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(Editor's note: This article originally appeared in the January 2005 issue of Scientific American magazine. We are posting it because of related news regarding swine flu.)

On September 7, 1918, at the height of World War I, a soldier at an army training camp outside Boston came to sick call with a high fever. Doctors diagnosed him with meningitis but changed their minds the next day when a dozen more soldiers were hospitalized with respiratory symptoms. Thirty-six new cases of this unknown illness appeared on the 16th. Incredibly, by September 23rd, 12,604 cases had been reported in the camp of 45,000 soldiers. By the end of the outbreak, one third of the camp's population would come down with this severe disease, and nearly 800 of them would die. The soldiers who perished often developed a bluish skin color and struggled horribly before succumbing to death by suffocation. Many died less than 48 hours after their symptoms appeared, and at autopsy their lungs were filled with fluid or blood.

Because this unusual suite of symptoms did not fit any known malady, a distinguished pathologist of the era, William Henry Welch, speculated that "this must be some new kind of infection or plague." Yet the disease was neither plague nor even new. It was just influenza. Still, this particularly virulent and infectious strain of the flu virus is thought to have killed as many as 40 million people around the world between 1918 and 1919.

This most lethal flu outbreak in modern history disappeared almost as quickly as it emerged, and its cause was long believed lost to time. No one had preserved samples of the pathogen for later study because influenza would not be identified as a virus until the 1930s. But thanks to incredible foresight by the U.S. Army Medical Museum, the persistence of a pathologist named Johan Hultin, and advances in genetic analysis of old tissue samples, we have been able to retrieve parts of the 1918 virus and study their features. Now, more than 80 years after the horrible natural disaster of 1918–1919, tissues recovered from a handful of victims are answering fundamental questions both about the nature of this pandemic strain and about the workings of influenza viruses in general.

The effort is not motivated merely by historical curiosity. Because influenza viruses continually evolve, new influenza strains continually threaten human populations. Pandemic human flu viruses have emerged twice since 1918—in 1957 and 1968. And flu strains that usually infect only animals have also periodically caused disease in humans, as seen in the recent outbreak of avian influenza in Asia. Our two principal goals are determining what made the 1918 influenza so virulent, to guide development of influenza treatments and preventive measures, and establishing the origin of the pandemic virus, to better target possible sources of future pandemic strains.

Hunting the 1918 Virus

In many respects, the 1918 influenza pandemic was similar to others before it and since. Whenever a new flu strain emerges with features that have never been encountered by most people's immune systems, widespread flu outbreaks are likely. But certain unique characteristics of the 1918 pandemic have long remained enigmatic.