DISCUSSION
Why viruses may not fulfill Koch’s postulates
Although Koch’s postulates provided a framework to identify a pathogen as an agent of a particular disease unambiguously, not all postulates can be applied to some infectious agents of disease. Koch himself became aware of the limitations of his postulates upon discovery that the bacterium Vibrio cholerae, which causes cholera, could be isolated from both sick and healthy individuals . In fact, it has been argued that the rigid application of these criteria to viral agents may have impeded early progress in the field of virology.
Application of Koch’s postulates to viruses can be problematic for several reasons . For example, the first postulate, which states that the microorganism must be “regularly associated” with the disease, does not hold true for many animal reservoirs, such as bats, in which the virus actively reproduces but causes no disease. Similarly, arthropod vectors, such as mosquitos, support reproduction of a variety of hemorrhagic viruses but do not die as a result. Moreover, the second postulate states that the microorganism must be grown in culture. However, some viruses, including papilloma-viruses that cause warts and cervical cancer, could be propagated in culture only recently, requiring complex conditions that must mimic the tissue complexity found in the infected host. Finally, recent studies addressing polymicrobial infections (that is, infections with more than one pathogen) have shown that, for some diseases, two or more organisms must work in synergy to cause a disease.
Highly sensitive molecular technologies, including quantitative polymerase chain reaction and DNA sequencing, have triggered a revision of Koch’s postulates for the modern era. Left panel courtesy of Granger Historical Picture Archive, image no. 0008494.
Assiduously applying the postulates has been particularly problematic for identifying viruses that cause human tumors . As noted in a review, Koch’s postulates “are a brilliant example of precision in scientific thinking, but they hold little practical value for 21st century tumor virology, as they cannot prove nor disprove most candidate tumor viruses to cause cancers.” Consequently, the postulates are a guide, not an invariant set of requirements to fulfill.
More recently, detection methods based on nucleic acid sequence have rendered Koch’s original postulates even less relevant. Such approaches are sufficiently sensitive to detect the presence of small quantities of viral nucleic acid in an apparently healthy individual. As such, a revised set of Koch’s postulates that takes into consideration new technical capabilities has been proposed (Volume I, Box 1.4).
Fredricks DN, Relman DA. 1996. Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 9:18– 33.
Moore PS, Chang Y. 2014. The conundrum of causality in tumor virology: the cases of KSHV and MCV. Semin Cancer Biol 26:4–12.
The First Human Viruses Identified and the Role of Serendipity
The first human virus that was identified was the agent that causes yellow fever. The story of its identification in 1901 is instructive, as it highlights the contributions of creative thinking, collaboration, serendipitous timing, and even heroism in identifying new pathogens.
Although not recognized, yellow fever was widespread in tropical countries since the 15th century, and was responsible for devastating epidemics associated with extraordinary rates of mortality (for example, over a quarter of infected individuals died in the New Orleans epidemic of 1853). While the disease can be relatively mild, with transient symptoms that include fever and nausea, more-severe cases result in major organ failure. Destruction of the liver causes yellowing of the skin (jaundice), the symptom from which the disease name is derived. Despite its impact, little was known about how yellow fever was spread, although it was clear that the disease was not transferred directly from person to person. This property prompted speculation that the source of the infection was present in the atmosphere, and led to desperate efforts to “purify” the air, including burning barrels of tar and firing cannons. Some believed that the pathogen was carried on fomites, such as bedding or clothing, although this hypothesis was disproved when volunteers remained healthy after sleeping in the nightwear of yellow fever victims.
The first real advance in establishing the origin, or etiology, of yellow fever came in 1880, when the Cuban physician Carlos Juan Finlay proposed that a bloodsucking insect, most likely a mosquito, played a part in the transmission of the dis ease. A commission to study the basis of yellow fever was established in 1899 in Cuba by the U.S. Army under Colonel Walter Reed. This commission was formed in part because of the high incidence of the disease among soldiers who at that time were stationed in Cuba. Jesse Lazear, a member of Reed’s commission, confirmed Finlay’s hypothesis when he allowed himself to be bitten by a yellow fever virus-infected mosquito. “I rather think I am on the track of the real germ,” wrote Lazear to his wife, sadly just days before he died of yellow fever himself. The results of the Reed Commission’s study proved conclusively that mosquitos are the vectors for this disease. In retrospect, a mosquito-borne mode of transmission made sense, as the disease was predominantly found in warm and humid regions (e.g., Cuba, New Orleans) where mosquitos were, and remain, abundant. The members of this courageous team, perhaps the first true epidemiologists, are depicted in a dramatic 1939 painting (Fig. 1.1).
The nature of the pathogen was established in 1901, when Reed and James Carroll injected diluted, filtered serum from the blood of a yellow fever patient into three healthy individuals. Two of the volunteers developed yellow fever, leading Reed and Carroll to conclude that a “filterable agent,” which we now know as yellow fever virus, was the cause of the disease. In the same year, a professor at the University of Havana attempted to produce immunity by exposing volunteers to mosquitos that were allowed to take a blood meal from an individual who showed signs of yellow fever. Of 19 volunteers, 8 contracted the disease, and 3 died. One of the deceased was Clara Louise Maass, a U.S. Army nurse. Maass’s story is of interest, as she had volunteered to be inoculated by infected mosquitos some time before, developed only mild symptoms, and survived. Her agreement to be infected a second time was to test if her earlier exposure provided protection from a subsequent challenge. This was a prescient idea, because at that time, virtually nothing was known about immune memory, which is the underlying principle of vaccines. Maass’s death prompted a public outcry and helped to end yellow fever experiments in human volunteers.
Figure 1.1 Conquerors of yellow fever. This painting by Dean Cornwell (1939) depicts the experimental exposure of James Carroll to infected mosquitos. Walter Reed, in white, stands at the head of the table, while Jesse Lazear applies the infected mosquitos to Carroll’s arm. Also depicted in this painting is Carlos Finlay, in a dark suit. Despite the care that Cornwell took to ensure accuracy of his portrayal of the participants and their uniforms, the event documented in this painting never took place; rather, artistic license was used to place all the major players in one depiction of a watershed moment in medical history. Courtesy of the Cornwall Historical Society, accessed April 1, 2020, http://www.cornwallhistoricalsociety.org/omeka/items/show/241.
Yellow fever had been endemic in Havana for many years, but the conclusions of Reed and his colleagues about the nature of the pathogen, and the vector that transmitted it, led to rapid implementation of effective mosquito control measures
