Robert Heinrich Hermann Koch was born Dec. 11, 1843 in Clausthal, a silver-mining town in northwest Germany. He was the son of Hermann Koch, a mining engineer, and Mathilde Julie Henriette, and the third of thirteen siblings. Koch demonstrated a gifted mind at an early age, reportedly by the age of 5 he had taught himself to read and write by using newspapers. He showed remarkable gifts in the sciences and mathematics and graduated from high school in 1862.
At the age of 19, Koch entered the University of Göttingen to study natural science. While a student, he won a research prize for his study on neuronal innervation of the uterus. This allowed him to travel to Hanover where he encountered Germany's most renowned physician, Rudolf Virchow. After three semesters, Koch decided to change his area of study to medicine. During his fifth semester, Jacob Henle, an anatomist who had published a theory of contagion in 1840, asked him to participate in a research project on uterine nerve structure. In his sixth semester, Koch began to conduct research at the Physiological Institute, where he studied the secretion of succinic acid, which is a signaling molecule that is also involved in the metabolism of the mitochondria. This would eventually form the basis of his dissertation.
If my efforts have led to greater success than usual, this is due, I believe, to the fact that during my wanderings in the field of medicine, I have strayed onto paths where the gold was still lying by the wayside.
In January 1866, Koch graduated from medical school cum extrema lauda. He travelled to Berlin for 6 months to improve his skills in chemistry. He then married Emma Fratz and saw the birth of his daughter and only child Gertrud, fourteen months later.
Robert Koch’s Family
Robert and Emma’s Daughter - Gertrud Koch
The very next year he joined the “General Hospital” in Hamburg as a physician. It was 2 years after joining the General Hospital that Koch successfully passed the District Medical Officers’ Examination. In 1870, he began volunteering for medical service as a field surgeon in the Franco-Prussian war (1870-71). The experience he gained in wound care and in dealing with typhoid fever later proved to be invaluable assets in his research. After his return from the war, he passed his exams as a state doctor. He was then sent to rural Wöllstein in the district of Poznan where he opened a private practice and built a small laboratory. His first microscope, a gift from his wife, was a source of great joy. Equipped with his microscope, a microtome (an instrument for cutting thin slices of tissue), and a homemade incubator, he began his study of algae, switching later to pathogenic bacteria that would eventually make him famous.
Discoveries in Bacteriology
Robert Koch’s Study
In 1875, Koch visited many of Germany's great scientific research centers, which introduced him to the emerging world of microbial science. Ferdinand Cohn had classified bacteria into four groups based on shape (sphericals, short rods, threads, and spirals), which is still in use today. Louis Pasteur showed that food spoils because of microorganisms, and invented pasteurization (which was originally used to prevent wine and beer from souring). Antoine Béchamp discovered “microzymas” and credited them with producing enzymes affecting cellular regeneration, while evolving amid favorable conditions (biological terrain) into bacteria – pleomorphism. Joseph Lister had developed techniques of antiseptic surgery; and Jacob Henle, Koch's anatomy teacher in Göttingen, was defending the idea of contagium animatum, which held that disease could be caused by living transferable entities. The “germ theory” was hotly debated, and the role of bacteria in contagious disease was uncertain.
Inspired by all this discovery, Koch began investigating anthrax - which was a major health problem around Wöllstein. Anthrax had been decimating European livestock and its people for centuries. In his rural practice, Robert Koch was confronted with the problem on a daily basis. Even grazing grounds that had been left lying fallow for years would see the epidemic come raging back once livestock were reintroduced. Koch decided to investigate.
In 1863, Casimir Davaine, a French physician known for his work in microbiology, reported the transmission of anthrax by the inoculation of healthy sheep with the blood of animals dying of the disease. He found microscopic rod-shaped bodies in the blood of both groups. Even though the bacillus associated with anthrax had been identified by Davaine, no significant advances had been made in the prevention or treatment of the disease.
