62 SCIENTIFIC AMERICAN JANUARY 2005CREDIT By Jeffery K. Taubenberger, Ann H. Reid and Thomas G. Fanning Flu VIRUSCapturing aKillerCOPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.www.sciam.com SCIENTIFIC AMERICAN 63CREDIT INFLUENZA VICTIMS lie at U.S. Army Camp Hospital No. 45, Aix-les-Bains, France, in 1918. Flu killed 43,000 American servicemen mobilized for World War I, representing nearly 40 percent of U.S. military casualties.The deadliest fl u strain in history has been resurrected. What can the 1918 VIRUS reveal about why it killed millions and where more like it may be lurking? COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.64 SCIENTIFIC AMERICAN JANUARY 2005 On September 7, 1918, at the height of World War I, a sol-dier 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 respira-tory 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 of-ten developed a bluish skin color and struggled horribly before succumbing to death by suffocation. Many died less than 48 hours after their symptoms ap-peared, and at autopsy their lungs were fi lled with fl uid or blood. Because this unusual suite of symp-toms did not fi t any known malady, a distinguished pathologist of the era, William Henry Welch, speculated that “this must be some new kind of infec-tion or plague.” Yet the disease was nei-ther plague nor even new. It was just in-fl uenza. Still, this particularly virulent and infectious strain of the fl u virus is thought to have killed as many as 40 million people around the world be-tween 1918 and 1919. This most lethal fl u outbreak in mod-ern history disappeared almost as quick-ly as it emerged, and its cause was long believed lost to time. No one had pre-served samples of the pathogen for later study because infl uenza would not be identifi ed 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 ques-tions both about the nature of this pan-demic strain and about the workings of infl uenza viruses in general. The effort is not motivated merely by historical curiosity. Because infl uenza viruses continually evolve, new infl uen-za strains continually threaten human populations. Pandemic human fl u virus-es have emerged twice since 1918—in 1957 and 1968. And fl u strains that usu-ally infect only animals have also peri-odically caused disease in humans, as seen in the recent outbreak of avian in-fl uenza in Asia. Our two principal goals are determining what made the 1918 in-fl uenza so virulent, to guide develop-ment of infl uenza treatments and pre-ventive measures, and establishing the origin of the pandemic virus, to better target possible sources of future pan-demic strains.Hunting the 1918 Virusin many respects, the 1918 infl u-enza pandemic was similar to others be-fore it and since. Whenever a new fl u strain emerges with features that have never been encountered by most people’s immune systems, widespread fl u out-breaks are likely. But certain unique characteristics of the 1918 pandemic have long remained enigmatic. For instance, it was exceptional in both its breadth and depth. Outbreaks swept across Europe and North Ameri-ca, spreading as far as the Alaskan wil-derness and the most remote islands of the Pacifi c. Ultimately, one third of the world’s population may have been in-fected. The disease was also unusually severe, with death rates of 2.5 to 5 per-cent—up to 50 times the mortality seen in other infl uenza outbreaks. ■ The fl u pandemic that swept the globe in 1918–1919 was exceptional for the sheer numbers it killed, especially the number of young people who succumbed to the unusually virulent fl u virus.■ What made the strain so deadly was a longstanding medical mystery until the authors devised techniques that allowed them to retrieve the 1918 virus’s genes from victims’ preserved tissues. ■ Analysis of those genes and the proteins they encode revealed viral features that could have both suppressed immune defenses and provoked a violent immune reaction in victims, contributing to the high mortality. ■ Known bird and mammal infl uenza hosts are unlikely sources of the pandemic virus, so its origin remains unsolved.Overview/The Mystery of 1918RED CROSS NURSES in St. Louis carry a fl u patient in 1918. Health workers, police and a panicked public donned face masks for protection as the virus swept the country. Nearly a third of all Americans were infected during the pandemic, and 675,000 of them died.GEORGE RETSECK (flu virus); CORBIS (hospital) (preceding pages); AMERICAN RED CROSS MUSEUM (this page) COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.www.sciam.com SCIENTIFIC AMERICAN 65By the fall of 1918 everyone in Eu-rope was calling the disease the “Span-ish” infl uenza, probably because neutral Spain did not impose the wartime cen-sorship of news about the outbreak prev-alent in combatant countries. The name stuck, although the fi rst outbreaks, or spring wave, of the pandemic seemingly arose in and around military camps in the U.S. in March 1918. The second, main wave of the global pandemic oc-curred from September to November 1918, and in many places yet another se-vere wave of infl uenza hit in early 1919. Antibiotics had yet to be discovered, and most of the people who died during the pandemic succumbed to pneumonia caused by opportunist ic bacteria that in-fected those already weakened by the fl u. But a subset of infl uenza victims died just days after the onset of their symp-toms from a more severe viral pneumo-nia— caused by the fl u itself—that left their lungs either massively hemorrhaged or fi lled with fl uid. Furthermore, most deaths occurred among young adults be-tween 15 and 35 years old, a group that rarely dies from