Bacteriology and Robert Koch
P. K. Ghatak, M.D.
The birth of Bacteriology had to wait till the microscope was invented. But there is considerable controversy regarding who actually invented the microscope. In 1590, Hans Lippershey in Holland applied for a patent for a microscope and naturally, he was credited for inventing the microscope. At the same time, Antonie van Leeuwenhoek lived in the same town. He made a microscope of his own design. He found living organisms in the rainwater and then he began examining everything with his handheld microscope. In 1676, he reported his findings to the Royal Society of London, England. He reported observing various forms of small and smaller living organisms and he called them Animalcules. Medical society credited him for his inversion of the microscope.
Reproduction of the first compound microscope made by Hans and Zacharias Janssen, circa 1590. From the National Museum of Health and Medicine, Washington, D.C. (Image credit: Public domain.)
The German scientist Ferdinand Cohn (1828 -1898), after years of pain streaking study of the various contradictory and confused publications on this subject, put his straightforward classification of bacteria in 1870. Many consider Cohn the originator of bacteriology but the majority gave the credit to Robert Koch.
The Spontaneous Generation of Life:
Louis Pasteur proved spontaneous generation was a myth.
People believed in the spontaneous generation of life. This was an age old concept from the observation that maggots grew on a piece of meat or cheese when left outside. Even Charles Darwin stated in his “Origin of Species” book that the human body could be conceived as a creature susceptible to the law of nature.
Louis Pasteur (1822-95) proved that the microscopic living organisms were turning grape juice into vinegar and the spoiling could be prevented by killing the microorganisms by heating the grape juice and then rapidly cooling it. This process is known as Pasteurization
Lois Pasteur became a household name for his rabies vaccine. In 1885, he saved the life of a nine year old boy, named Joseph Meister, who was mauled by a vicious rabid dog. Pasteur administered his own laboratory grown vaccine. The Incubation period for rabies is 2 to 8 weeks, usually 3 weeks. If an adequate level of antibodies can be raised, in the body by administering a vaccine during the incubation period, then rabies would not develop. Pasteur's vaccine saved Meister, he did not develop rabies. Pasteur was a pioneer in attenuating the virus by successively passing it through a suitable laboratory animal thereby making the virus much less virulent but retaining the antigenic property, and then using that attenuated virus as a vaccine. He was working for several years with the rabies vaccine when Jeseph was brought to him by his mother,
Because Pasteur was dealing not only with bacteria but also with viruses, parasites and fungi he called the study of the microscopic organisms as Microbiology, instead of bacteriology.
Anthrax:
Like the wine industry in France, humans and livestock in Germany were dying from an unknown disease after a short illness. The task of finding the cause of illness and a cure fell on the shoulders of a multi talented medical doctor and head of bacteriology of Prussia (then in Germany), Dr. Robert Koch. He pretty soon found a rod shaped bacteria in the blood of the dead sheep.
He invented an oil immersion lens of a microscope for close up view. He developed ways to photograph the bacteria. He grew bacteria in pure culture in his specially formulated solid growing media of agar plate. By producing pictures of bacteria he left no doubt about the presence of the bacteria, Anthrax, was killing the animals. He collected soil and vegetation from the pastures detected spores of Anthrax and documented the full life cycle of anthrax. Spores were also infectious, if the spores were ingested or inhaled the spores germinated into the vegetative form and produced illness. He recommended burning the carcass of the dead animal or buried deep underground, in order to prevent spore formation and limit the spread of anthrax.
The Germ Theory of Illness:
By providing direct evidence, he left no doubt that germs are the cause of illness and after he found Mycobacteria tuberculosis which was the cause of TB, he put forward his Germ Theory of Illness.
Koch's Postulates:
After Koch discovered bacteria and medical communities accepted his germ theory, everywhere, many were finding bacteria and linked that bacterium to that illness. There were no checks and balances and no established criteria for verifying those claims. Koch designed 4 basic criteria for accepting a specific bacterium for a specific disease. It is known as Koch's Postulates.
Koch's four postulates are:
The organism causing the disease can be found in sick individuals but not in healthy ones.
The organism can be isolated and grown in pure culture.
The organism must cause the disease when it is introduced into a healthy animal.
The organism must be recovered from the infected animal and shown to be the same as the organism that was introduced.
The fundamental concept of Koch's postulates is still operative today with a few adjustments, for example, asymptomatic carriers like Typhoid Marry; recurrence of disease after apparent cure, as latent tuberculosis. Some human infectious disease has no real animal counterpart as in the case of cholera.
