that established themselves in human populations were undoubtedly transmitted from animals, much as still happens today. Early human groups that domesticated and lived with their animals were almost certainly exposed to different viruses than were nomadic hunter/gatherer societies. Similarly, as many different viruses are endemic in the tropics, human societies in that environment must have been exposed to a greater variety of viruses than societies established in temperate climates. When nomadic groups met others with domesticated animals, human-to-human contact could have provided new avenues for virus spread. Even so, it seems unlikely that viruses such as those that cause measles or smallpox could have entered a permanent relationship with small groups of early humans. Such highly virulent viruses, as we now know them to be, either kill their hosts or induce lifelong immunity. Consequently, they can survive only when large, interacting host populations offer a sufficient number of naive and permissive hosts for their continued propagation. Such viruses could not have been established in human populations until large, settled communities appeared. Less virulent viruses that enter into a long-term relationship with their hosts were therefore more likely to be the first to become adapted to reproduction in the earliest human populations. These viruses include the modern retroviruses, herpesviruses, and papillomaviruses.
Evidence for knowledge of several diseases that we now know to be caused by viruses can be found in ancient records. The Greek poet Homer characterizes Hector as “rabid” in The Iliad (Fig. 1.3A), and Mesopotamian laws that outline the responsibilities of the owners of rabid dogs date from before 1000 B.C.E. Their existence indicates that the communicable nature of this viral disease was already well-known by that time. Egyptian hieroglyphs illustrate what appear to be the consequences of poliovirus infection (a withered leg typical of poliomyelitis [Fig. 1.3B]). Pustular lesions characteristic of smallpox have also been found on Egyptian mummies. The smallpox virus was probably endemic in the Ganges River basin by the fifth century B.C.E. and subsequently spread to other parts of Asia and Europe. This viral pathogen has played an important part in human history. Its introduction into the previously unexposed native populations of Central and South America by colonists in the 16th century led to lethal epidemics, which are considered an important factor in the conquests achieved by a small number of European soldiers. Other viral diseases known in ancient times include mumps and, perhaps, influenza. Europeans have described yellow fever since they discovered Africa, and it has been suggested that this scourge of the tropical trade was the basis for legends about ghost ships, such as the Flying Dutchman, in which an entire ship’s crew perished mysteriously.
Humans have not only been subject to viral disease throughout much of their history but have also manipulated these agents, albeit unknowingly, for much longer than might be imagined. One classic example is the cultivation of marvelously patterned tulips, which were of enormous value in 17th-century Holland. Such efforts included deliberate spread of a virus (tulip breaking virus or tulip mosaic virus) that we now know causes the striping of tulip petals so highly prized at that time (Fig. 1.4). Attempts to control viral disease have an even more venerable history.
Figure 1.3 References to viral diseases from the ancient literature. (A) An image of Hector from an ancient Greek vase. Courtesy of the Penn Museum, object 30-44-4. (B) An Egyptian stele, or stone tablet, from the 18th dynasty (1580–1350 B.C.E.) depicting a man with a withered leg and the “drop foot” syndrome characteristic of poliomyelitis. Image courtesy of SPL/Science Source.
The First Vaccines
Measures to control one viral disease have been used for the last millennium. The disease is smallpox (Fig. 1.5), and the practice is called variolation. The process entails taking material directly from the smallpox lesions of an infected individual and scratching it onto the skin of healthy individuals with a lancet. Widespread in China and India by the 11th century, variolation was based on the recognition that smallpox survivors were protected against subsequent bouts of the disease. Variolation later spread to Asia Minor, where its value was recognized by Lady Mary Wortley Montagu, wife of the British ambassador to the Ottoman Empire. She introduced this practice into England in 1721, where it became quite widespread following the successful inoculation of children of the royal family. George Washington is said to have introduced the practice among Continental Army soldiers in 1776. However, the consequences of variolation were unpredictable and never pleasant: serious skin lesions invariably developed at the site of inoculation and were often accompanied by more generalized rash and disease, with a fatality rate of 1 to 2%. From the comfortable viewpoint of an affluent country in the 21st century, such a death rate seems unacceptably high. However, in the 18th century, variolation was perceived as a much better alternative than naturally contracting natural smallpox, a disease with a fatality rate of 25% in the whole population and 40% in babies and young children.
Figure 1.4 Three Broken Tulips. A painting by Nicolas Robert (1624–1685), now in the collection of the Fitzwilliam Museum, Cambridge, United Kingdom. Striping patterns (color breaking) in tulips were described in 1576 in western Europe and were caused by a viral infection. This beautiful image depicts the remarkable consequences of infection with the tulip mosaic virus. © Fitzwilliam Museum, Cambridge.
Figure 1.5 Characteristic smallpox lesions in a young victim. Illustrations like these were used as examples to track down individuals infected with the smallpox virus (variola virus) during the World Health Organization campaign to eradicate the disease. Courtesy of CDC/Dr. Robinson (CDC PHIL ID#10398). See also the interview with Dr. Donald Henderson: http://bit.ly/Virology_Henderson.
In the 1790s, Edward Jenner, an English country physician, established the principle on which modern methods of viral immunization are based, even though viruses themselves were not to be identified for another 100 years. Jenner himself was variolated with smallpox as a young boy and was undoubtedly familiar with its effects and risks. Perhaps this experience spurred his abiding interest in this method. Although it is commonly asserted that Jenner’s development of the smallpox vaccine was inspired by his observations of milkmaids, the reality is more prosaic. As a physician’s apprentice at age 13, Jenner learned about a curious observation of local practitioners who had been variolating farmers with smallpox. No expected skin rash or disease appeared in farmers who had previously suffered a bout with cowpox. This lack of response was typical of individuals who had survived earlier infection with smallpox and were known to be immune to the disease. It was supposed therefore that, like smallpox survivors, these non-responding farmers must somehow be immune to smallpox. Although the phenomenon was first observed and later reported by others, Jenner was the first to appreciate its significance fully and to follow up with direct experiments. From 1794 to 1796, he demonstrated that inoculation with material from cowpox lesions induced only mild symptoms in the recipient but protected against the far more dangerous disease. It is from these experiments that we derive the term vaccination (vacca = “cow” in Latin); Louis Pasteur coined this term in 1881 to honor Jenner’s accomplishments.
Initially, the only way to propagate and maintain the cow-pox-derived vaccine was by serial infection of human subjects. This method was eventually banned,