Koch designed elaborate inoculation studies using mice, guinea pigs, rabbits, dogs, frogs, and birds. He discovered that inoculating a mouse with blood from a sheep that had died of anthrax caused the mouse to die the following day. He discovered that under optimal conditions – a warm, moist, aerated environment – the bacteria would swell, elongate, and form long filaments. The filaments acquired granules, which developed into refractile spheres. The filaments then decomposed, but the spheres remained. Koch hypothesized that the spheres were spores, resilient structures that appear in harsh environments. He demonstrated that these spores, in the absence of bacteria, could cause anthrax. Their formation explained how contaminated soil could remain toxic for years. The finding explained the recurrence of the disease in pastures long unused for grazing, for the dormant spores could, under the right conditions, develop into the rod-shaped bacteria (bacilli) that cause anthrax. The anthrax life cycle (pleomorphic cyclogeny), which Koch had discovered, was announced and illustrated at Breslau in 1876, at the invitation of Ferdinand Cohn, an eminent botanist.
Although monomorphic germ-theory and bacterial pleomorphic observation preceded him, Koch became the first to link a specific bacterium with a specific disease. He presented his experiments to Ferdinand Cohn, Germany's most renowned botanist of the time. Deeply impressed, Cohn offered to publish Koch's paper in his own botanical journal. That paper was published in 1876, when Koch was thirty-two years old. His work was illustrated by superb photomicrographs.
In his paper, he described his meticulous culture methods and technique of preparing thin layers of bacteria on glass slides and fixing them by gentle heat. He also described the “hanging-drop” technique, whereby microorganisms could be cultured in a drop of nutrient solution on the underside of a glass slide. His stellar work was enthusiastically recognized by the scientific community.
Koch's drawing of the anthrax bacillus at various stages of development. (Reference: Koch R. Die Ätiologie der Milzbrandkrankheit, begründet auf die Entwicklungsgeschichte des Bacillus Anthracis. Beiträge zur Biologie der Pflanzen 1876; 2:277–310.)
First published photographs of the anthrax bacillus. (Reference: Koch R. Verfahren zur Untersuchung, zum Conservieren und Photographieren der Bakterien. Beiträge zur Biologie der Pflanzen 1877; 2:399–434.)
In 1877, Koch began his studies of wound infections in animals. With his new techniques for identifying bacteria, he distinguished various disease states – septicemia, gangrene, abscess – at the microscopic level. He advanced the theory that bacteria exist as distinct species, each producing a unique clinical syndrome, and he discredited the popular notion that bacteria with different morphologies were derived from the same species. In doing so, he demonstrated the futility of generalizing about all infectious diseases. Only by studying a specific pathogen could a specific disease be understood. In 1878, Koch summarized his experiments on the etiology of wound infection. He observed differences in pathogenicity for different species of hosts and demonstrated that the animal body is an excellent terrain for the cultivation of bacteria.
At this time, microscopy was challenging because of poor illumination and because bacteria were transparent and mobile in fluid. Koch confronted each of these problems. He discovered that he could “fix” bacteria to a slide by drying them in liquid solution. By applying aniline dyes –eosin, fuchsin, safranin, and methyl violet – he could see bacteria more easily and detect subtle morphological traits. He began working with microscope developers on methods to improve lighting and resolution. He became the first physician to use an oil immersion lens, the first to use a condenser (darkfield), and the first to publish photographs of bacteria.
Microscopy
A Seibert microscope of the type Koch used to study the anthrax bacillus. Later Koch used Zeiss microscopes. (Reference: Brock TD. Robert Koch: a life in medicine and bacteriology. Washington, DC: American Society of Microbiology Press; 1999. p. 55.)
In 1879, Koch moved to Breslau, in modern-day Poland, to become district physician. Unhappy there, he moved to Berlin the following year at the invitation of the Imperial Government where he joined the staff of the Imperial Health Office.
There he tirelessly worked to develop his plate technique for generating “pure” cultures of bacteria. One of his assistants, Julius Petri (developer of the Petri dish), designed a shallow, covered dish into which media could be poured, cooled to solidity, and protected from contamination. Koch now had all the tools for his “plate technique”.