Asepsis:
Due to shear ignorance, doctors have killed thousands of patients over centuries, examples are plenty but to mention a few- bloodletting in Postpartum hemorrhage, antiphlogistic plaster in lobar pneumonia [https://digirepo.nlm.nih.gov/ext/dw/101299441/PDF/101299441.pdf] and performing an operation without scrubbing hands and delivering babies with unwashed hands.
Joseph Lister ( 1827 -1912).
He introduced soap and water washing hands and dipping hands in an antiseptic solution prior to vaginal deliveries. This simple hygienic method cut postpartum infection and death to a minimum.
Edward Jenner (1660 -1720)
He introduced the cowpox vaccine for the sure prevention of smallpox – one of the three curses of the ancient human civilization, the two others are Cholera and Leprosy.
Elie Metchnikoff (1845 – 1916).
In the early formative days of immunology, she demonstrated the phagocytic property of Neutrophils. Neutrophils devour bacteria before they have a chance to start an infection. The cellular immunity was born.
Emile Roux (1853 -1915) and Alexandre Emil Jean Yersin (1749 -1823):
They demonstrated the presence of the Diphtheria toxin in the liquid of the bacterial culture in broth. This opened the door for an effective way to mitigate paralysis of muscles of breathing and swallowing.
Paul Ehrlich (1854 – 1915):
He found an effective agent for African sickness and introduced Salvarsan for the treatment of Syphilis.
Alexander Fleming:
Fleming introduced the first ever antibiotic - Penicillin. Penicillin saved thousands of lives by healing the wound infections, especially of the WW soldiers.
Just looking at the dates of a few pioneers in infectious diseases barely mentioned here, one can see that microbiology had a precocious childhood and became an adolescent by the end of 1900. Microbiology reached adulthood with the discovery of DNA and RNA analytic methodologies. The identification of microorganisms by stained slides and cultures is often unnecessary since rapid and more accurate identification is possible by detecting the specific DNA / RNA of bacteria and microorganisms by the PCR test.
Robert Koch.
The great German physician cum bacteriologist was born in Chausthal, Germany in 1843. He graduated in Natural Science from the University of Gottingen in 1866. Then Koch went to work under the direction of Jacob Henle ( the man after whom the Loop of Henle of the Kidney is known), and there he came in contact with another great German, Rudolf Virchow. He subsequently entered the medical college and graduated in 1866. He received a microscope from his parents as a graduation gift. That changed the trajectory of his passion and he immersed himself in the pursuit of finding the cause of diseases. After finding the bacterium Anthrax and later a mycobacterium for Tuberculosis, he proposed the Germ Theory of Illness. And put an end to the myth – the spontaneous generation of life.
He was awarded the Noble Prize in Medicine in 1905, for his research on tuberculosis.
A war broke out between Germany and France in 1870. He volunteered as an army doctor and served for 2 years. At the end of the war, he was made a district medical office in Wotszten, Germany (now in Poland) and accepted the position of the director of Bacteriology laboratory. His innovations in laboratory work are:
1. New method of bacterial culture using solid media containing agar and gelatin.
2. Working with his associate, Richard Petri, he improved his solid culture media and made a disc shaped culture medium which is known as the Petri dish, which is still used in all bacteriology laboratories today.
3. Designed condenser of light for the microscope.
4. Used oil immersion lens for further magnification of objects.
5. Developed Microphotography, direct photography through the microscope.
Anthrax and Koch's Postulates: - see the bacteriology section, above.
Cholera:
A cholera epidemic broke out in Egypt in 1883. The German government sent Dr. Koch to Egypt as the head of a medical mission with the task of finding the cause and control of infection. Because Dr. Koch was employed by the government, his research papers were not published in medical journals, instead, all his work on cholera was dispatched to the German government and those papers were made available to newspapers. He reported finding a comma shaped bacteria in the mucosal layer of the small intestine during autopsy, but not in the blood vessels or in the distal organs and tissue. Before he could find a suitable animal for the experiment and grow the bacteria in a pure culture, the epidemic in Egypt subsided. He requested and was granted to move to Calcutta for the continuation of his research where cholera was still raging.
He arrived in Calcutta in December 1883. He was able to culture the comma shaped organism. In one of his dispatches to the German government on January 7,1814, he stated that he had successfully isolated the bacteria in pure culture. That the autopsy findings and the nature of the bacteria had been the same as those in Egypt. He detected this curved bacteria in drinking water, ponds, rivers and in the clothes of cholera victims and relatives and even in the vegetation. He recommended boiling drinking water as a precaution. He did not find a suitable animal for further study of cholera. Dr. Koch found enteritis of the small bowel in cholera victims and predicted that the symptoms and fatalities in cholera were due to cholera toxins, and not due to septicemia.
