if you were, for whatever macabre reason, seeking the most catastrophic moment in the history of humankind, you might well settle on this: About 10,000 years ago, as people first began to domesticate animals and farm the land in Mesopotamia, India, and northern Africa, a peculiar virus leaped across the species barrier. Little is known about its early years. But the virus spread and, whether sooner or later, became virulent. It ransacked internal organs before traveling through the blood to the skin, where it erupted in pus-filled lesions. Many of those who survived it were left marked, disfigured, even blind.

As civilizations bloomed across the planet, the virus stalked them like a curse. Some speculate that it swept through ancient Egypt, where its scars appear to mar the mummified body of Pharaoh Ramses V. By the fourth century A.D., it had gained a foothold in China. Christian soldiers spread it through Europe during the 11th- and 12th-century Crusades. In the early 1500s, Spanish and Portuguese conquistadors conveyed it west across the Atlantic, where it ravaged native communities and contributed to the downfall of the Aztec, Mayan, and Inca empires.

By the end of the 1500s, the disease caused by the virus had become one of the most feared in the world. About a third of those who contracted it were dead within weeks. The Chinese called it tianhua, or “heaven’s flowers.” Throughout Europe, it was known as variola, meaning “spotted.” In England, where doctors used the term pox to describe pestilent bumps on the skin, syphilis had already claimed the name “the great pox.” And so this disease took on a diminutive moniker that belied the scale of its wretchedness: smallpox.

Over time, different communities experimented with different cures. Many noticed that survivors earned lifetime immunity from the disease. This discovery was passed down through the generations in Africa and Asia, where local cultures developed a practice that became known as inoculation—from the Latin inoculare, meaning “to graft.” In most cases, people would stick a sharp instrument into a smallpox-infected pustule to collect just a little material from the disease. Then they would stick the same blade, wet with infection, into the skin of a healthy individual. Inoculation often worked—pustules would form at the injection site, and a low-grade version of the disease would typically follow. But the intervention was terribly flawed; it killed about one in every 50 patients.

Not until the early 1700s did a chance encounter in the Ottoman empire bring the process to Britain, and bend the axis of history. In 1717, Lady Mary Wortley Montagu, an English aristocrat living in Constantinople with her husband, a diplomat, heard about inoculation from her acquaintances in the Ottoman court. Circassian women, from the Caucasus Mountains and in great demand for the Turkish sultan’s harem, were inoculated as children in parts of their bodies where scars would not easily be seen. Lady Montagu asked the embassy surgeon to perform the procedure on her son—and upon her return to London a few years later, on her young daughter.

Word spread from court physicians to members of the College of Physicians to doctors across the continent. Within a few years, inoculation had become widespread in Europe. But many people still died of smallpox after being deliberately infected, and in some cases inoculation transmitted other diseases, like syphilis or tuberculosis.

One boy who went through the ordeal of inoculation was Edward Jenner, the son of a vicar in Gloucestershire, England. He trained as a physician in the late 1700s, and carried out these rough smallpox inoculations regularly. But Jenner also sought a better cure. He was taken by a theory that a disease among cows could provide cross-immunity to smallpox.