Now, they've found viral DNA of an ancient strain of smallpox in Viking Age archaeological remains from northern Europe.
The samples, dated at the earliest to 603 CE, provide definitive genetic evidence that smallpox was around 1,000 years earlier than our previous best records.
Certain features of the ancient virus also suggest it was widespread well before the 20th century, where it caused as many as 500 million deaths.
Caused by the variola virus (VARV), smallpox remains the first and only disease we've managed to eradicate in humans with the use of vaccination - that victory was finally declared in 1980.
The spread of smallpox can be traced through history. It was with the Moors when they invaded Spain and Portugal in the 8th century and later spread into Europe during the Crusades.
It also plagued the Egyptian and Hittite empires. A smallpox-like rash found on the ancient Egyptian mummy Ramses V, who died in 1157 BCE, suggests smallpox was around some 3,000 years ago or more.
Those observations are nowhere near conclusive, not like actual viral DNA, and likewise other written records describing early smallpox-like infections can be ambiguous. Earlier, tangible evidence is hard to find.
Current thinking suggests smallpox originated several thousand years ago in rodents somewhere in Africa before it jumped across to people, though scientists still can't be sure; they're only working backwards from the samples we have.
Knowing how ancient smallpox viruses and modern strains are related could also help researchers to work out how smallpox evolved to be so deadly. Either way, it means getting their hands on more ancient viral DNA samples.
Before this latest discovery, the earliest DNA evidence we had was from a 17th-century Lithuanian mummy (discovered by accident) and two specimens from the 19th and 20th centuries held in the Czech National Museum. Comparison of the DNA in those specimens to samples of the modern smallpox virus dates their most recent common ancestor to between 1530 and 1654 CE.
Virologist Barbara Mühlemann, from the University of Cambridge's Centre of Pathogen Evolution, and colleagues went looking for traces of ancient smallpox in the archaeological remains of nearly 1,870 individuals who lived in Eurasia and the Americas up to 31,000 years ago.
"Ancient virus sequences recovered from archaeological remains provide direct molecular evidence for past infections and can reconcile the discrepancy between the written historical record of possible early infections and the time to the oldest available genetic sequences," the team explained in their paper.
Their shotgun sequencing approach recovered fragments of ancient viral DNA (aVARV) related to modern smallpox from the bones and teeth of 26 long-deceased northern European individuals. Thirteen folks had enough viral DNA material for deeper sequencing, and eleven of those were dated to the Viking Age, between 603 and 1050 CE.
Of those 11 samples, the team reconstructed near-complete viral genomes (representing at least 96 percent of the virus's full sequence) from just four human remains. But it was enough to get the evidence they were after.
"The Viking Age sequences reported here push the definitive date of the earliest VARV infection in humans back by ~1,000 years and reveal the existence of a previously unknown, now-extinct virus clade," the authors said.
"The dating of the aVARV samples, from as early as 603 CE, matches that of multiple written accounts of likely smallpox infections in southern and western Europe from the late 6th century onwards."
This result also backs the going theory that smallpox first originated in rodents - the ancient viral samples were actually more closely related to a taterapox virus, another virus from the same poxvirus family that infects gerbils, than the modern smallpox virus.
The now-extinct aVARV had a few extra genes that the modern smallpox lacked. These genes are found in other less harmful poxviruses and could have helped aVARV infect a variety of animal hosts, according to virologist Antonio Alcamí from the Severo Ochoa Centre for Molecular Biology in Madrid.
"Maybe ancient VARV evolved as a relatively common zoonosis that caused mild infection in humans, rodents, and perhaps other hosts for centuries," he said in a commentary about the new discovery.
The researchers aren't so sure. The now-extinct ancient virus was widespread across northern Europe, but not much can be said about its severity from DNA alone. "We cannot be sure that the individuals died as a result of their infections," the authors noted.
They observed diverse patterns of gene inactivation among the ancient viruses detected in their study, and only go so far as to conclude that they "existed over a period of at least ~450 years and circulated widely among humans during the Viking Age."
The research was published in Science.