Smallpox, Syphilis and Salvation

by Sheryl Persson

  Because of Ehrlich the potential for the diphtheria serum to save lives on a mass scale was now feasible and Behring entered into a formal partnership with Ehrlich, one which would come to an acrimonious end. They had a contract drawn up which laid down the terms of their future collaboration. Together they organised a laboratory under the railroad circle, the Stadtbahnbogen, in Berlin, so that diphtheria serum could be produced in sufficiently large amounts.[22] Even though the diphtheria serum and the antiserum could be standardised using guinea pigs, in order to extract enough antitoxin it was necessary to use large animals, as had been the case with the tetanus serum, and they began with sheep.[23]

  After a series of experiments, Ehrlich and Behring determined that high-quality antitoxin could be obtained from horses as well as from sheep and this opened the way for large-scale production. In 1894 the Hoechst pharmaceutical company began the production and marketing of the diphtheria therapeutic serum and a successful commercial partnership was established between Behring and the company. But this was to have a detrimental effect on the partnership between Behring and Ehrlich.

  ***

  While working on the development of the diphtheria serum Behring was given the opportunity to leave the army and start an academic career. One of the leading officials from the Prussian Ministry of Education and Cultural Affairs, Friedrich Althoff, who wanted to improve the control of epidemics in Prussia by supporting bacteriological research, secured a position for Behring at the University of Halle-Wittenberg in 1894. After a short time in the position of Professor of Hygiene, he was again recruited by Althoff to take over the vacant chair of Hygiene at Philipps University of Marburg in April 1895.[24]

  Behring’s appointment as a full professor followed shortly after but the moment was marred when professional snobbery raised its head. There was vehement opposition to Behring from members of the faculty who, although acknowledging his outstanding discoveries, believed that the position of university lecturer in hygiene would be better filled by someone from within the field (no doubt one from amidst their ranks) not by Behring, who came from a medical background. Althoff rejected all the counterproposals, however, and Behring took over as Director of the Institute of Hygiene at Marburg University. His position included giving lectures on hygiene and on the history of medicine. In 1896, the institute moved to a new location which gave Behring the opportunity to divide it into two departments: a Research Department for Experimental Therapy and a Teaching Department for Hygiene and Bacteriology. He remained director of the institute for the next twenty years until his retirement in May 1916.

  During his early career Behring had been totally committed to his work and for whatever reason had not married, although lack of funds has been suggested. The year 1896 brought another change to Behring’s life when at the age of 40 he married Else Spinola who was half his age. Else was the daughter of Werner Spinola, the administrative director of Charité, the university medical hospital in Berlin.

  During their life together Else and Behring had seven children.[25] Friends described Behring as a contented family man, although somewhat patriarchal, which was entirely in keeping with society in the early twentieth century and with his stature in the scientific world. Behring’s passionate devotion to his work meant that Else and the children had to share him. Behring had a vast number of contacts and belonged to an eclectic and distinguished discussion group called ‘the Marburg Circle’. Among its members were the zoologist Eugen Korschelt, the botanist Arthur Meyer, the physiologist Friedrich Schenk and the pathologist Carl August Beneke, to name a few.

  The incestuous nature of the scientific elite becomes evident when looking at who the early medical pioneers had as their friends and sometimes their enemies. The list of godfathers Behring chose for three of his sons reads like a who’s who from the Berlin Institute of Hygiene and the Pasteur Institute. Behring chose his friend and co-worker Erich Wernicke and the bacteriologist Friedrich Loeffler to be godfathers to his first son, Fritz. The godfather of his third son, Hans, was the Prussian Under-Secretary of Education and Cultural Affairs, Friedrich Althoff, who supported Behring’s career. The godfathers of his fifth son, Emil, were Elie Metchnikov, founder of the theory of phagocytosis, with whom Behring had a continuous scientific exchange of ideas, and Emile Roux who, like Behring, conducted groundbreaking research on diphtheria.[26]

