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 a microscope. In 1590, Hans Lippershey in Holland applied for a patent for a microscope and naturally, he was credited for inventing the microscope. In 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 rain water 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 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 straight forward classification bacteria in 1870. Many consider Cohn as the originator of bacteriology but majority gave the credit to Robert Koch.
The Spontaneous Generation of Life:
Louis Pasteur proved spontaneous generation was a myth.
People believed in 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 of rabies is 2 to 8 weeks, usually 3 weeks. If an adequate levels of antibodies can be raised, in the body by administering a vaccine during the incubation period, then rabies would not develop. Pasteur's vaccne saved Meister, he did not developed rabies. Pasteur was a pioneer in attenuating the virus by successively passing it through a suitable laboratory animal and therby making the virus much less virulent but retaining the antigenic property, and then use that attenuated virus as a vaccine. He was working for several years with 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 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 oil immersion lens of 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 and left no doubt about presence of the bacteria, Anthrax, was killing the animals. He collected soil and vegetation from the pastures and 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 the direct evidence, he left no doubt the 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 discoverd bacteria and medical communities accepted his germ theropy, everyehere, many were finding bacteria and linked that bacterium to that illness. There was no check and balances and any established critreia for varifying those claims. Koch designed 4 basic creteria 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, as for example, asymptomatic carriers like Typhoid Marry; recurrence of disease after apparent cure, as latent tuberculosis. And some human infectious disease has no real animal counterpart as in case of cholera.
Asepsis:
Due to shear ignorance, the doctors have killed thousands of patients over centuries, examples are plenty but to mention a few- blood letting in Postpartum hemorrhage, antiphlogestine plaster in lobar pneumonia [https://digirepo.nlm.nih.gov/ext/dw/101299441/PDF/101299441.pdf] and performing 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 antiseptic solution prior to vaginal deliveries. This simple hygienic method cut postpartum infection and death to a minimum.
Edward Jenner (1660 -1720)
He introduced cowpox vaccine for a 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 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, specially of the WW solders.
Just looking at the dates of a few pioneers in infectios diseases barely mentioned here, one can see the 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 microorganism by stained slides and cultures are often unnecessary, since rapid and more accurate identification is possible by detecting the specific DNA / RNA of bacteria and micro organism 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), there he came in contact with another great German, Rudolf Virechow. He subsequently entered the medical collage 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 in the pursuit of finding cause of diseases. After finding the bacterium Anthrax and later a mycobacteria for Tuberculosis, he proposed the Germ Theory of Illness. And put an end of 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 discs shaped of culture medium which is known as Petri dish, which is still used in all bacteriology laboratory today.
3. Designed condenser of light for microscope.
4. Used oil immersion lens for further magnification of objects.
5. Developed Microphotography, direct photography through the microscope.
Anthrax and Koch's Postulates:
Stated in the previous section.
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 the medical journals, instead all his work on cholera, were dispatched to 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 experiment and grow the bacteria in a pure culture, the epidemic in Egypt subsided. He requested and was granted to move to Calcutta for continuation of his research where cholera was still raging.
He arrive in Calcutta in December 1883. He was able to culture the comma shaped organism. One of his dispatches to 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 and rivers and in the cloths 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 fatalites 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 the 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 activatates of 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 covered the smear by a coverslip and then treated it with Methyline 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 full filled all 4 criteria of Koch's postulates. He announced his findings in 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 in 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. But the skin test was unreliable due to presence of contaninants.
Charles Mantoux purified the tuberculin and reintroduced the skin test, PPD (purified protein derivative of tuberculin) in 1907 and named it Pirquet test but now it is known as Mantoux skin test used for detectiion TB infection.
iKoch's Phenomenon:
People who has active tuberculosis, if they receive tuberculin or BCG vaccine, develop severe allergic skin reaction, the skin at the injection site become 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 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 development of immunity from prior infections. Investigators looked into it at a later date and found Koch was right.
Other areas Koch's contribution:
In his early days of his long carrier, Dr Koch conducted investigation of mitochondria function and discovered the Succinic acid in the cycle, what is known today as Krebs Cycle.
He also contributed in detecting 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 his biggest blunder of his distinguished carrier as an investigator.
He steadfastly believed that Bovine tuberculosis was not a danger to humans. It is an irony that his discovery of bovine tubercular bacillus gave birth to 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 begining of the BCG vaccine.
Down fall:
In 1893, Dr. Koch divorced his wife and within two month he married an actress. The fiasco with Tuberculin diminished him and people also accused him of greed for giving the manufacture right of Tuberculin by a private company for money, while his research was supported by the German government. He also accused of making attempts to sale the license to an American company for a large sums of money for manufacturing and marketing.
He suffered a stoke and died 1910.
A final word:
Among the giants in the public health and clinical medicine, none stands taller than this trio - Jenner, Pasteur and Koch. Koch's talent was multidisciplinary from biochemistry to yet to define 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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