What Have We Learned by Resurrecting the 1918 Influenza Virus?

The 1918 Spanish influenza pandemic was one of the deadliest infectious disease events in recorded history, resulting in approximately 50-100 million deaths worldwide. The origins of the 1918 virus and the molecular basis for its exceptional virulence remained a mystery for much of the 20th century because the pandemic predated virologic techniques to isolate, passage, and store influenza viruses. In the late 1990s, overlapping fragments of influenza viral RNA preserved in the tissues of several 1918 victims were amplified and sequenced. The use of influenza reverse genetics then permitted scientists to reconstruct the 1918 virus entirely from cloned complementary DNA, leading to new insights into the origin of the virus and its pathogenicity. Here, we discuss some of the advances made by resurrection of the 1918 virus, including the rise of innovative molecular research, which is a topic in the dual use debate.