In 1997, a particularly lethal form of the influenza virus swept through Hong Kong, killing one in three of the people it infected. New research on this deadly strain, dubbed H5N1, has revealed how it differs from more benign flus. The frightening answer is not much. "We have found that a limited number of very tiny genetic changes in a specific gene, one called PB2, can have a big effect on how potent the influenza virus is," Yoshihiro Kawaoka of the University of Wisconsin-Madison says. "Because the influenza virus constantly mutates, and because only a few changes can make a non-pathogenic virus highly pathogenic, we should assume that an outbreak of any new strain or subtype is potentially dangerous to humans."

Kawaoka and colleagues, who publish their findings today in Science, tested samples of H5N1 in mice, which respond to the virus much as humans do. Based on the lab animals' reactions, they divided the samples into two groups: highly lethal and relatively benign strains. Next they genetically engineered influenza viruses from scratch and started swapping into them one by one genes from the lethal and harmless viruses. In this way, they narrowed in on the key difference that made strains of H5N1 so dangerousnamely a single change in an RNA unit of the PB2 gene.

Scientists believe the PB2 gene may encode an enzyme that helps the virus force host cells to crank out more virus particles. "We don't know if the mutation we studied is involved in that process," Kawaoka adds, "but our next step will be to find out."