He could grow bacterial colonies and subject them to steam and various chemicals, thus advancing the fields of disinfection and sterilization. He learned that while certain chemicals killed bacteria, others merely inhibited them – a distinction that would be important in the antibiotic era. This technique would be one of his greatest contributions to bacteriology. “Pure” cultures, which were essential to the study of bacteria, were difficult to obtain by conventional means. Klebs and Lister had devised techniques using liquid media, but these were time-consuming and often unreliable. Later, in a manuscript published in 1881, he described his plate technique in exquisite detail. Others could now replicate his studies. Koch's paper became the “Bible of Bacteriology”.
In 1880, Koch, who was now recognized as a scientific investigator of the first rank, was appointed as a professor at the University of Berlin. There he finally had access to a specialized laboratory after making do with an inadequate one for years. With his collaborators, he devised new research methods to isolate pathogenic bacteria. Koch proposed guidelines to demonstrate that certain infectious diseases are caused by specific organisms. These guidelines became known as Koch's Postulates.
Koch's postulates were invaluable at the time and remain largely valid for a relatively small number of defined circumstances in which bacteria can be precisely tied to the cause of a clinical syndrome. Their main purpose today (in a world in which viruses cause cancer and non-cultivable bacteria can be demonstrated by molecular probes) is to provide a framework to ensure the application of scientific rigor when proposing an organism as the cause of a disease – exactly as Koch intended when he first conceived them. Although these postulates have limitations and cannot be applied in all cases, they do retain historical importance to the development of scientific thought.
Koch’s Postulates
Koch's Postulates
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The bacteria must be present in every case of the disease.
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The bacteria must be isolated from the host with the disease and grown in pure culture.
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The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.
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The bacteria must be recoverable from the experimentally infected host.
Tuberculosis Research
Koch traveled to London, where he presented his plate technique to Louis Pasteur and Joseph Lister. Soon the application of his techniques for culturing bacteria became widespread. Koch was promoted to Senior Medical Officer. His assistant, Friedrich Loeffler, discovered the glanders (bacterium Burkholderia mallei) and diphtheria bacilli in 1882 and 1884, respectively. George Gaffky, also a pupil of Koch, discovered the typhoid bacillus in 1884.
Yet, still the most feared disease, tuberculosis, remained enigmatic. In Europe, tuberculosis was responsible for one of every seven deaths. Koch intently focused his research on the study of tuberculosis, with the aim of isolating its cause. Although it was suspected that tuberculosis was caused by an infectious agent, the organism had not yet been isolated and identified. By modifying the method of staining, Koch discovered the tubercle bacillus and established its presence in the tissues of animals and humans suffering from the disease. Using Ehrlich's methylene blue stain, he detected a few tiny rods in tuberculous tissue. When he added a brown counter stain for photographic contrast, he “uncovered” more bacteria. He then noticed that “old” stains were more effective than fresh stains and hypothesized that the old stains had absorbed a useful chemical from the air. He surmised that the chemical was ammonia, which had alkalinized the methylene-blue stain.
Thus, he began adding caustic potash to his stains to achieve a similar effect. Now countless bacteria were visible. A fresh difficulty arose when for some time it proved impossible to grow the organism in pure culture. Eventually, he isolated the organisms from tubercular lesions and grew them successfully in pure cultures. This was a remarkable achievement for its time, for the bacillus is fastidious in its nutrient requirements and grows very slowly.
In 1881, at the age of 37, Koch announced his discovery of the tubercle bacillus. Koch had succeeded in isolating the organism in a succession of media and then induced tuberculosis in animals by inoculating them with it. Its etiologic role was thereby established.
Koch also isolated tuberculin, a protein component extracted from a killed culture of tubercle bacillus. Unfortunately, his dream of discovering a therapeutic agent, or even a vaccine against tuberculosis, did not come true. While tuberculin proved to be a valuable diagnostic tool, it had no effect as a curative agent. Koch originally offered it to the public as a treatment and presented tuberculin as a curative agent at the Tenth International Medical Congress in Berlin in 1890. However, it proved to be ineffective. Long-term cures failed, and some patients even died after treatment. However, Koch’s discovery of tuberculin was important diagnostically and is still routinely used in TB screening tests. Tuberculin aids in manifesting an immune reaction (seen as a red wheal on the skin) to those that have been exposed to TB bacteria.
