As the novel coronavirus pandemic reshapes lives and entire economies, historians tell us this is not the first time. The earliest written records of tiny infectious organisms overhauling human societies stretch back as far as the Plague of Justinian in A.D. 541, which is thought to have killed up to 50 million people, or even the earlier Antonine Plague in A.D. 165, which left 5 million dead, a substantial portion of the world then.

Now, paleogenomics — a nascent field that studies DNA in remnants of ancient teeth — is rewriting the first chapter of humanity’s entanglement with disease to thousands of years older than originally thought. The growing evidence suggests that these first epidemics forced societies to make epoch-defining transformations.

“In the case of covid-19 [the disease caused by the coronavirus], we see similar processes, but we are watching it unfold in real time,” said Anne Stone, regents professor in the School of Human Evolution and Social Change at Arizona State University, whose focus is anthropological genetics. She also has studied evidence of tuberculosis in ancient DNA.

Hannah Jewell looks back at plague and yellow fever outbreaks in Europe and New Orleans, which revealed stark divides between the rich and poor. (The Washington Post)

Paleogenomics, which adapts high-end medical tools similar to some now being used to track the coronavirus, has amounted to a “revolution” in understanding disease history, says Maria Spyrou, a microbiologist at the Max Planck Institute in Germany.

“This is one of the things that we can now start saying,” said Spyrou, adding that where historical records are lacking, DNA evidence offers the possibility of filling in gaps, sometimes in surprising ways.

“One of them is plague,” Spyrou said. “Until 2015, we thought that plague was maybe a 3,000-year-old disease.”

Scientists and archaeologists now believe, however, that the plague bacteria, which caused the medieval Black Death that killed up to half of Europe’s population, infected humans roughly 5,000 years ago in the Stone Age. The bacteria, after it had entered the bloodstream and likely killed the host, circulated into the pulp chamber of teeth, which kept its DNA insulated from millennia of environmental wear and tear. In the past decade, scientists have been able to extract and analyze that DNA.

Stone Age plague

The Stone Age plague was, however, an ancestor with a slightly different genetic identity. Tracking how those differences evolve helps infectious-disease biologists better understand what causes disease and how to prepare for current outbreaks. The plague bacteria in the Stone Age, for example, lacked the genes necessary to jump from fleas to humans, which likely spread the Black Death widely. Without the flea gene, the disease probably used another animal transmitter that came into contact with humans. In 2018, a University of Copenhagen team published the first evidence, based on early data three years before, that the ancient plague bacteria, found in a Swedish settlement, had the power to kill and may have threatened life in the age’s “mega-settlements” that could spread diseases quickly.

“It probably was the first pandemic,” said Simon Rasmussen, a genomicist at the university and lead researcher on the plague study. In the Stone Age, also called the Neolithic period, humans made unprecedented moves to gather in large settlements with up to 10,000 people in close quarters with animals and virtually no sanitation. “It’s the textbook place of where you could have a new pathogen,” he said.

Paleogenomics has also allowed archaeologists to fill in one of the biggest silences in the archaeological record: disease. Pathogens rarely leave traces on bones, and populations without writing could die out without any readable record of the cause. With the ability to read traces of DNA preserved in teeth, historians are learning about the organisms inside ancient humans.

Kristian Kristiansen, a University of Copenhagen archaeologist and a co-author of the plague study, believes his group’s research illuminates the causes of a Stone Age demographic transformation, called the Neolithic decline, which archaeologists have long studied.

Settlements at the time were disappearing faster than they were appearing, and within a few hundred years, most of the population had been replaced by migrants from the Eurasian Steppe. Researchers had only ever hypothesized that disease may have played a role in crippling the native population before it was overtaken, but now they have evidence, Kristiansen says.

Changing history

“The steppe migrations would not have succeeded without the plague . . . and [those living in what is now Europe] would not all have spoken Indo-European languages,” Kristiansen said. “Later prehistory has been turned upside down to say the least.”

In 2018, a paleogenomics team analyzed ancient teeth from Neolithic sites in present-day Germany and discovered the hepatitis B virus stretched back at least 7,000 years. Another study the same year extended our knowledge of the history of parvovirus B19 from a few hundred years to 6,900 years. Parvovirus B19 causes a mild rash in humans and leads to outbreaks in the United States every few years

In February, researchers at the Massachusetts Institute of Technology published evidence that types of Salmonella bacteria, which sicken about a million people in the United States every year, were afflicting humans 6,500 years ago. Microbiologist Felix Key identified Salmonella DNA in teeth recovered from burial sites near the Volga River in present-day Russia, where archaeological evidence has shown that humans began to abandon foraging for pastoral living. The Salmonella DNA in their teeth is the first evidence, Key says, that the adoption of this lifestyle in close contact with animals may have introduced pathogens to humans.

“This ancient DNA could give us the means to prove or disprove the hypothesis that the Neolithic revolution was the major event for introducing diseases into humans,” said Key, who is now at the Max Planck Institute for the Science of Human History. “My hunch is that it did facilitate the disease, because humans and animals were co-housed.”

Like many paleogenomicists, Key uses dentist tools and dons what looks like a hazmat suit that blocks possible DNA contamination from teeth recovered from settlements thousands of years older than the Roman Empire.

DNA extraction methods

New methods of extracting DNA that were developed for medical purposes have made paleogenomics possible in the past decade. After using dentist tools to recover and pulverize material locked inside a tooth, molecular biologists use a technique called “shotgun sequencing” to extract all genetic material without needing to know what to look for. Decrypting the data then requires that bioinformatic specialists can match the genetic identities to known pathogens. As the disease database grows, it becomes easier to identify signals from noise. Archaeologists then have the task of putting human disease into historical context.

The process is expensive, and it’s dominated by labs in Europe with equipment and funding. Conducting a complete survey of teeth can cost upward of $1 million. That depends, still, on a team’s good fortune in finding enough ancient teeth that have experienced the right conditions over millennia to preserve pathogen DNA. In the study of the Salmonella bacteria, Key’s team analyzed 3,000 samples and found just eight with preserved Salmonella bacteria.

Rasmussen, of the Copenhagen plague study, said that, while he is fairly certain his team’s evidence describes the oldest human pandemic, more DNA samples must be found and analyzed. The DNA used in his study come from just one small settlement in the area of modern-day Sweden. To prove a pandemic, Rasmussen said, scientists will need to find DNA evidence in some larger sites — in other parts of Europe.

Even so, Stone said, paleo­genomics has shown that humans have been in “an arms race with pathogens” for thousands of years.

“Periodically, pathogens jump into humans,” she said, “and it’s really easy to become complacent when you don’t happen to have a pathogen affecting large segments of your population at the moment. But you let those resources go at your peril, which we’re seeing right now.”