The credit for identifying the cholera toxins and defining their properties went to Dr. Shambhu Nath Dey of Medical Collage of Calcutta. In 1959, he published his research paper in the journal Nature and described an endotoxin and another toxin- exotoxin of cholera. Endotoxin is heat labile and produces severe watery diarrhea and hyponatremia and death. Endotoxin activates the enzyme Adenyl cyclase which activates cyclic AMP. Cyclic AMP opens the pores of enterocytes of the entire small intestine, and the plasma of the blood is depleted rapidly and produces vasomotor collapse and death. The exotoxin is heat table, antigenic and has no enzymatic properties.
Tuberculosis:
Before Dr. Koch proved tuberculosis was a bacterial infection, people believed tuberculosis was an inherited disease. Koch was engaged in research on tuberculosis for many years. He developed a new bacterial staining technique by making the smears on a glass side and covering the smear with a coverslip and then treating it with Methylene blue and potassium hydroxide for 24 hrs. Using this stain, he was able to find a slender long bacteria. He went to isolate the bacteria and fulfilled all 4 criteria of Koch's postulates. He announced his findings in the Berlin Physiological Society meeting on March 24, 1882.
Tuberculin:
Koch continued to work on tuberculosis in order to find a cure. He announced discovering a substance that could arrest tuberculosis at an international medical congress in August 1890. He called it Tuberculin. He did not reveal the chemical nature of tuberculin. He extracted a liquid from the tuberculosis culture and then dissolved it in glycerine. But tuberculin failed totally to control tuberculosis, instead, the tuberculin reactivated old TB lesions and produced severe allergic reactions. Before tuberculin use was discontinued 124 people died from reactions after receiving tuberculin injection.
Tuberculin Test:
Clemens von Pirquet (1874 -1929) a professor in medicine at the University of Vienna, ( who discovered Serum sickness and Antigen-Antibody Reaction), developed a skin test using Koch's tuberculin, for the detection of TB infection. However, the skin test was unreliable due to the presence of contaminants.
Charles Mantoux purified the tuberculin and reintroduced the skin test, PPD (purified protein derivative of tuberculin) in 1907 and named it the Pirquet test but now it is known as the Mantoux skin test used for detecting TB infection.
Koch's Phenomenon:
People who have active tuberculosis, if they receive tuberculin or BCG vaccine, develop severe allergic skin reactions, the skin at the injection site becomes necrotic and ulcerates. This is known as Koch's phenomenon.
Local Immunity:
Koch went to German New Guinea to investigate malaria. He discovered that the local people carry a high amount of malaria parasites in their blood but do not suffer from malaria, whereas, the visitors from other countries fell sick in a very short time. He explained this resistance to malaria in the local people was due to the development of immunity from prior infections. Investigators looked into it at a later date and found Koch was right.
Other areas of Koch's contribution:
In the early days of his long career, Dr Koch conducted the investigation of mitochondria function and discovered the Succinic acid in the cycle, what is known today as the Krebs Cycle.
He also contributed to detecting the cause of the following diseases -
Typhoid fever, Trypanosomiasis. Diphtheria, Syphilis, and Plague.
Where Koch was wrong:
Introducing Tuberculin without further scrutiny and giving the manufacturing right to a private company, was the biggest blunder of his distinguished career as an investigator.
He steadfastly believed that Bovine tuberculosis was not a danger to humans. It is a irony that his discovery of bovine tubercular bacillus gave birth to the BBC vaccine which stemmed the tide of childhood infection of TB.
BCG vaccine:
Albert Camette of the Pasteur Institute corroborated with Camille Guerin, a veterinarian who was suffering from TB, and began working on developing a bovine TB vaccine. After 230 subcultures in 13 years, they found a totally non-infectious TB bacillus but it retained its antigenic property. In 1921, they administered the vaccine to an infant whose mother was suffering from advanced TB. The vaccine saved the infant and the child remained healthy while the mother died of tuberculosis. That was the beginning of the BCG vaccine.
Downfall:
In 1893, Dr. Koch divorced his wife and within two months he married an actress. The fiasco with Tuberculin diminished him and people also accused him of greed for giving the manufacturing right of Tuberculin to a private company for money, at the same time, his research was supported by the German government. He was also accused of making attempts to sell the license to an American company for a large sum of money for manufacturing and marketing.
He suffered a stroke and died in 1910.
A final word:
Among the giants in public health and clinical medicine, none stands taller than this trio - Jenner, Pasteur, and Koch. Koch's talent was multidisciplinary from biochemistry to defining the parameters of immunology. Koch was an inventor of gadgets as well as a visionary. His work on tuberculosis alone will be remembered for centuries to come.
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