Since its first documented case in the 17th century, a great mystery surrounded yellow fever. What was its cause? Theories included "fomites" — contaminated objects like clothing and bedding from yellow fever patients — and airborne particles. It took a group of scientists in Cuba at the turn of the 20th century to discover the real answer.

In the Air
The genesis of the discovery took place in 1879. After a yellow fever epidemic had devastated the Mississippi Valley the year before, the U.S. National Health Board Yellow Fever Commission traveled to Cuba to investigate the disease. Carlos Finlay, a physician and scientific investigator in Havana, worked with the commission, which also included George Sternberg. After several months studying the disease in Cuba and in South America, the commission concluded: "Yellow fever is an epidemic, transmissible disease and the agent capable of transmitting the disease must be in the air." Following his assignment on the commission, Finlay theorized from his study of microscopic slides of tissue from yellow fever victims that the disease must be spread through the blood vessels. By 1881 Finlay had fixed on mosquitoes as the cause, but his theory was largely dismissed.

More Deadly Than War
After the Spanish-American War of 1898, during which far more U.S. troops died from yellow fever than in battle, another board came to Cuba in 1900 to study the disease. Walter Reed, an Army major and physician, headed the United States Army Yellow Fever Board, whose members visited Finlay and heard his theory of mosquito transmission. The board could find no other solution, so members decided to test Finlay's theory. There was only one way to do it, Reed believed. "Personally, I feel that only can experimentation on human beings serve to clear the field for further effective work," Reed told Army Surgeon General George Sternberg.

Infection
Board member Jesse Lazear hatched Finlay's mosquito eggs for the experiments. He took the insects to Las Animas Hospital in Havana to "load" them with the infected blood of yellow fever patients. The mosquitoes then fed on volunteers nine times from August 11 to August 25, with no infections resulting. On August 27, Lazear placed a mosquito on fellow board member James Carroll and four days later on a soldier volunteer. Both of them contracted yellow fever. The mosquito that had bitten the men differed from the mosquitoes in the earlier experiments in one important respect: The insect that transmitted the disease had fed on a yellow fever patient at least 12 days before and had been incubating her deadly cargo. Both men recovered. Lazear, who had probably exposed himself to an infected mosquito as well, did not. He died from yellow fever on September 25, 1900.

Camp Lazear
Upon his return to Cuba on October 4 from a trip to Washington, Reed was determined to substantiate his late colleague's work. Skepticism remained. When Reed presented the transmission theory before the American Public Health Association on October 23, the Washington Post called it "silly and nonsensical." Based on information in Lazear's notebook about the incubation period of the mosquitoes that transmitted the disease, in November Reed sought further proof in an isolated spot outside Havana he called Camp Lazear. Paid volunteers were isolated in separate buildings. One contained "fomites" from yellow fever patients. Volunteers who stayed in this building remained free of the disease. The other building was sterilized, but contained infected mosquitoes that bit volunteers. Several of them contracted yellow fever (all recovered).

Final Proof
Describing the experiments to his wife in a letter on December 9, Reed wrote: "[W]e have succeeded in demonstrating this mode of propagation of the disease, so that the most doubtful and skeptical must yield." Reed presented "The Etiology of Yellow Fever" to the Pan-American Medical Congress in Havana on February 6, 1901. Subsequent efforts to eliminate mosquitoes in Havana resulted in the near immediate cessation of the disease that had long plagued the city. It was the final piece of evidence that the mosquito theory was indeed correct.