On March 24, 1882, Koch presented his findings on tuberculosis at a meeting of the Berlin Physiological Society. That demonstration, which included more than 200 microscopic preparations, is now regarded as one of the most influential presentations in medical history. Paul Ehrlich, who attended the lecture, was inspired by Koch's work. He would later refine Koch's staining techniques and influence Hans Christian Gram, as well as Franz Ziehl and Friedrich Neelsen, after whom the Gram and Ziehl–Neelsen stains are named. Koch's paper on the etiology of tuberculosis was published the following month. As news spread worldwide, Koch became internationally famous.
Koch’s work in tuberculosis was temporarily interrupted by an outbreak of cholera in Egypt and the danger of its transmission to Europe. As a member of a German government commission, Koch and his team went to Egypt to investigate the disease. The team, comprised of four scientists, began its work in Alexandria, but later traveled to Calcutta once the Egyptian epidemic had subsided.
Egypt and India Travels and Cholera
Robert Koch with Colleagues in Alexandria, Egypt 1891
Koch began by examining the intestinal mucosa of the deceased. In uncomplicated cases – those with little or no epithelial damage – a morphologically identical organism predominated: a comma-shaped bacillus. Using different media, Koch cultured and characterized the organism as motile, aerobic, and fast-growing. He noted that in intestinal fluid, it grew rapidly, before receding as the medium “decayed”. It was susceptible to acids and desiccation and produced no spores. With nourishment it could survive outside the body.
He conducted almost a hundred autopsies and found the bacilli in every case. They were especially numerous in the distal small bowel, where intestinal disease was greatest. In other diarrheal conditions, they were absent. He also noted that when incubated with red blood cells, the bacilli caused the cells to die. He attributed this to a “poison”, which explained how bacteria could cause disease with little or no penetration of the intestinal wall.
Eventually, he tracked its transmission by way of polluted water and pointed out that it could be controlled by keeping drinking water clean. Although he soon had reason to suspect a comma-shaped bacterium as the cause of cholera, the epidemic ended before he was able to confirm his hypothesis. To continue his investigations of the cholera bacterium he traveled to India, where cholera is endemic. Koch's epidemiological analysis was meticulous.
He noted that there were no “spontaneous” epidemics outside India. Only in the Ganges Delta was the disease predictable in its periodicity and was determined to be the origin of recurring pandemics. River flooding produced swamps, where vegetation was abundant. Refuse from densely populated areas supplied bacteria, which grew readily in the moist, fertile environment. Intestinal exposure to contaminated water caused disease in susceptible hosts. Through excrement, the bacteria would return to the water supply. Pilgrimages and navigation spread disease throughout the country and to distant shores. Thus, he completed his task, identifying both the organism responsible for the disease and its transmission via drinking water, food, and clothing. Koch's discovery meant that access to clean water was necessary to prevent the spread of cholera. To that end, filtered water lines were placed in Calcutta. Soon the incidence of disease fell. Koch's discovery was a public health triumph.
Upon his return from India, Koch was honored by Kaiser Wilhelm I and by Chancellor Otto von Bismarck. He was appointed Professor of Hygiene at the University of Berlin and Director of the Hygiene Institute. This would be the only academic position he would ever hold. He worked as the director for 5 years and made remarkable progress in his field of bacteriology. There he studied some of the most important human diseases, namely, tuberculosis, diphtheria, and typhus. He worked on these investigations with his pupils and longtime assistants, Friedrich Loeffler and Georg Gaffky. For all three diseases the specific bacteria were studied in detail.
In 1891, Koch was made honorary Director and Professor at the Institute of Infectious Diseases in Berlin. In 1893, Koch separated from his wife Emma and married the actress Hedwig Freiberg.
Institute of Hygiene
Hedwig Freiberg with Robert Koch
Hedwig Freiberg Travelling with Robert Koch Egypt 1896
As head of the Institute for Infectious Diseases, Koch investigated leprosy, bubonic plague and malaria with fruitful results. From 1896 onwards, Koch spent several months each year on expeditions to investigate tropical diseases. His second wife, Hedwig Freiberg, nearly always accompanied him. In 1896, he returned to Africa to study rinderpest in cattle and developed a vaccine against it. He led the German Sleeping Sickness Expedition, which studied the disease in Africa and traced the tsetse fly’s role in it.
