In the opening pages of "To Bhola Island," Preston provides a brief natural history of poxviruses. Smallpox originated when the virus "jumped" from another species and adapted to infect human hosts. Typically, poxviruses are species-specific: seals, pigeons, horses, and kangaroos have their own unique forms of pox, while various other poxes target insect species, torturing and destroying their hosts from the inside out. Smallpox or "variola," for its part, might have been derived from a pox that targeted rodents. Its inadvertent spread was facilitated by the creation of increasingly large civilizations, and crises in ancient Greece and ancient Rome may well be linked to the presence of variola. This virus also devastated societies in North and South America, including the Inca Empire and then the Native American communities that grappled with smallpox when it was used as a biological weapon in the French and Indian War.

The effort to eradicate smallpox worldwide was spearheaded by Donald Ainslie (D.A.) Henderson, a CDC researcher assigned to put together such a program for the World Health Organization. His work began in the 1960s, and was facilitated by an approach known as "ring vaccination." First used by William H. Foege, the ring vaccination strategy involves isolating smallpox outbreaks by vaccinating all the people in the area that circles a smallpox danger zone.