For a century, three glass jars with bleached lungs in spirits in the basement of the Charité hospital in Berlin kept their secret hidden. Until molecular virologist Sébastien Calvignac-Spencer of the neighboring Robert Koch Institute came to poke around.
His mission: to study the development of the H1N1 influenza virus, which caused the deadliest pandemic of the twentieth century, the Spanish flu, in 1918 and 1919.
Inside the glass jars were the lungs of two soldiers, aged 17 and 18, who had been struck down by the flu in Berlin in June 1918. And of a 17-year-old woman who died of the disease in Munich that year.
“Let’s start with that,” thought Calvignac-Spencer pragmatically. He wanted to better understand how that dangerous 1918 flu virus had developed.
The lids were removed from the jars, and Calvignac-Spencer obtained from each lung 200 milligrams of tissue mini-chunks infused with the fixative formalin. He also obtained material from two other preserved lungs from that time, from the Natural History Museum in Vienna. To his great delight, in his laboratory, he was able to extract the genetic material of the virus, the RNA, from it. This allowed him to map large pieces of the hundred-year-old virus. He even managed to unravel the complete genome of the 1918 virus from the lung of the woman from Munich – this had only been done twice before for this virus.
50 to 100 million dead
The study provides the most detailed look ever into the course of that catastrophic pandemic. The results show that the seasonal flu viruses H1N1 that continued to circulate in the years following the pandemic are direct descendants of the pandemic virus. The study appeared in the scientific journal on Tuesday Nature Communications†
“We were extremely lucky to have those rare lungs from 1918,” Calvignac-Spencer said at a press conference about his research. He didn’t expect much from the drill. “Most of the tissues from that era collected in museums are terribly difficult to work with. I really just wanted to do a first technical test. But the processing and analysis of the material went great from day one.”
The Spanish flu virus emerged all over the world in the spring of 1918, peaked in the fall of that year, and continued into the winter of 1919. An estimated 50 to 100 million people died from it, mostly healthy young people. At the time, people already suspected that this pandemic was caused by a virus. But it was not until 1933 before it became clear that it was an influenza virus, a flu virus. And it wasn’t until the late 1990s that molecular techniques were sufficiently developed that scientists were able to extract the virus from tissue samples kept in labs and from the lungs of flu victims buried in permanently frozen ground. It was only then that it was determined to be an influenza virus of type A, of the subtype H1N1.
We were very lucky with those rare lungs
Sébastien Calvignac-Spence, molecular virologist
Those studies yielded fragments of the genetic makeup of the virus that these people – sixteen in total – were infected with. The complete genetic sequence of a 1918 flu virus has only been determined twice before, the first time in 2005, from samples taken from deceased people in New York and Alaska.
Thanks to these studies, virologists had a sketchy picture of the origin of the pandemic virus, and of the evolution of the virus after the pandemic. But what happened during the first wave in the summer and the second wave in the fall of 1918 was still a mystery. One of the big questions was whether, just like now during the corona pandemic, new variants also continued to arise in the first year of the pandemic. And whether the virus only circulated in humans or whether it also mixed with other influenza viruses at some point in pigs. The new research shows that the answer to both questions is ‘no’.
No new variants
With virologist Thorsten Wolff, Calvignac-Spencer compared the new Berlin H1N1 viruses before the first pandemic peak with those of the previously found US viruses, from September and November 1918, and with samples before and after that time. In this way they could see which mutations had arisen during the course of the pandemic.
“We saw no evidence that new variants were displacing old ones in the first year of the pandemic, as we are now seeing with SARS-CoV-2 variants,” Calvignac-Spencer said. They also saw no major changes in the composition. Influenza viruses consist of eight components (subunits). All eight sub-units of the seasonal flu virus that continued to circulate after the pandemic were from the pandemic strain.
“The analysis clearly shows that those early pandemic viruses looked completely like bird flu viruses, and that it has not been genetically mixed with other flu viruses in pigs since the summer of 1918,” says Ron Fouchier, virologist at Erasmus MC in Rotterdam and not involved in the study. the study. “There was still some doubt about that. Pigs are a mixing vessel for flu viruses.”
Also read this interview: Evert Galama (104) survived the Spanish flu: ‘I wonder if you die the same way with corona’ (2020)
The H1N1 influenza virus still circulating today is not the same as that of 1918, Fouchier emphasizes. “That 1918 virus circulated until 1957, when it was displaced by a pandemic involving another type, H2N2. In 1977, the H1N1 virus, dating from 1918, returned to humans, probably through experiments with attenuated virus vaccines and exposure studies done on prisoners and soldiers in China and Russia. It circulated until 2009 after that. Then it was supplanted by the Mexican flu or swine flu. That’s also an H1N1 flu virus, that’s related to it, but a completely different virus. Five of the eight subunits of this flu virus have been replaced in the intermediate host, pigs, by components from other flu viruses.”
Adjusted
In one of the virus genes, the researchers did see a striking number of mutations in virus types later in the pandemic: in the enzyme that the virus needs to reproduce itself, polymerase. When they copied both versions in the lab and tested how efficiently they worked, they saw changes. “That indicates that the virus has adapted during the pandemic to optimize itself for the human population,” said co-author Wolff.
The authors hope to find even more samples that will help them characterize more viral genomes. “We were incredibly lucky to find this just around the corner from us,” says Calvignac-Spencer. “I have since written to 70 other pathology collections around the world and have only found one or two other specimens from that time.”
Read more about the history of the Spanish flu: The lesson of the Spanish flu: keep your distance!
A version of this article also appeared in the newspaper of 11 May 2022
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