  Paul Ehrlich was not on the list. Despite their early scientific collaboration and friendship, tension developed between the two and they fell out. After Ehrlich was made director of a government-supported institute near Berlin the relationship never recovered. When the institute was transferred to Frankfurt am Main in 1899 it was called the Royal Institute for Experimental Therapy and Ehrlich was given a free rein in his research there. This irked Behring, who wanted his colleague to continue specialising in immunology and serum therapy but Ehrlich was moving in a different direction. Inherent personality differences had also strained the relationship. Ehrlich was utterly indifferent to monetary rewards and he saw Behring as having aligned himself with wealthy industrialists. He resented Behring’s ambition and was content to immerse himself in research for its own sake and that of the greater good. Friedrich Althoff attempted to mediate but the friendship between the two scientists was never really restored. It is interesting to note that what was believed to be the only photograph showing Behring and Ehrlich together, which appeared on the cover of a Berlin newspaper to celebrate their 60th birthdays in 1914—Ehrlich was born on 14 March 1854 and Behring was born on the 15th—was actually two separate photographs spliced together.[27]

  Because of what they had achieved together, however, diphtheria was no longer invincible and despite some early difficulties with production, widespread use of the diphtheria antitoxin followed. Some specific problems with the serum also had to be overcome. It had to be administered soon after infection but this was not always possible because getting an accurate diagnosis was not a straightforward matter. As with anything new in the medical field the antitoxin soon had its critics, who spoke out in a very audible and public way. Resistance did not last long, however. Several studies published in the 1890s attested to the serum’s miraculous success and even with the delays in administering the antitoxin, the number of deaths from dipththeria was soon almost halved.

  In fact, the fall in the diphtheria death rate around the turn of the twentieth century was one of the sharpest ever recorded for any treatment. In Germany alone, an estimated 45,000 lives per year were saved. It is for this unprecedented contribution to humankind, and to children in particular, that Emil von Behring was celebrated throughout the world when he was awarded the very first Nobel Prize in Physiology or Medicine in 1901 for his work on Serum Therapy. It was the decision of the Nobel committee that Behring, through his discovery of Serum Therapy and its particular application against diphtheria, ‘had opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths’.[28]

  BEHRING RESEARCHES TB, CONTINUES DIPHTHERIA WORK

  Established in his position at Marburg University, settled in his domestic life and celebrated for his contribution to humanity, Behring turned his mind to one of his other research interests, the fight against tuberculosis. Robert Koch had failed disastrously with his tuberculosis therapy, tuberculin, in 1893, so Behring began to search for an effective therapeutic agent against this disease. However, very soon, he had to admit that combating tuberculosis using Serum Therapy was not feasible. He changed course and began to concentrate on a preventive vaccine. For reasons that were not positive Behring was able to spend more time on tuberculosis research from 1901 onwards: he began to suffer from poor health and was no longer able to sustain his rigorous academic work.

  Assuming that the different forms of tuberculosis found in humans and in cattle were actually closely related, Behring experimented, immunising calves with a weakened strain of the human tuberculosis bacillus but the results were di
sappointing.[29] Although his bovine vaccine was widely used for a time in Germany, Russia, Sweden and the United States, it was found that the cattle later excreted micro-organisms that were still virulent and could cause further infection. Nevertheless, Behring’s basic idea of using a bacillus from one species to benefit another influenced the development of later vaccines. Each piece of new information added to the armoury of disease-fighting weapons.

  While working on tuberculosis, Behring did not entirely abandon his work on diphtheria. In 1898, while collaborating with Erich Wernicke, Behring had found that immunity to diphtheria could be produced in animals by injecting them with diphtheria toxin neutralised by diphtheria antitoxin. In 1901, Behring, for the first time, used a vaccination of diphtheria bacteria with reduced virulence. Whereas the first therapeutic serum he had developed could prevent diphtheria for only a short period of time, Behring hoped that with this active immunisation the body would be stimulated to produce its own antitoxins.[30] It is well-established knowledge today that active vaccination stimulates antitoxins, which we now call antibodies.

