To Catch a Virus. John Booss

few years later, he inoculated his son with smallpox, which failed to take, implying protection against smallpox (43) conferred by the earlier treatment.

Jenner’s powers of observation as a naturalist were strong; he was elected to the Royal Society based on observations on the nesting behavior of the cuckoo. Those talents are on display in his self-published pamphlet on cowpox in 1798 (21). Jenner noted that “. . . but what renders the Cow-pox virus so extremely singular, is that the person who has been affected is for ever after secure from the infection of the Smallpox; neither exposure to the various effluvia, nor insertion of the matter into the skin, producing the distemper.” Jenner’s Case I was Joseph Merret, who had tended horses with sore heels, an infectious disease called “the grease.” Merret developed sores on his hands and swelling and stiffness in his axillae. It was Jenner’s belief that the grease was transmitted by farm workers to cows which then transmitted cowpox to milkers, thereby protecting them from smallpox. Twenty-five years later, Merret was inoculated with “variolous matter,” but it did not take. Jenner noted that since the population was thin and any case of smallpox recorded, it was certain that Merret had not had smallpox in the intervening years. Apparently the relationship between the grease and cowpox was discredited (35). However, the link between cowpox and immunity to smallpox was sustained. Then came what history has recorded as the decisive event.

Jenner attempted artificial infection by cowpox of a boy, James Phipps, with matter taken from a sore on the hand of a dairymaid, Sarah Nelms, who had been infected by her master’s cows. Lesions of the incisions “were much the same as when produced in a similar manner by variolous matter,” and a week after inoculation he had a brief episode of axillary discomfort and systemic symptoms. The crucial test came on 1 July following when he was inoculated with variolous matter: “No disease followed.” Several months later he was again challenged with variolous matter, “but no sensible effect was produced on the constitution” (7). Phipps was the same age, 8 years, as Jenner had been when Jenner experienced the arduous preparation for variolation (2).

It is a paradox that this first experimental observation of what was the most beneficial medical public health intervention ever devised was first rejected by the Royal Society in 1797. Hopkins has aptly put it, “Because his evidence was so slim and his conclusion so audacious, the paper was quietly returned . . .” (19). Despite resistance among some (Fig. 3), the value of vaccination was very promptly recognized and vaccination was taken up by others. In just a decade after James Phipps was vaccinated, Thomas Jefferson was able to write to Edward Jenner in 1806, “Further generations will know by history only that the loathsome smallpox has existed” (19). It is an extraordinary achievement that came to pass. In 1966 the WHO undertook the Global Eradication Programme to rid the world of smallpox, which was accomplished and certified in 1979, closing the magnificent chapter in smallpox history. Further accounts of this momentous accomplishment are detailed in “the big red book,” Smallpox and Its Eradication (13).

Figure 3 Triomphe de la Petite Vérole (Triumph of Smallpox). Vaccination was feared on the European continent as well as in England. This French caricature satirized that fear. It shows a woman with smallpox turning into a mermaid, a physician riding a cow, and an apothecary with a giant syringe pursuing frightened children. (Courtesy of the Wellcome Library, London, United Kingdom.)

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      Start of the Science of Immunology: Phagocytosis and Humoral Immunity

Theories of humoral immunity, the basis of serological testing, were forged against Elie Metchnikoff’s (Fig. 4) theory of phagocytosis in host defense. Metchnikoff’s studies of phagocytosis evolved from his interest in digestion by invertebrates in the latter 1870s (40). In her biography of Metchnikoff, Olga, his second wife, gives a charming quote describing the inception of her husband’s phagocyte theory: “One day when the whole family had gone to a circus to see some extraordinary performing apes, I remained alone with my microscope, observing the life in mobile cells of a transparent star-fish larva, when a new thought suddenly flashed across my brain. It struck me that similar cells might serve in the defense of the organism against intruders” (27). Metchnikoff devised a simple experiment in which he “introduced them (rose thorns) at once under the skin of some beautiful star-fish larvae as transparent as water.” The following morning he confirmed that the thorns were surrounded by mobile cells. “That experiment formed the basis of the phagocyte theory, to the development of which I devoted the next twenty-five years of my life.”

Figure 4 Elie Metchnikoff. Metchnikoff’s studies of phagocytosis initiated the science of immunology, specifically cellular immunity. With Paul Ehrlich, who developed the theoretical basis for the action of antibodies or humoral immunity, Metchnikoff received the Nobel Prize in 1908. (Courtesy of Wikimedia Commons.)

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      On showing his experiments to Rudolf Virchow, the father of modern pathology, Metchnikoff was advised to proceed with caution. As opposed to Metchnikoff’s view of inflammation as “a curative reaction,” contemporary medicine viewed leukocytes as supporting the growth of microbes (27). Metchnikoff left Messina and on subsequent travels through Vienna, the word “phagocytes” was suggested by zoologists as a Greek translation of “devouring cells” (27).

In 1884, Metchnikoff published a seminal work on phagocytosis in Virchow’s Archive (26). Regretfully, however, as his wife recorded, “. . . the memoir passed unnoticed; the full significance of it had not been grasped” (27). Over a century later, A. M. Silverstein, in his history of immunology, amplified that observation: “One may conclude that the cellular theory of immunity advanced by Elie Metchnikoff in 1884 did not constitute just one further acceptable step in a well-established tradition; rather it represented a significant component of a conceptual revolution with which contemporary science had not yet fully learned to cope” (40).

As described in the 1884 work, Metchnikoff investigated a fungal disease of Daphnia, a transparent water flea (22). Daphnia ingested asci, sac-like structures in which spores are formed. Upon release into the digestive tract, spores traversed the intestinal wall to the body cavity, where they were attacked by blood cells, ultimately disintegrating into granules. Host giant cells were seen to have formed from the fusion of ameboid cells; however, the host did not always win out.

Using