Viking Age smallpox complicates story of viral evolution

The evolution of the deadliest virus in human history — smallpox — is only partly understood. Like the novel coronavirus and many other disease-causing viruses, smallpox seems to have originated in animals, probably rodents, and spilled over to humans, probably thousands of years ago. In the 20th century alone it killed hundreds of millions of people.

Until now, the earliest confirmed case of smallpox had been found in the mummified remains of a Lithuanian child from the 17th century. On Thursday, an international team of researchers pushed that date back 1,000 years, reporting in the journal Science that they had recovered smallpox DNA from the remains of people in northern Europe in the Viking Age.

The virus they found is now extinct and has not been found in other, more recent skeletal remains. It is not an ancestor of the modern smallpox virus but an evolutionary dead end. It has more genes than the modern virus, and scientists have observed that among the many different pox viruses in nature, fewer genes tend to mean a more deadly virus. Putting those facts together caused one prominent smallpox specialist to suggest that the modern virus might have become more deadly as it evolved. Most viruses become less deadly over time.

Pox viruses are not closely related to coronaviruses, and the research has no direct application to the current spread of the novel coronavirus. But in the midst of a pandemic, even the thought of some viruses evolving to be more deadly is decidedly uncomfortable.

The early date of the new smallpox virus, experts said, is significant but not surprising. Like other pox virus experts, the authors think that although DNA evidence is so far lacking, smallpox almost certainly goes much further back in time.

Terry Jones, who studies the evolution of disease-causing organisms at the University of Cambridge and was one of the senior authors, said that, judging by historical sources, “it seems quite likely that the virus was around in, let’s say, India or maybe China 1,000 or 1,500 years before the Common Era.”

What was most intriguing about the find, Jones said, was the genetic makeup of the smallpox virus recovered from the bones of 11 people who lived between 600 and 1050 and the fact that the old viral strain is now extinct. The modern version, as the authors call it, was eradicated from the human population by 1980.

The Latin name of the smallpox virus is Variola, and other strains of Variola are known. Variola minor, which was eradicated along with smallpox (Variola major), caused a mild illness with less than a 1% death rate, whereas smallpox killed about 30% of those it infected. Why it was less lethal is not known.

The differences in the Viking variant are significant enough for the virus to make up a new group, or clade, of Variola. It is not an earlier version of the modern virus. Both modern smallpox and the newly discovered variant descended from a common ancestor but diverged at least 1,700 years ago. Jones said, “The Viking viruses were on a different evolutionary path that could not have led to the modern viruses.”

Klaus Osterrieder, a pox virus specialist at the City University of Hong Kong who was not part of the research, said that the analysis of the Viking virus and the establishment of a new clade was quite convincing.

The genetic details of the Viking virus are what prompted speculation that perhaps the smallpox virus may have become more deadly. Barbara Mühlemann, also a virologist at Cambridge and the first author on the paper, said that the general understanding of pox viruses is that the ones with fewer genes directed at deceiving the immune system of a host are actually more deadly. The reason is not clear, although with viral infections, a very strong immune reaction is often what kills the victim.

“The pattern that we’ve seen in the paper,” she said, “is that there has been a loss of genes over time” in the modern smallpox virus compared to the Viking virus, which had more active genes than the modern virus. But, she cautioned, she and her colleagues have no direct evidence that the Viking version of the virus was less deadly.

Antonio Alcami, a smallpox specialist at the Autonomous University of Madrid, wrote a commentary in the same issue of Science raising the hypothesis that smallpox actually evolved to become more deadly.

He said that the standard view of viral evolution, in which viruses become less virulent, might not always be true. Variola virus evolved in humans over time. “Maybe it was a mild disease for a while,” he said.

That idea has been suggested before, Jones said, by historians who proposed that smallpox may once have been a relatively benign illness.

The way this kind of evolution might have happened is “counterintuitive,” Alcami said. The genes that are inactivated in modern smallpox and other deadly pox viruses are ones that help weaken or evade immune responses of the infected host. But why lose those genes, since they should help a virus?

Somehow, loss of those genes seems to help the virus, Alcami said. Perhaps with fewer active genes the virus may replicate faster and therefore improve its chances of transmission to another person, even though it is provoking an out-of-control immune reaction, which in the end is what kills the host. He emphasized that he was raising the idea only as a hypothesis to promote discussion and further investigation.

Osterrieder said that even though the idea was still speculative, he thought it made sense. “I think it’s a very compelling hypothesis,” he said.

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