Koch in Kimberley, South Africa Investigating the Rinderpest Pathogen
Malaria and Quinine
Although its prior use had had limited success, Koch was successful in treating patients with malaria using quinine. This is because he understood the life stages of the malaria parasite. Quinine had been the “miracle drug” of the day; however, it did not always work. It was frequently used at the wrong stage of malaria and sometimes made the condition worse. Many physicians only applied quinine when there was an active infection. Those cases that were latent, showing no symptoms at all, were usually not treated. As a result, some people who had latent infections would develop Blackwater fever.
Blackwater fever is a grave condition associated with malignant malaria, but its clinical picture is distinct. It is an acute, massive lysis of red blood cells marked by high levels of hemoglobin and waste products in blood and urine. The urine is a very deep dark red color and an indication of renal failure. In recent years, it has declined dramatically due to the use of quinine for prophylaxis, which was originally Koch’s idea.
Vivid proof of the success of Koch’s quinine method came in 1900. In Brioni, an island in the Adriatic Sea, about 300 people were threatened with malignant malaria (probably P. falciparum). All 300 were tested, but only 22% had the serious form. After diagnosis, Koch administered quinine in precisely the right amount and saved them from almost inevitable death. In honor of this great success, the island erected a statue in his likeness.
Nobel Prize 1905
Robert Koch and Fredrich Karl Dissecting a Crocodile to Investigate the Sleeping Sickness Pathogen on the SSese Islands off Uganda 1906
Koch’s discovery of tuberculosis was celebrated worldwide (including in the USA, where the National Tuberculosis Association was founded in 1904). In 1905, the Nobel Prize in Physiology or Medicine was awarded to Robert Koch "for his investigations and discoveries in relation to tuberculosis." In that year, he was also recognized for demonstrating that specific bacteria can cause common infectious diseases. Tuberculosis was the specific disease mentioned in the Nobel Prize, but Koch was already known for many other accomplishments in microbiology and tropical medicine.
After receiving the Nobel Prize, Koch set out on a long period of international travel. In Italy, Indonesia, and New Guinea, he studied malaria, establishing guidelines for its prevention. In India, he studied plague and in East Africa sleeping sickness. At the invitation of the British Government, he visited Rhodesia (now South Africa) to study rinderpest, an infectious disease of ruminants, especially cattle, caused by a paramyxovirus. There he also studied malaria, sleeping sickness, and horse-sickness, which is a highly infectious and deadly disease caused by a virus of the genus Orbivirus belonging to the family Reoviridae. It commonly affects horses, mules, and donkeys. He also studied relapsing fever which is a recurring febrile disease caused by several species of the spirochete Borrelia, transmitted primarily by lice ticks.
Robert Koch retired from his directorship of the Royal Prussian Institute in 1904 but continued to conduct research. In 1906 and 1907, a commission led by Koch was sent to East Africa to experiment with ways of treating sleeping sickness or African trypanosomiasis. This is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei. David Bruce had already identified the tsetse fly as its intermediate host.
Koch had limited initial success by treating patients with Atoxyl, a drug containing arsenic. But the parasite that caused the infection was only suppressed in the sufferer’s bloodstream for a short time. Although he was aware of the risks associated with the toxic drug, Koch doubled the dose of Atoxyl. Many patients suffered from pain and colic, and some even went blind and died. Koch continued to experiment with arsenic on sick and healthy alike. The minor successes were offset by major drawbacks, as the treatment soon killed more people than the disease.
In 1908, Koch traveled to the USA to visit relatives and to raise money for the study of tuberculosis. A banquet was held in his honor at the Waldorf Astoria in New York. In attendance was Andrew Carnegie, who had given 500,000 marks to the Robert Koch Foundation for the Conquest of Tuberculosis. After New York, Koch traveled to the Midwest to visit two of his brothers. (One lived in St. Louis, the other in Keystone, Iowa.)
Robert Koch and his Wife Hedwig in Japan 1908
In 1908, Koch and his wife Hedwig traveled to Japan, but his visit was cut short when he accepted an invitation to attend the International Tuberculosis Congress in Washington. The Congress was convened to discuss the relation of human and bovine tuberculosis. Koch's opinion was sought because he had previously stood against the prevailing notion that bovine tuberculosis was harmful to humans.
