Koch's postulates (//) are four criteria designed to establish a causative relationship between a microbe and a disease. The postulates were formulated by Robert Koch and Friedrich Loeffler in 1884, based on earlier concepts described by Jakob Henle, and refined and published by Koch in 1890. Koch applied the postulates to describe the etiology of cholera and tuberculosis, but they have been controversially generalized to other diseases. These postulates were generated prior to understanding of modern concepts in microbial pathogenesis that cannot be examined using Koch's postulates, including viruses (which are obligate cellular parasites) or asymptomatic carriers. They have largely been supplanted by other criteria such as the Bradford Hill criteria for infectious disease causality in modern public health.
Koch's postulates are the following:
- The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
- The microorganism must be isolated from a diseased organism and grown in pure culture.
- The cultured microorganism should cause disease when introduced into a healthy organism.
- The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
However, Koch abandoned the universalist requirement of the first postulate altogether when he discovered asymptomatic carriers of cholera and, later, of typhoid fever. Asymptomatic or subclinical infection carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex, HIV, and hepatitis C. As a specific example, all doctors and virologists agree that poliovirus causes paralysis in just a few infected subjects, and the success of the polio vaccine in preventing disease supports the conviction that the poliovirus is the causative agent.
The second postulate may also be suspended for certain microorganisms or entities that cannot (at the present time) be grown in pure culture. Viruses also require host cells to grow and reproduce and therefore cannot be grown in pure cultures.
The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis and cholera, not all organisms exposed to an infectious agent will acquire the infection. Noninfection may be due to such factors as general health and proper immune functioning; acquired immunity from previous exposure or vaccination; or genetic immunity, as with the resistance to malaria conferred by possessing at least one sickle cell allele.
There are a few other exceptions to Koch's postulates. A single pathogen can cause several disease conditions. Additionally, a single disease condition can be caused by several different microorganisms. Some pathogens can not be cultured in the lab, and some pathogens only cause disease in the human species. 
In summary, an infectious agent that satisfies Koch's postulates has sufficient evidence to be classified as the infectious agent, but due to the postulates' shortcomings they are not strictly a necessary condition of an organism being the infectious agent responsible for a disease.
Koch's postulates were developed in the 19th century as general guidelines to identify pathogens that could be isolated with the techniques of the day. Even in Koch's time, it was recognized that some infectious agents were clearly responsible for disease even though they did not fulfill all of the postulates. Attempts to rigidly apply Koch's postulates to the diagnosis of viral diseases in the late 19th century, at a time when viruses could not be seen or isolated in culture, may have impeded the early development of the field of virology. Koch's postulates have been recognized as largely obsolete by epidemiologists since the 1950s. Therefore, while Koch's postulates retain historical importance and continue to inform the approach to microbiologic diagnosis, they are not routinely used to demonstrate causality.
Koch's postulates have also influenced scientists who examine microbial pathogenesis from a molecular point of view. In the 1980s, a molecular version of Koch's postulates was developed to guide the identification of microbial genes encoding virulence factors.
For the 21st century
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Koch’s postulates have played an important role in microbiology, yet they have major limitations. For example, Koch was well aware that in the case of cholera, the causal agent, Vibrio cholerae, could be found in both sick and healthy people, invalidating his first postulate. Furthermore, viral diseases were not yet discovered when Koch formulated his postulates, and there are many viruses that do not cause illness in all infected individuals, a requirement of the first postulate. Additionally, it was known through experimentation that H. pylori caused mild inflammation of the gastric lining when ingested. As evident as the inflammation was, it still did not immediately convince skeptics that H. pylori was associated with ulcers. Eventually, skeptics were silenced when a newly developed antibiotic treatment eliminated the bacteria and ultimately cured the disease. Contradictions and occurrences such as these have led many to believe that a fifth postulate may be required. If enacted, this postulate would state that sufficient microbial data should allow scientists to treat, cure, or prevent the particular disease.
More recently, modern nucleic acid-based microbial detection methods have made Koch’s original postulates even less relevant. These nucleic acid-based methods make it possible to identify microbes that are associated with a disease, but in many cases the microbes are uncultivable. Also, nucleic acid-based detection methods are very sensitive, and they can often detect the very low levels of viruses that are found in healthy people without disease.
The use of these new methods has led to revised versions of Koch’s postulates: Fredricks and Relman have suggested the following set of Koch’s postulates for the 21st century:
- A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found preferentially in those organs or gross anatomic sites known to be diseased, and not in those organs that lack pathology.
- Fewer, or no, copies of pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease.
- With resolution of disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.
- When sequence detection predates disease, or sequence copy number correlates with severity of disease or pathology, the sequence-disease association is more likely to be a causal relationship.
- The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms.
- Tissue-sequence correlates should be sought at the cellular level: efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible microorganisms or to areas where microorganisms are presumed to be located.
- These sequence-based forms of evidence for microbial causation should be reproducible.
These modifications are still controversial in that they do not account well for established disease associations, such as papillomavirus and cervical cancer, nor do they take into account prion diseases, which have no nucleic acid sequences of their own.
- Bradford Hill criteria
- Causal inference
- Mill's Methods
- Molecular Koch's postulates
- Willoughby D. Miller
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