseases, of providing immunity by stimulating side-chains to act against toxins, but in cases where effective serums could not be discovered, new chemicals could be synthesised to do the same thing. Instead of serum therapies, the magic bullets would be chemical therapies, or ‘chemotherapies’, a term that Ehrlich coined.[31] As Ehrlich saw it, he would create new substances that would have a specific affinity for pathogens such as bacteria and the chemotherapies would act only on these, and possessing no affinity for any other cells in the body would therefore cause no harm.

  With his Side-chain Theory of Immunity and his magic bullet vision of chemotherapy, the chemical understanding of disease and its treatment became possible. Ehrlich’s key insight was to think of the specific molecular structure of a substance as leading to specific biological effects.[32] Ehrlich eschewed orthodoxy and to make his vision of magic bullets a reality, against the advice of his colleagues he left the potentially profitable field of serum therapy to immerse himself in developing chemical antitoxins and vaccines that would stimulate the body to fight disease. Ehrlich was motivated by the science and the possibilities for curing disease, never profit.

  And so began the third phase of Ehrlich’s eclectic research. In the thesis that he had written as a young man he had foreshadowed the direction he would eventually take. Ehrlich had written that the chemical constitution of drugs must be studied in relation to their mode of action and their affinity for the cells of the organisms against which they were directed.[33] Now the time had come. Paul Ehrlich’s aim was, as he put it, to find the chemical substances that would naturally go to, or seek out, pathogenic organisms because they are specifically related, in the same way that antitoxins go to toxins. In lay terms he would shoot chemical magic bullets at disease-causing organisms.

  ***

  Paul Ehrlich began conducting his chemotherapeutic research in earnest at the Institute of Experimental Therapy but he faced opposition from Emil von Behring and his ally the Under-Secretary of Education and Cultural Affairs, Friedrich Althoff. Pressure was applied on Ehrlich to give up his chemical research. Another powerful opponent was Dr Hans Wolfert, the head of the Medical Board who like many doubters amongst the medical profession saw Ehrlich’s project as a pipe-dream and a waste of money. Opposition to Ehrlich was also tinged with an undercurrent of anti-Semitic feeling in Germany at the time. Undaunted Ehrlich carried on regardless even when, without warning, his funding was cut in half.

  In 1906 fortune smiled on the beleaguered Ehrlich. A benefactor, Frau Franziska Speyer, founded Georg Speyer Haus, a research institute dedicated to chemotherapy. Built next to Ehrlich’s institute it had its own staff directed by Ehrlich. In another windfall, the Hoechst and Cassella chemical companies, confident that Ehrlich’s project would be a commercial success, entered an agreement with Georg Speyer Haus giving the company the right to patent, manufacture and market preparations discovered by Ehrlich and his colleagues. The companies further agreed to supply the chemical substances that were needed for the chemical synthesis.[34]

  Paul Ehrlich decided to find a magic bullet to aim at trypanosomiasis, human sleeping sickness, the disease which Robert Koch had spent time researching in Central Africa. He targeted trypanosomes, the protozoa that were known to be responsible for a number of diseases including sleeping sickness, with coal-tar dyes, but he had no success. An arsenical compound, Atoxyl, had been discovered in England in 1906 and had proven to be effective with some trypanosomes but it caused damage to the optic nerve. Ehrlich became embroiled in a debate with other chemists about the chemical structure of Atoxyl but his preliminary work proved that he was correct.[35]

  The exhaustive and obsessive search for an arsenical compound began. Setting a punishing schedule Ehrlich and his assistants began creating chemical variants, seeking one that would possess maximum killing power against the trypanosomes while at the same time cause minimum damage to other cells. Ehrlich and his team created 417 separate compounds and tested each thoroughly on laboratory animals before Number 418, arsenophenylglycine, proved somewhat effective against tropical diseases caused by trypanosomes. The repetitive research continued. In 1907, compound 606 was created, the hydrochloride of dioxydiaminoarsenobenzene.[36] The compulsive and patient Ehrlich was optimistic about this compound but an assistant erroneously reported that it had no effect whatsoever on trypanosomes, and so it was put aside.

  It was at this point that Ehrlich changed tack. He decided to pursue the spirochaete Treponema pallidum, the micro-organism that causes syphilis and which had been isolated in 1905. While engrossed in this research, in 1908, Paul Ehrlich’s remarkable contribution to science was recognised when he was awarded the Nobel Prize in Medicine or Physiology for his scientific work in the field of immunity. He shared this honour with Elie Metchnikov. Ehrlich’s work on serums and antitoxins had provided the key concept that the body produces substances that fight disease-causing micro-organisms, which we now call antibodies. Metchnikov, for his part, had discovered that certain body cells, white blood corpuscles, which he called phagocytes, could destroy pathogens by simply engulfing or eating them. Because of the discoveries made by Ehrlich and Metchnikov it is now known that the incredibly complex human immune system mounts attacks in both of these ways.[37] When Ehrlich received the Nobel Prize, however, some of his finest work was still ahead of him.

  COMPOUND 606, THE WONDER DRUG

  An event that proved critical to finding a cure for syphilis was the arrival at the institute of Dr Sahachiro Hata from Tokyo. The scientific world was somewhat incestuous. Hata was a pupil of Professor Shibasaburo Kitasato who had worked with Emil von Behring on tetanus twenty years earlier, at the time that Ehrlich had joined Robert Koch’s team. In Japan Sahachiro Hata had been experimenting with syphilis in rabbits and was sent to Frankfurt for further study.[38] His first assignment after joining Ehrlich was to test every arsenical compound that the team had developed thus far in their search for a cure for sleeping sickness, on animals infected with syphilis. This was a daunting ta
sk but also a prime example of Ehrlich’s rigour and the commitment he expected from those who worked with him.

  Hata set about the task in a thorough and logical way and the breakthrough came in 1909 when he tested compound 606, which had been discarded in 1907 as being ineffective against sleeping sickness. Hata reported to Ehrlich that it was by far the most effective against syphilis and also the least toxic of all the compounds.[39] Here was a magic bullet that destroyed the micro-organism Treponema pallidum. It had been three years of painstaking work for Erhlich and his team, testing over 900 different compounds. Compound 606, a cure for syphilis, would soon be marketed under the more manageable name, Salvarsan. The name was chosen by Ehrlich and its meaning, ‘that which saves by arsenic’, is inherently paradoxical.[40]

  Ehrlich was pleased, but true to his nature he demanded further tests, hundreds more tests, to determine effective and safe doses of the compound and to establish whether cures were permanent or whether relapses would occur. Hata tested compound 606 over and over again, on mice, on guinea pigs and on rabbits. All had been infected with syphilis and all were completely cured within three weeks. Testing then commenced on humans. Patients at nearby hospitals who were suffering with dementia associated with the final stages of syphilis were treated by physicians willing to cooperate in the trials. Astonishingly, several of these terminal patients recovered after treatment. When hundreds of experiments had repeatedly proved that Salvarsan cured syphilis, Ehrlich announced its release.