by Cassie, Associate Publicist
Michael B. A. Oldstone is a Member (Professor) at the Scripps Research Institute, where he directs a laboratory of viral immunobiology. He is also the author of Viruses, Plagues, and History: Past, Present, and Future, a look at viruses from smallpox to ebola to West Nile to the flu. In this excerpt, Oldstone explains how pigs, dogs, and ferrets help scientists discover that the flu was a virus, not bacteria.
Although suspected influenza epidemics occurred during several decades of the 1700s, Robert Johnson, a physician from Philadelphia, is generally credited with the first description of influenza during the 1793 epidemic. With his description available and improved public health statistics, epidemics were documented in 1833, 1837, 1847, 1889–90, and 1918.
However, the identity of the infectious agent that caused influenza remained debatable. In Germany, Richard Pfeiffer discovered “bacteria” present in great numbers in the throats and lungs of patients with influenza. Because of this agent’s large size, it could not pass through a Pasteur-Chamberland-type filter, causing many observers to speculate that influenza originated from a bacterium and not a virus.
Only by serendipity was the true nature of influenza as a virus discovered. This is a tale of pigs, hounds, foxes, and ferrets—all of which played decisive roles in the determination that influenza was a virus…
The story begins with J. S. Koen of Fort Dodge, Iowa, an inspector for the U.S. Bureau of Animal Husbandry. In 1918, he observed in pigs a disease that resembled the raging human influenza plague of 1918–19:
Last fall and winter we were confronted with a new condition, if not a new disease. I believe I have as much to support this diagnosis in pigs as the physicians have to support a similar diagnosis in man. The similarity of the epidemic among people and the epidemic among pigs was so close, the reports so frequent, that an outbreak in the family would be followed immediately by an outbreak among the hogs, and vice versa, as to present a most striking coincidence if not suggesting a close relation between the two conditions. It looked like “flu,” and until proved it was not “flu,” I shall stand by that diagnosis.
Koen’s views were decidedly unpopular, especially among farmers raising pigs, who feared that customers would be put off from eating pork if such an association were made. Ten years later, in 1928, a group of research veterinarians in the U.S. Bureau of Animal Husbandry, led by C. N. McBryde, reported the successful transmission of influenza infection from pig to pig by taking mucus and tissue from the respiratory tracts of sick pigs and placing it into the noses of healthy pigs. However, these investigators were unable to transmit the disease after passing the material through a Pasteur-Chamberland-type filter. Therefore, no evidence was yet available that a virus caused influenza. That situation changed when Richard Shope, working at the Rockefeller Institute of Comparative Pathology at Princeton, New Jersey, repeated McBryde’s experiments within a year of the negative report. By reproducing influenza disease in healthy pigs after inoculating them with material taken from sick pigs and passed through the Pasteur-Chamberland filter, Shope provided the first evidence that viruses transmitted influenza of swine.
…Initially, dogs were used for research on the [canine distemper] virus and for studies to develop the vaccine, but problems soon surfaced. Among the difficulties was the issue that some dogs had become immune because of a previous encounter with canine distemper virus so did not contract the disease when exposed; additionally, antivivisectionists and some pet owners objected to using “man’s best friend” as a research tool. These problems vanished when ferrets were substituted for dogs. Hound keepers on the English country estates had noticed that ferrets also developed distemper, presumably transmitted from dogs. Soon ferrets replaced dogs in canine distemper studies at both the Wellcome and the MRC laboratories.
In 1933, the first epidemic of influenza since 1919 struck London and, as before, spread quickly. Among the many humans infected were several members of the research staff at Wellcome and MRC laboratories. However, unexpectedly, ferrets kept at the Wellcome laboratory also became ill, with symptoms of wheezing, sneezing, and coughing reminiscent of human influenza infection. When Wilson Smith, a senior researcher at the MRC unit, recognized the situation, he infected ferrets with nasal washings from influenza-infected patients. As the ferrets came down with the influenza-like syndrome, both Smith and Christopher Andrewes examined them. A story soon told was that a sick ferret sneezed in Christopher Andrewes’ face. A few days later, Andrewes came down with influenza. Smith obtained washings from Andrewes’s throat, passed the material through a Pasteur-Chamberland-like filter, then injected the filtrate into healthy ferrets. Soon they too began sneezing and coughing, discharging phlegm from the nose and eyes and spiking a temperature. Here was the first evidence that a virus caused human influenza, at the same time fulfilling Koch’s postulates.
Following his studies with tuberculosis, Robert Koch formalized the criteria eventually called Koch’s postulates to distinguish a microbe causing disease from one that is a happenstance passenger. According to the postulates, a link between agent and disease is valid when the organism is regularly found in the lesions of the disease; the organism can be isolated in pure culture on artificial media; inoculation of this culture produces a similar disease in experimental animals, and the organism can be recovered from the lesions in these animals. These postulates require modification for viruses, however, because they cannot be grown on artificial media (viruses require living cells for their replication), and some are pathogenic only for humans. Nevertheless, these experiments with ferrets, humans, and influenza virus filled the bill for a modified Koch’s postulate. Considering the role serendipity played in the use of ferrets and the initial isolation of human influenza virus, one agrees with Pasteur: “Chance favors the prepared mind.”