Smallpox, Syphilis and Salvation

by Sheryl Persson

  Koch worked with a passion, injecting ground tuberculous material into the eyes of rabbits and under the skins of guinea pigs. He also smeared the infected tissue on glass slides which he spent days observing, but the tubercle bacillus proved elusive. Koch then began to soak the tissue in various dyes and finally the bacteria took up sufficient colour to stand out from the diseased lung cells. The tiny blue-coloured rods that Koch observed were tubercle bacillus, one-third the size of the anthrax bacillus. When Koch dissected the animals he found identical yellowish tubercles and the same tiny blue-coloured rods. Convinced that he had identified the tubercle bacillus, Koch obtained infected tissue from the bodies of other hospital patients who had died of tuberculosis and meticulously and obsessively injected it into guinea pigs, rabbits, three dogs, thirteen cats, ten chickens, twelve pigeons, white mice, field mice, rats and two marmots.[11] In both diseased humans and animals Koch found the blue-stained rods.

  Following his postulates, the next step for Koch was to grow the organism in pure culture. It was trial and error to find the right media. He inoculated a blood-serum agar, a gelatinous substance which he made from heat-sterilised animal blood combined with tissue from the lung of a diseased guinea pig.[12] His patient vigil continued long after others would have admitted defeat and begun again. After fifteen days Koch was rewarded when he observed minuscule colonies of bacteria on the surface of the agar. After working alone and secretively for six months, Koch had successfully isolated the bacteria on various media and was able to infect guinea pigs with tuberculosis.

  On 24 March 1882, when Koch announced to the Physiological Society of Berlin that he had isolated and grown the tubercle bacillus that caused all forms of tuberculosis, the distinguished audience was silent. Rudolf Virchow left without saying a word, which must have come as no shock to Koch. When Koch had hoped to gain Virchow’s support for his work on anthrax, Virchow had flipped through the report as Koch waited in suspense and dismissed the findings as highly improbable. However, Koch won the approbation of another rising star who was in the audience. Paul Ehrlich, a young German scientist, later recalled that evening as his greatest scientific moment. Ehrlich, who would become famous for finding a cure for syphilis in 1909 literally overnight, developed an improved method of staining tubercle bacilli, a method Koch soon adopted.

  The day after Koch’s announcement, the discovery of the tubercle bacillus was front-page news throughout the world and ushered in an era of ‘microbe hunting’ and a new generation of scientists who, like Ehrlich, were inspired by the work of both Koch and Pasteur.[13] They were the new guard, crusaders, determined to hunt down and destroy the disease-causing micro-organisms that most afflicted humanity.

  ***

  Koch’s work on tuberculosis was continuing when, in 1883, he was sent to Egypt as leader of the German Cholera Commission to investigate an outbreak of cholera in the Nile delta. The French scientific community was also involved, and because Pasteur was fully occupied in Paris with his rabies cure he sent a four-man mission in his place, which included his two assistants Emile Roux and Louis Thuillier. They reached Alexandria in mid August. Koch’s team, which included Gaffky and Bernhard Fischer, arrived nine days later equipped with microscopes and experimental animals. Old rivalries persisted and a race between the French and the Germans to find the cholera bacillus began.

  Just as Koch targeted a comma-shaped bacillus as the specific cause, the cholera epidemic suddenly began to wane. The two French scientists who had had no success in isolating the bacilli from the cultures they worked on, became less focused on the quest while Koch and Gaffky laboured in the heat examining the last of the infected material that they could get hold of. Inadvertently they discovered the bacilli that cause amoebic dysentery.[14] Tragedy struck when Louis Thuillier was infected by the microbe he was hunting and died of cholera. Despite the rivalry between the French and German researchers, Koch acted as one of the pallbearers at Thuillier’s funeral before rushing back to Berlin with specimens containing the prime cholera-causing suspect, the little comma-shaped, vibrating bacterium, or ‘vibrio’.

  To prove the vibrio was indeed the offending bug, Koch, Gaffky and Fischer went to India in 1884 to study cholera in regions where it was endemic. Two months after arriving in Calcutta they observed the same bacillus in 70 cholera victims. Despite being unable to produce the disease in experimental animals—one of his postulates—Koch asserted that the bacillus was the specific cause of cholera and could be easily grown on beef broth agar. More importantly Koch identified the method of transmission: via drinking water, food and clothing.

