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Measles Diverged from Cattle-Infecting Relative Earlier than Thought

autopsy report from 1912 measles case
Autopsy report for 1912 measles case archived by the Berlin Museum of Medical History. | Navena Widulin/Berlin Museum of Medical History at the Charité

The measles virus diverged from a closely related cattle-infecting virus in approximately the sixth century BCE — around 1,400 years earlier than current estimates — according to a new study of dozens of measles genomes published in the June 18 issue of Science.

The results paint a new portrait of the evolutionary history of the measles virus, showing that the pathogen emerged far earlier than previously suspected by scientists. The discovery also implies that measles began to circulate among human populations at a time that coincided with the rise of large urban centers throughout Eurasia and South and East Asia.

As one of humanity's oldest microbial foes, the measles virus has been a major target not only for health authorities but for scientists who study the evolutionary paths of common human pathogens. Measles has been described and studied in texts going as far back as the 10th century CE, when the Persian physician Rhazes described one of the first clinical cases of the disease.

Modern-day researchers suspect that the measles virus emerged when its relative rinderpest, an eradicated cattle-infecting virus, spilled over from cows into human populations, according to the study. However, there is still a lot of uncertainty about when this divergence took place in history.

"We were interested in the origins of measles because there was no established consensus," said Sébastien Calvignac-Spencer, a scientist at the Robert Koch Institute in Berlin, Germany and senior author of the new study. "People agreed that it could only have emerged after the Neolithic transition — the rise of large settlements based on agriculture — because [the virus] needed large human populations to persist."

Calvignac-Spencer added that earlier estimates based on molecular clocks — scientific models of genetic changes that estimate when two species diverged — all gave relatively recent dates, with the most reliable estimate pegging the event to around the year 899 CE. However, many researchers suspected those dates were significantly underestimated due to shortcomings in molecular dating methods.

Ariane Düx, a Ph.D. candidate at the Robert Koch Institute and lead author of the new study, and colleagues had previously been searching for specimens of respiratory viruses such as the 1918 flu strain. While going through the basement of the Berlin Museum of Medical History, the scientists came across lung samples from a two-year-old girl who perished from measles in 1912.

"When we found this specimen, we immediately thought about the question of the origins of the disease," said Calvignac-Spencer. Older genomes of viruses can allow scientists to more accurately trace the pathogen's evolutionary path, meaning these new samples could offer fresh insight into the origins of measles.

Excited by their discovery, the team performed genetic sequencing on the lung samples of the 1912 case, and successfully reconstructed most of the genome of that particular measles virus. But they still needed more genetic information, so they searched for other, more recent strains of measles they could use as comparisons.

Eventually, the researchers uncovered and determined the genomes of two other strains of measles that had been isolated in 1960. They also assembled a catalog of 127 modern measles genomes as a reference point for their later experiments.

The scientists then harnessed various evolutionary and molecular clock models, using them to compare and contrast differences between the 1912 and 1960 genomes, the modern measles genomes, and genomes from rinderpest and another related cattle virus named peste des petits ruminants virus.

Eventually, they managed to trace the divergence of measles from rinderpest to a period of time between the years 1,174 BCE and 165 CE, with a mean estimate of 528 BCE, according to the study.

Importantly, the new estimate doesn't necessarily mean that measles first infected humans at the same time that it diverged from rinderpest, according to Calvignac-Spencer. Rather, the results extend the possible range for the emergence of measles earlier in time, and suggest that the virus could have emerged at an average of around 1,400 years earlier than previously thought.

One of the study's major implications is that the emergence of measles was closely tied to the rise of large cities in the late first millennium BCE. Before then, human settlements in the Neolithic, Bronze, and Iron ages were simply too small to support the transmission of measles, said the authors.

However, societal and technological advances meant that by the late first millennium BCE, human cities surged in size in Europe, China, India and other regions. Calvignac-Spencer noted that urban centers such as Babylon, Athens, and Rome began to surpass the minimum populations of 250,00 to 500,000 people needed to sustain measles transmission by around 300 BCE, soon after his team's divergence estimate.

The authors therefore speculate about a scenario where a bovine virus ancestor circulated among cattle for thousands of years, before jumping to humans once societies had grown in complexity. After the sixth century BCE, large outbreaks such as the plague of Athens could have been caused by the emergence of measles, they theorize.

The topic of viral evolution may also raise questions about the study's relevance to emerging diseases, such as the ongoing COVID-19 outbreak. However, as each pandemic is unique, Calvignac-Spencer cautions that the results can't directly inform how we understand SARS-CoV-2 and other emerging viruses.

In future research, the team plans to analyze other measles specimens from the first half of the 20th century, according to Calvignac-Spencer. They're interested in studying how the diversity of the measles virus changed during the first large-scale vaccination campaigns in the 1960s, and are also working on an ongoing project based on genomes of the 1918 flu pandemic.

"Our study will probably help others realize that pathology collections are an amazing and largely untapped resource to study ancient pathogens, and particularly RNA viruses," said Calvignac-Spencer.

[Credit for related image: preserved lung from 1912 measles patient. | Navena Widulin/Berlin Museum of Medical History at the Charité]