rel="nofollow" href="#ulink_637aa4a2-fcd3-5662-b539-6c69e2760d1d">63).
The motivation to select a particular experimental problem by a scientist is usually complex and may reflect the less tangible facts of the scientist’s life. The distinguished Pasteur biographer René J. Dubos, an eminent 20th-century biologist, noted that “There is something odd in the selection by Pasteur of rabies as the next subject for his experimental studies” (12). Perhaps Pasteur’s horrifying experience as a young boy witnessing the effects of a rabid wolf’s attack was a motivation. More pressing than the relatively low prevalence of rabies was the nature of the disease itself. As well summarized by Gieson, “. . . rabies embodied the ultimate in agony and degradation, stripping its victims of their sanity and reducing them to quivering convulsive shadows of their former selves” (21).
Pasteur refined the animal model. Vallery-Radot noted that “Evidently the saliva was not a sure agent for experiments, and if more information was to be obtained, some other means had to be found of obtaining it” (63). With the growing realization of a seat of infection in the brain, Pasteur and his collaborators—“actually it was Emile Roux” as noted by Geison—developed an intracranial method of inoculation (2). The skull was trephinated, and infected cerebral matter from the rabid animal was deposited under the dura mater on the surface of the brain. This method achieved success: in the words of Vallery-Radot, “. . . rabies was contracted surely and swiftly” (63), and according to Geison, these collaborators “. . . had at last developed a uniformly successful method of transmitting the disease from animal-to-animal” (21). The next step was development of a brief and reproducible incubation period. Subdural transmission in rabbits resulted in a progressively shortened, “fixed” incubation period, as brief as 7 days (63).
What followed in the Pasteur story of rabies postexposure prophylaxis is the stuff of legend. Briefly told, a method of attenuating the infectivity of the rabid rabbit CNS by desiccation was devised, and the material could protect dogs from virulent infection. Circumstances led to the historic postexposure treatment in 1885 of Joseph Meister, a 9-year-old boy brought to Pasteur from Alsace (Fig. 3). Because the boy was suffering severe bites from a rabid dog, his case was thought likely to be fatal (69). The dog was killed and its stomach was found to contain hay, straw, and wood fragments, apparently leaving “no doubt that the dog was rabid” (34). Such was the state of diagnostic virology! After a series of inoculations of progressively more virulent rabies spinal cord tissue, Meister survived. The floodgates of postexposure treatment opened, with hundreds arriving from all parts of the globe. Gieson, in his review of Pasteur’s laboratory notebooks, observed “some remarkable discrepancies between the public and private versions of this celebrated story” (21). According to the notebooks, Joseph Meister was not the first person in whom the antirabies treatment was attempted. Of importance, however, is the train of events leading to the demonstration of rabies as a filterable virus.
Figure 3 Rabies prevention. The recognition that the Pasteurian treatment could prevent rabies after the bite of a rabid animal resulted in dramatic public acceptance. In this print from 1885, Pasteur is depicted observing the inoculation of a boy to prevent hydrophobia (rabies in humans). (Courtesy of the National Library of Medicine.)
doi:10.1128/9781555818586.ch2.f3
In 1884, “. . . Pasteur did concede that he and his collaborators had still not managed to isolate and cultivate a rabies microbe in artificial media” (21). While rabies virus was incapable of growth on artificial media, one of the criteria that defined a viral agent, rabies was transmissible to susceptible animal hosts. The stage was set for the demonstration that rabies was a filterable, “ultravisible” agent. That task would prove to be a technical challenge. However, in 1903, Paul Remlinger, the Director of the Imperial Institute of Bacteriology at Constantinople, reported “Le passage du virus rabique à travers les filtres” (51). His success depended on the techniques of filtration and inoculation and on the number of experimental animals tested. As summarized by a contemporary, John McFadyean, a veterinarian, the most porous of the Berkefeld filters would allow passage of the virus, whereas more finely porous filters would hold the agent back. The filtrates were deposited under the dura, and several rabbits were inoculated with each filtrate (41). The success in filtration was confirmed by others (41). Remlinger was gracious, attributing to Pasteur the idea of rabies as ultramicroscopic (51). It was a fitting tribute to Pasteur.
Coincidentally, in 1903, A. Negri described inclusions in the neurons of the CNS of rabid animals and humans (44). While the inclusions were misinterpreted as parasites, they became in the following years “an extremely important method of diagnosis” (28). Thus, 1903 was a seminal year in the study of rabies. Using the animal model developed by Galtier and refined by Pasteur and his colleagues, Remlinger demonstrated the filterable, that is, viral, nature of the agent of rabies. Negri developed a histopathological hallmark for rabies which, when positive, was a “rapid viral diagnostic technique.”
Polio: Monkeys
Thought to exist for centuries as a sporadic disease, polio was a rare crippler of infants and children. John Paul, a student of polio, used a figure of an ancient Egyptian stele showing a young priest with a withered leg as evidence of such early observations in his 1971 volume, A History of Poliomyelitis (47). As Paul described, “Under such endemic conditions paralytic poliomyelitis could have remained under cover for centuries in populations in which infant mortality was high.” Yet the individual experience of the paralytic form of the disease, from sporadic to epidemic times, has been consistent. Walter Scott was born in 1771 in an area characterized as “. . . a cramped dimly lit alleyway with poor sanitation and little fresh air” (15a). He described the onset of polio at 18 months: “One night, I have often been told, I showed great reluctance to be caught and put to bed, and after being chased about the room, was apprehended and consigned to my dormitory with some difficulty. It was the last time I was to show such personal agility. In the morning I was discovered to be affected with the fever which often accompanies the cutting of large teeth. It held me three days. On the fourth, when they went to bathe me as usual, they discovered that I had lost the power of my right leg” (47). The contagiousness of polio was not recognized in the centuries when polio was understood to be a sporadic disease, and Scott’s fever was attributed to the cutting of teeth.
The evolution of polio from