  When Koch returned to Berlin in May 1884 banquets were held in his honour. Finding the cause of any disease that beleaguered people in all corners of the globe brought notoriety. The Kaiser awarded Koch the Order of the Crown with Star and the Reichstag granted him 100,000 marks. As could be expected, not all scientists were convinced that the vibrio caused cholera. One asked Koch to send him a vial of the bacilli, which he publicly swallowed, luckily—although Koch may not have concurred—without ill effect. Controversy continued to rage until August 1892, when Koch was asked by the city of Hamburg to help with a cholera outbreak. In a ten-week period 18,000 people had been infected and 8000 had died. Koch successfully implemented his measures for cholera containment—early detection and isolation of cases, the disinfection of patient excreta and the sanitisation of water supplies—measures that are still in use today.[15]

  KOCH’S ‘CURE’ FOR TUBERCULOSIS

  In 1885, the year after his triumphant return to Berlin, Koch was appointed Professor of Hygiene and Director of the newly established Institute of Hygiene at the University of Berlin but something was amiss. For the next five years Koch’s scientific output paled in comparison to his earlier work. Koch’s star was no longer ascending. Pasteur’s international successes with the anthrax and rabies vaccines put Koch under great pressure from the German government and the press. He had become a symbol of German superiority.[16] Koch began working secretively again. He was seeking a cure for tuberculosis. What would provide salvation for the multitudes he hoped would also save him from anonymity.

  Koch investigated the effect an injection of dead tubercule bacilli would have on a person who subsequently received a dose of living bacilli. He concluded that the local reaction produced might be the means by which the disease could be diagnosed and cured in the early stages. On 4 August 1890, at the tenth International Medical Congress in Berlin, Koch announced that, after testing many chemicals, he had isolated a substance that had the power to prevent the growth of the tubercle bacilli. Guinea pigs that had been injected with the substance he called tuberculin had become resistant to tuberculosis and he claimed that it could arrest the disease in humans.

  Clinical trials began. In November 1890 Koch claimed success and again his name was on everyone’s lips. Doctors and patients made pilgrimages to Berlin, filling hospitals, clinics and hotels, clamouring for his ‘cure’ for tuberculosis. Honours were again being flung his way by foreign rulers and prestigious societies. He was given the freedom of various cities including Berlin and received the Grand Cross of the Red Eagle from the Kaiser. In 1891 he became an Honorary Professor of the medical faculty of Berlin University and Director of the new Institute for Infectious Diseases located next to the Charité Hospital.[17]

  It was soon realised, however, that tuberculin was not all that Koch had purported. His desire for success had influenced his science. In January 1891, Rudolf Virchow, ever the critic, revealed that 21 consumptive patients who had been treated with tuberculin had died riddled with miliary tuberculosis. Amidst the ensuing uproar Koch was forced to reveal the exact nature of tuberculin. To produce his ‘miracle cure’, Koch, for whatever reason, had used a method previously employed by Emile Roux to isolate diphtheria toxin. Koch had grown the tubercle bacilli on a glycerine broth for several weeks before killing the bacteria with heat, but the filtrate still retained active virulent organisms and many peop
le died because not all the bacteria had.[18]

  At the same time that Koch’s professional life was disintegrating his personal life was in turmoil. His unhappy marriage to Emmy ended in divorce and scandal in 1893. At the age of 45 he had fallen in love with and married a beautiful seventeen-year-old art student, Hedwig Freiburg. Enemies were waiting in the wings and the divorce led to more criticism and censure for Koch. Vicious rumours circulated that he had sold his patent on tuberculin to a company in Marburg and allowed it to be tried on patients prematurely because he needed the money to support his second wife. Koch rode out the scandal and found happiness with his new wife.

