In a glass jar at the University of Zurich, a lung has been sitting in silence for more than a hundred years. Preserved in formalin, the organ belonged to an 18-year-old Swiss man who died during the first wave of the 1918 influenza pandemic. The Spanish Flu pandemic of 1918-1920 is estimated to have killed between 50 and 100 million people worldwide.
Now, this century-old lung is revealing the genetic story behind the flu that killed the patient.
Using cutting-edge RNA sequencing techniques, researchers have reconstructed the full genome of the influenza A virus (IAV) responsible for this particular strain of the Spanish Flu. What they found challenges long-held assumptions about how and when the virus evolved into one of the deadliest pathogens in human history.
“This is the first time we’ve had access to an influenza genome from the 1918 to 1920 pandemic in Switzerland,” said Verena Schünemann, a paleogeneticist at the University of Basel and senior author of the study, published in BMC Biology. “It opens up new insights into the dynamics of how the virus adapted in Europe at the start of the pandemic.”
A Viral Time Capsule
The 1918 flu pandemic—often called the “Spanish flu”—killed between tens of millions of people worldwide, with an unusually high toll among young adults. But for all its devastation, only a handful of viral genomes from that era have ever been sequenced. And until now, none were from the early phase of the pandemic in continental Europe.
That changed with specimen ZH1502: a lung stored in Zurich’s medical collection since July 15, 1918. Researchers extracted viral RNA from the lung using a newly developed ligation-based sequencing method, which is designed to recover even the most degraded RNA fragments. The protocol proved crucial. Unlike DNA, RNA degrades quickly—especially in tissues preserved in harsh chemicals like formalin.
“Ancient RNA is only preserved over long periods under very specific conditions,” said Christian Urban, the study’s lead author, in a press release. “That’s why we developed a new method to improve our ability to recover ancient RNA fragments from such specimens.”
The result was a complete, precisely dated genome from the early first wave of the pandemic in Europe—a rare and invaluable find.
Early Mutations Set the Stage for Disaster
What makes this genome especially remarkable is the story it tells about the virus’ evolution.
Previous thinking held that certain mutations—those that allowed the influenza virus to infect humans more efficiently—arose only later, as the pandemic accelerated during its deadly second wave in the fall of 1918. But the Zurich genome shows that some of the most important of these mutations were already in place in July.
“By July 1918, first wave viruses had already evolved several critical adaptations to their new human niche,” the researchers write.
Two of these mutations affected how the virus evaded MxA, a protein in the human immune system that blocks replication of avian-like influenza viruses. Another altered hemagglutinin, a surface protein that helps the virus latch onto human cells. This change made the virus better at infecting people—similar to how the SARS-CoV-2 virus evolved to bind more tightly to the ACE2 receptor during the COVID-19 pandemic.
All high-coverage second-wave genomes carry these mutations, indicating they gave the virus a clear advantage. The Zurich genome is the earliest to show all three.
A Broader Genetic Picture
The researchers compared the Zurich genome to others from Germany and North America. What they found paints a picture of surprising genetic diversity early in the pandemic.
Of the 35 differences between ZH1502 and a previously sequenced European genome (MU-162), 14 caused changes in viral proteins. The most variation appeared in the gene coding for a polymerase protein known as PB2, a segment of the virus critical for replication.
When researchers compared the 1918 virus to samples from the 2009 H1N1 flu pandemic, they found the older strain showed more genetic variation in several segments, including PB2 and hemagglutinin. This hints at rapid adaptation—and perhaps early reassortment between different viral strains.
“The fact that the same HA variant was found associated with clearly divergent other segments (especially in PB2) is a first hint at potential reassortment early in the pandemic,” the authors note.
Lessons for the Next Pandemic
By resurrecting this ancient genome, scientists have opened a new window into how pandemics evolve.
A better understanding of how influenza adapted to humans in 1918 helps us model future outbreaks. The team’s findings suggest that the virus began adapting sooner than previously thought—and that critical mutations were already spreading before the pandemic’s most lethal wave.
The study also raises the tantalizing possibility of what else might be hiding in historical tissue collections. With better methods for recovering ancient RNA, medical museums and pathology archives around the world could become invaluable resources for studying old—and possibly new—disease threats.
Countless lungs in jars may still have stories to tell.