  Research on diphtheria had also been carried out in other laboratories during the 1890s. In 1891, a pathologist in New York City, Anna Wessels Williams, isolated a stronger and more effective strain of diphtheria antitoxin.[31] In 1894, Emile Roux developed a diphtheria antitoxin serum using horses. He used this serum to successfully treat more than 300 diseased children in the Hôpital des Enfantes-Malades in Paris and was hailed as a hero throughout Europe.

  The development of an active vaccine took some years as Behring was unable to work consistently. The demon that drove him to work also plunged him into the depths of depression and he sought treatment in a sanatorium between 1907 and 1910. Behring was also coping with a condition that increasingly impaired his mobility, the result of fracturing one of his thighs. He was far from finished, however. By 1913, the year before war broke out in Europe, Behring had managed to resume his work and had successfully completed the new phase of his diphtheria research. He then publicly announced his diphtheria protective agent, toxin–antitoxin (T.A.).[32]

  T.A. contained a mixture of diphtheria toxin and therapeutic serum antitoxin. The toxin was meant to cause a light general response from the body, without causing the disease itself. In addition, it was a longer lasting vaccine designed to provide long-term protection. A range of trials proved it to be non-harmful and effective. In the same year that T.A. was announced, the Hungarian scientist and paediatrician Bela Schick produced another medical marvel: a simple and reliable test to determine whether a person is susceptible to diphtheria.[33] The Schick test involves injecting a small amount of toxin under the skin. If a red, swollen rash appears around the injection, the person is susceptible and should be immunised.

  Subsequent modifications which refined Behring’s toxin–antitoxin mixture resulted in the modern methods of immunisation that have largely banished the blight of diphtheria. Behring himself saw this as the crowning achievement of his life’s work. In the same way that Jenner believed that smallpox could be eradicated, Behring believed in the possibility of ridding the world of diphtheria.

  ***

  Emil von Behring was a man of great intellect and he was a tireless worker both in research and in academia, for which he enjoyed many financial rewards. Unlike many of his peers he also had business acumen and his commercial arrangements with private pharmaceutical firms added to his prosperity. Behring owned an impressive estate at Marburg which was large enough to accommodate the livestock he needed for use in his own experiments. He and Else opened their house as a gathering place for society and the couple also owned a vacation home on the island of Capri in the Mediterranean, where they had honeymooned.

  In 1914 Behring took stock and changed tack. To regain autonomy over his scientific work he founded the Behringwerke in Marburg, an institute where the manufacture of serums and vaccines could be under his control and he could also determine the nature of research that was undertaken.[34] His independent wealth made this possible. Today the Behringwerke is a large corporation with worldwide operations in pharmaceutical manufacture. Research is still conducted there, mainly in the field of immunology.

  When the war began in 1914, Behring was able, because of the Behringwerke, to make the decision to cease his efforts to combat tuberculosis and dedicate himself entirely to the development of the tetanus serum as this was the greater need. The overwhelming success of the serum during the war went some way towards consoling him for the wanton waste of life that he was witnessing. The obscenity of war saddened him. His life’s work had been dedicated to wiping out diseases, the enemy of the human species, but he had no vaccine that could be used to prevent humans turning on each other.

  Emil von Behring, the ‘Saviour of the German Soldiers’, like many soldiers, did not live to see the end of the war. Behring was already in a precarious state of health when he contracted pneumonia in 1917. His frail body was unable to withstand the added strain and he died on 31 March in Marburg and was entombed in a mausoleum at the Marburg Elsenhöhe. Else von Behring lived on without her husband until 1936 when Germany was witnessing the rise of Adolf Hitler and the National Socialist Party. Else died from a heart attack at the age of 59.

  Apart from receiving a Nobel Prize in 1901, Emil von Behring was honoured in many ways during his lifetime for his extraordinary medical achievements. He was elevated to the status of the nobility and in 1903 he was elected to the Privy Council with the title of Excellency. He was granted honorary memberships of societies in Italy, Turkey, France, Hungary and Russia; he became an officer of the French Legion of Honour and an honorary freeman of Marburg.[35] However, despite all outward appearances of wealth and personal and professional success Behring had endured his share of difficulties, disappointments and ill-health.

  DIPHTHERIA INTO THE TWENTIETH CENTURY AND BEYOND

  In the early 1900s death rates from diphtheria remained high in countries where immunisation was not widespread. In the United States in the 1920s there were an estimated 100,000 to 200,000 cases of diphtheria per year, resulting in 13,000 to 15,000 deaths. Children still represented the large majority of cases and fatalities.[36] Behring’s work was taken up by new pioneers. A new vaccine for diphtheria, a formalin-inactivated toxin (formalin rendered the toxins harmless) was developed in the United States by Alexander Glenny and Barbara Hopkins in 1923. Standardisation was required, as with Behring’s toxoid, and was carried out using guinea pigs. In the same year, Gaston Ramon, working at the Pasteur Institute in France, chemically detoxified diphtheria toxin by using formaldehyde—and provided the world with one of its safest and most reliable vaccines.[37]

  The uptake of diphtheria vaccination was patchy from the mid 1920s onwards. Behring had hoped for more. Progress was slow in Britain but successes in various local health districts eventually led to acceptance. Widespread vaccination began to occur across the country in the 1940s when the death rate from diphtheria was still at about 10 per 100,000 of population. Over the following ten years the incidence of diphtheria dropped to virtually zero. There was a similar pattern in the United States: by 1989 there were only 24 cases of diphtheria reported and only two were fatal. Astonishingly, only one case of diphtheria was reported in the United States in 1999.

  Diphtheria has now been largely eradicated in developed nations due to the combined DPT (diphtheria–pertussis–tetanus) vaccination programs. DTP is a combination vaccine that was developed in the 1940s containing weak toxins that serve to stimulate the growth of antibodies to diphtheria and tetanus combined with inactivated pertussis (whooping cough) bacterial cells.[38] However, in areas where the immunisation rate has fallen, such as Eastern Europe and the newly independent states of the former Soviet Union, tens of thousands of people have suffered from diphtheria in recent years. In 1990, an outbreak began in Russia and over a period of four years spread to every state of the former Soviet Union. By the time the epidemic was contained, over 150,000 cases and 5000 d
eaths had been reported.[39] A vast public health immunisation campaign was implemented and had largely confined the epidemic by 1999.

  In 1991, the Food and Drug Administration in the United States licensed the DTaP (diphtheria–tetanus–acellular pertussis) vaccine. While DTP vaccine was made using whole cells of the pertussis germ, DTaP is made using only small, purified pieces of the germs. Fewer side-effects have been reported with the DTaP vaccine than with DTP, which is no longer recommended for use in the United States. DTP is currently still widely used in other countries and is equally effective.

  Today 1 out of every 10 people who get diphtheria still dies from the disease. Universal immunisation is the most effective means of preventing and eradicating it. With DTP it is recommended that three injections be administered two months apart, beginning at about two months after birth. Booster shots are given at fifteen months and four to six years. The most important treatment for diphtheria remains a prompt injection of diphtheria antitoxin which neutralises any circulating exotoxin. It is still made from horse serum because a human antitoxin is still not available for the treatment of diphtheria. Antibiotics such as penicillin, ampicillin or erythromycin are given to wipe out the bacteria, to prevent the spread of the disease and to protect the patient from developing pneumonia but they are not a substitute for treatment with antitoxin.[40]

  As with other diseases, the World Health Organization monitors the incidence of diphtheria internationally. In 2003 there was an outbreak in Afghanistan in a resettlement camp for internally displaced persons in Kandahar. Around 75 per cent of the cases were children aged five to fourteen. In response the WHO undertook a mass vaccination of around 40,000 people.[41]

  The acceptance of immunisation has also led to a significant decline in tetanus in many countries. The first tetanus vaccine to be made from tetanus toxoid, an inactivated toxin, was produced in 1924 and was successfully used to prevent tetanus during World War II.[42] The same procedure used to develop the diphtheria vaccine was used to protect against tetanus: first, passive immunisation using horse anti-tetanus serum—Behring’s Serum Therapy—followed by active immunisation with the tetanus toxoid. In this form it became part of the DTP vaccine. A tetanus booster is recommended every ten years, with an additional tetanus injection administered if a person suffers a severe wound.