  By the 1890s it was widely accepted that TB was contagious and in response governments in many countries made it a notifiable disease and adopted health measures such as bans on spitting in public areas in the hope that this would help to control its spread. But a cure was still elusive. Although struggling to cope with his fall from grace, Koch was not entirely defeated by the humiliation of his failure and attempted to find a cure one more time. In 1896 he announced that he had developed a new tuberculin which proved to be a diagnostic tool, but not a cure. Koch noticed that within 48 hours of vaccination, tuberculous patients exhibited a reddish allergic reaction at the spot where tuberculin was injected into the skin. This reaction, called the Koch phenomenon, allows doctors today to determine through a skin test whether an individual has been infected with tubercle bacilli, even before symptoms develop.

  With his reputation in a parlous state, in 1896 Koch accepted an invitation from the Cape Colony government in South Africa to investigate rinderpest, a disease which was ravaging cattle. Koch’s thirst for foreign travel was revived and suddenly he saw new horizons for his microbial research and Hedwig was happy to go with him. As soon as they arrived in the Cape, Koch assembled a menagerie of experimental animals and began work. Although he did not identify the cause of rinderpest he succeeded in developing a method of vaccinating farm stock and limited the outbreak.

  India was next. When Koch reached Bombay in May 1897, bubonic plague was epidemic in upper India. Various European governments had previously sent scientific missions in the hope of finding a cure. The bacillus Yersionia pestis, the cause of bubonic plague, had been discovered in Hong Kong in 1894 by both Alexandre Yersin, who led a French mission, and Shibasaburo Kitasato, who had worked in Koch’s laboratory and was head of a Japanese team. While in Bombay, Koch concluded that rats were the source of the plague and that they spread the disease through cannibalism. Koch urged that measures be taken to control the rodents, unaware, as was everyone at the time, that it was the fleas on the rats that played the crucial role in the spread of bubonic plague.

  Koch returned to Africa and in Tanganyika (part of modern-day Tanzania) discovered two protozoan diseases: surra, which affected horses, and Texas cattle fever. Malaria and blackwater fever were his next targets. Returning to Berlin in May 1898, after eighteen months away, Koch delivered an address to the German Colonial Society in which he described four types of malaria. Koch believed that malaria was a mosquito-borne disease but before he could prove his theory the British bacteriologist Ronald Ross published findings supporting the same conclusion. Koch next visited malarial districts in Italy where he confirmed Ronald Ross’s discovery.

  Koch’s expedition then headed for the tropics. Although Robert Koch seemed indestructible, in German New Guinea, where malaria was prevalent, Hedwig became ill. Koch was desolate as he had no choice but to send Hedwig home and continue his work without her. He made huge inroads into controlling malaria by devising a control policy that aimed to destroy the parasite within its host. Although success was limited by a lack of drug supplies and trained physicians, the regimen was adopted throughout the German empire and Koch was again the centre of attention. The Kaiser Wilhelm Academy elected Koch to its senate because of the value of his discovery to the health of Germany’s military forces.

  The pace of travel and discovery was frenetic. After having spent only nine months in Germany over a period of four years Koch returned to Berlin in October 1900. By that time, Pasteur, Koch and their disciple microbe hunters, seeking salvation for humankind and perhaps a little glory for themselves, had in the space of just over two decades identified 21 germs that cause disease. ‘As soon as the right method was found, discoveries came as easily as ripe apples from a tree,’ Koch said.[19] And it was Robert Koch who had developed those methods.

  Despite his myriad achievements Koch remained interested in tuberculosis and late in his career came to the conclusion that the bacilli that cause human and bovine tuberculosis are not identical. He suggested using the bovine bacillus as a human vaccine. Never far from controversy, his views met opposition at the International Medical Congress on Tuberculosis in London in 1901. He also proposed that infection of human beings by bovine tuberculosis is so rare that taking measures against it was not necessary. Koch’s view, in time, proved to be correct and a strain of bovine tubercule bacillus was used some decades later to produce an effective vaccine.

  As his sixtieth birthday approached, Robert Koch decided to retire from state service. His contribution to national health had been immeasurable and the Kaiser awarded Koch the Order of Wilhelm. But retirement was anathema to Robert Koch and after working as a consultant at the Institute for Infectious Diseases he headed off to remote locations, once again accompanied by Hedwig, who had made a full recovery. Early in 1905, on an expedition to Dar-es-Salaam, Koch investigated the lifecycle of the tsetse fly, the cause of the debilitating human disease African trypanosomiasis, or sleeping sickness.

