Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska, that significant genetic research was made possible.

Though initial data from a recent reconstruction of the virus suggested that it jumped directly from birds to humans, without traveling through swine,[a] this has since been cast into doubt.

[5] In 1995, Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP), wondered if it might be possible to recover the virus of 1918 flu pandemic from the dried and fixed tissue of victims.

Taubenberger, Ann H. Reid and Thomas G. Fanning were able to amplify short segments of the viral nucleic acid using polymerase chain reaction (PCR).

[7] On August 20, 1997, Johan Hultin recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska.

The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects.

[13] These were subsequently used to experimentally infect mice, ferrets, and macaques giving valuable insights into influenza virus biology and pathogenesis, providing important information about how to prevent and control future pandemics.

In December 2008, research by Yoshihiro Kawaoka of University of Wisconsin showed the presence of the three specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from the H1N1 1918 flu samples was enough to trigger similar symptoms in animal testing.

[23] On 18 January 2007, Kobasa et al. reported that infected monkeys (Macaca fascicularis) exhibited classic symptoms of the 1918 pandemic and died from a cytokine storm.

Another important factor is the change of the HA protein to a binding preference for alpha-2,6 sialic acid (the major form found in the human respiratory tract).

[25] In the worldwide 1918 flu pandemic, "physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci).