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, as it was often associated with transmission of other diseases such as syphilis and hepatitis. By 1860, the vaccine had been passaged in cows; later, horses, sheep, and water buffaloes were also used. The origin of the current vaccine virus, vaccinia virus, is now thought to be horsepox virus (Box 1.3).
The first rabies vaccine was made by Louis Pasteur, although he had no idea at the time that the relevant agent was a virus. In 1885, he inoculated rabbits with material from the brain of a cow suffering from rabies and then used aqueous suspensions of dried spinal cords from these animals to infect other rabbits. After several such passages, the resulting preparations were administered to human subjects, where they produced mild disease but effective immunity against rabies.
Today, viral vaccine strains selected for reduced virulence are called attenuated, a term derived from the Latin prefix ad, meaning “to,” and tenuis, meaning “weak.” Safer and more efficient methods for the production of larger quantities of these first vaccines awaited the recognition of viruses as distinctive biological entities and parasites of cells in their hosts. Indeed, it took almost 50 years to discover the next antiviral vaccines: a vaccine for yellow fever virus was developed in 1935, and an influenza vaccine was available in 1936. These advances became possible only with radical changes in our knowledge of living organisms and of the causes of disease.
Microorganisms as Pathogenic Agents
The 19th century was a period of revolution in scientific thought, particularly in ideas about the origins of living things. The publication of Charles Darwin’s The Origin of Species in 1859 crystallized startling (and, to many people, shocking) new ideas about the origin of diversity in plants and animals, until then generally attributed directly to the hand of God. These insights permanently undermined the perception that humans were somehow set apart from all other members of the animal kingdom. From the point of view of the science of virology, the most important changes were in ideas about the causes of disease.
The diversity of macroscopic organisms has been appreciated and cataloged since the dawn of recorded human history. However, a vast new world of organisms too small to be visible to the naked eye was revealed through the microscopes of Antony van Leeuwenhoek (1632–1723). Van Leeuwenhoek’s vivid and exciting descriptions