  Koch enjoyed a brief respite later that year when, in Stockholm, his work on tuberculosis was recognised internationally with the award of the Nobel Prize for Physiology or Medicine for his investigations and discoveries in relation to tuberculosis. There was no time for the ageing scientist to rest on his laurels, however. In 1906 Koch returned to Central Africa leading the German Sleeping Sickness Commission and travelled to the remote and dangerous Sesse Islands in Uganda and to north-western Lake Victoria where trypanosomiasis was rampant. Living and working in primitive conditions he confirmed that the drug atoxyl was somewhat effective in treating sleeping sickness.

  ***

  Koch was a driven man to the end of his life. His passion for science was ingrained. The overwhelming contribution he had made to the advancement of humankind was acknowledged in his lifetime with innumerable prizes, medals, orders and honorary doctorates. Robert Koch was the first medical person to be awarded the German Order of the Red Eagle and was granted the rare honour of foreign membership to the Paris Academy of Sciences. In 1908 in Berlin he received the first Robert Koch Medal, instituted to commemorate the greatest living physicians. The inveterate traveller, while undertaking yet another overseas tour with Hedwig, was greeted as a hero wherever he went. In Japan he was welcomed by his former colleague Shibasaburo Kitasato and presented ceremoniously to the Emperor.

  In 1907 after a celebration to commemorate the 25th anniversary of the discovery of the tubercle bacillus, a proposal to establish a Robert Koch Foundation to combat tuberculosis had gained momentum. Funding came from the public, the medical profession, the German Kaiser, and the American philanthropist Andrew Carnegie in 1908 contributed funds for its establishment, reflecting the desire of the international community to combat the disease. Predictably, the last years of Robert Koch’s life were devoted to tuberculosis control. Working daily at the Institute for Infectious Diseases, which had moved in 1897 to its present-day location in Nordufer in north-west Berlin, Koch supervised the production and clinical trials of new tuberculins.

  On 9 April 1910, three nights after lecturing on the epidemiology of tuberculosis before the Berlin Academy of Sciences, Koch suffered a severe angina attack and on 27 May died peacefully at a sanatorium in Baden-Baden. In December his ashes were placed in a mausoleum at the institute, which the Kaiser renamed after him. Family, friends, and luminaries from the scientific and pol
itical community attended the ceremony, even erstwhile rivals. Elie Metchnikov represented the Pasteur Institute and presented a memorial plaque. It is possible today to visit Robert Koch’s sepulchre on the ground floor of the institute. On the western wall there is a relief of Koch and on the eastern wall the important dates of his life are listed under the heading ‘ Robert Koch—Werke und Wirken’ (works and achievements).[20] The list is indeed long. Although at times a victim of his own hubris, the good that Robert Koch bequeathed to future generations cannot be overlooked.

  Paul Ehrlich dubbed Robert Koch one of the few princes of medical science, despite his arrogance, his failure to give credit where it was due and his reluctance to admit mistakes. Like Louis Pasteur, Robert Koch seemed suspicious and aloof with strangers but to friends and colleagues he appeared kind and considerate. Koch uttered words reminiscent of Pasteur’s when he said in New York in 1908:

  I have worked as hard as I could and have fulfilled my duty and obligations. If the success really was greater than is usually the case, the reason for it is that in my wanderings through the medical field I came upon regions where gold was still lying by the wayside.[21]Perhaps where tuberculin was concerned it was fool’s gold, Koch’s judgment having been temporarily clouded by personal ambition and his altruism pushed aside. In the first paper that he wrote on tuberculosis Koch expressed that his primary motivation for undertaking his research had been to benefit public health in the short and long term. He had built on the work of Louis Pasteur, finally extinguishing the belief that ‘bad air’ caused disease. Robert Koch isolated the germs that cause three feared diseases—the anthrax bacillus, Mycobacterium tuberculosis and Vibrio cholerae—and identified the method of transmission of bubonic plague and sleeping sickness. He demonstrated that a specific microbe causes a specific disease and developed research techniques that enabled other scientists throughout the world to find treatments and cures for many diseases . Koch’s dedication was unflinching and, despite the failure and tragedy associated with tuberculin, he made future advances against tuberculosis possible.