At the meeting, Koch maintained that bovine tuberculosis did not play a major pathogenic role in human disease. Opposing him were those who wished to prevent disease transmission by eliminating human consumption of infected meat and milk. They sought mandatory inspection of cattle, pasteurization of milk, and purging of infected livestock. Still, Koch refused to advocate these public health measures. As a result, his reputation, already injured by the tuberculin therapy failure, took another blow. Ultimately, the US health establishment distanced itself from Koch and moved towards universal pasteurization of milk.
A pasteurizing temperature was ultimately chosen to be adequate to kill tubercle bacilli.
Koch's health declined soon afterward. At the beginning of April 1910, he suffered a massive heart attack in Berlin and died at a sanatorium in Baden-Baden, May 27, 1910. The urn containing his ashes was laid to rest in a specially constructed mausoleum – including 1,500 letters, award certificates, lecture manuscripts and publications, photographs and prepared microscope slides – preserved at the Robert Koch Institute.
Koch perfected new methods of isolating, culturing, and identifying bacteria. Perhaps the key method Koch developed was the isolation of pure cultures. Pure cultures of multicellular organisms are often more easily isolated by simply picking out a single individual to initiate a culture. This is a useful technique for pure culture of fungi, multicellular algae, and small metazoan. Developing pure culture techniques is crucial to the observation of the specimen in question. The most common method to isolate individual microbes and produce a pure culture is to prepare a streak plate. The streak plate method is a way to physically separate the microbial population and is performed by spreading the inoculate back and forth with an inoculating loop over the solid agar plate. Upon incubation, colonies will arise, and single cells will have been isolated from the biomass.
Koch was also able to investigate disinfectants and methods of disease prevention important for hygiene and give advice concerning the early detection and combating of epidemic diseases such as cholera, typhus and malaria. Koch conducted important investigations of malaria, tropical dysentery, African sleeping sickness, bubonic plague, and the Egyptian eye disease (trachoma).
He also tackled typhus as seen in tropical Africa. Koch conducted work of critical importance concerning a number of tropical cattle diseases, such as rinderpest (known as cattle plague), Surra (a protozoan disease also found in horses), Texas fever, Rhodesian red water fever, and the well-known African sleeping sickness (trypanosomiasis) transmitted by the tsetse fly. Appropriately, Koch is historically recognized as one of the founders of medical microbiology.
“Koch was one of the most influential and dedicated medical researchers of the nineteen century.”
— American microbiologist Thomas Brock
His close friend and colleague, Ehrlich, placed him among the “princes of medical science” and thought that Koch was an experimenter par excellence.
“Careful and patient observation, hard work and keen insight were the tools of his trade.”
Overview of Koch’s Contributions
Koch's motto, nunquam otiosus (never idle) expressed the essence of his life.
References
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• Brock, Thomas D. Robert Koch: a life in medicine and bacteriology. Madison, WI: Science Tech Publishers, 1988.
• Bulloch, W., 1938. The history of bacteriology, New York: Dover Publications.
• Daniel, T. M. Robert Koch and the pathogenesis of tuberculosis [Founders of Our Knowledge]. The International Journal of Tuberculosis and Lung Disease 9, no. 11 (2005): 1181-1182.
• Evans, Alfred S. Causation and disease: the Henle-Koch postulates revisited. The Yale journal of biology and medicine49, no. 2 (1976): 175.
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• Finkelstein, R. A. The cholera enterotoxin-Robert Koch revisited [proceedings]. Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Erste Abteilung Originale. Reihe A: Medizinische Mikrobiologie und Parasitologie 235, no. 1-3 (1976): 13-19.
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• Kaufmann, Stefan HE, and Ulrich E. Schaible. 100th anniversary of Robert Koch's Nobel Prize for the discovery of the tubercle bacillus. Trends in microbiology 13, no. 10 (2005): 469-475.
• Knight, D. C. 1961. Robert Koch: Father of Bacteriology (Immortals of Science Series) New York. Franklin Watts, Incorporated.
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