Darío Ramirez processes a pathological human bone in the ancient DNA facility of the Max Planck Institute for Evolutionary Anthropology.
In 1495, a devastating infection began to sweep across Europe, causing pustules and sores to erupt on people's bodies and faces. Accusatory finger-pointing about the scourge, syphilis, began almost immediately. The Italians called it "the French disease"; the French called it "the Neapolitan disease"; the Russians called it "the Polish disease."
The sexually transmitted disease remains a public health menace today, despite the fact that it is easily cured with antibiotics. But the scientific debate still rages about the ancient origins of syphilis -- including why the wave of illness that swamped Renaissance Europe was so virulent.
Did syphilis initially emerge in the Americas and arrive in Europe in early 1493 when explorer Christopher Columbus returned to Spain, in the reverse of so many other illnesses that wiped out Indigenous peoples? Or was it a much older "pre-Columbian" disease that has been infecting humanity much longer -- one that flew under the radar, perhaps mistaken for leprosy or another ailment in Medieval Europe?
In a study published last week in the journal Nature, an international team studied ancient DNA harvested from lesion-ridden bones or teeth of five people who lived in Peru, Chile, Argentina and Mexico either before or around the time of Columbus. They found that early versions of the microbe, Treponema pallidum, that causes syphilis and related diseases were already diverse and widespread. Their analysis suggests that syphilis emerged in the Americas within the last 8,000 years and spread across the globe fueled by European colonization.
"The syphilis debate was a big one, and it was a very emotional one ... a famous paleopathologist described it as one of the most enigmatic questions in science," said Kirsten Bos, group leader for molecular paleopathology at the Max Planck Institute for Evolutionary Anthropology and one of the leaders of the work. She argued the new evidence would settle the matter. "It's a very clear slam dunk: OK, this clearly came from the Americas."
Several outside researchers agreed the study provides valuable new evidence strongly suggesting an American origin for syphilis, but added that it wouldn't close the debate.
"This paper, by being able to anchor when and where it emerged, is going to be fundamental in improving our basic knowledge of syphilis, and therefore act as building a foundation for additional work," said Molly Zuckerman, a paleopathologist at Mississippi State University.
Tracking the 'great imitator'
Today, syphilis and other treponemal diseases caused by subspecies of the same bacteria -- including the neglected tropical diseases, yaws and bejel -- remain a public health threat. There are more than 8 million new infections of syphilis a year globally. Yaws, a disfiguring skin disease caused by closely related bacterial infection, is endemic in 15 countries.
These illnesses are treatable with antibiotics today, but Zuckerman sees understanding how these diseases emerged as key to unlocking a present-day mystery: Why is syphilis so variable in its symptoms today -- which helps it to go undiagnosed and untreated?
For decades, the major tool scientists had to probe these ancient questions were examinations of skeletal remains. Syphilis is a disfiguring illness that damages organs and causes neurological problems in the long run, but it also leaves marks on a person's skeleton, including pitted bones.
Scientists have found evidence of ancient skeletons with such lesions in the Americas. But there were also some accounts of "venereal leprosy" from Medieval Europe and European skeletons have been unearthed with bone-scarring that resembles syphilis, lines of evidence that suggested it may have already been in Europe. The disease is sometimes called the "great imitator" because its symptoms can be so similar to others.
The science of ancient DNA opened up new opportunities to go beyond interpreting lesions and pin down the evolutionary history of syphilis.
It is particularly hard to get ahold of the microbe, Treponema pallidum, that causes the disease in ancient samples, said Anne Stone, an anthropological geneticist at Arizona State University. That makes the new study featuring ancient genomes especially exciting -- though she said the results also raise new puzzles.
Syphilis-like diseases
The researchers recovered ancient DNA from bacteria that are the extinct precursors of the microbe that causes modern-day syphilis, as well as bejel and yaws.
They used those genomes to estimate when the most recent ancestor to Treponema pallidum emerged, and found that it was 8,000 years ago. That fits best with a New World origin for this group of diseases. But Stone questioned whether that date might get pushed back as more ancient genomes are found, pointing out that much of the world is a black box with a lack of samples to say whether the disease existed or not. She noted that the turn of the 15th century was a time when people were roving the world.
"It's not just the Americas that we're 'discovering' -- it's also a time when people are exploring the world in general and going to all sorts of places -- and it's basically a bunch of lonely sailors on a boat. There's the various trade routes, and we have no ancient DNA from the rest of the world on this pathogen," she said. "This study is great, in the sense we have more data and more genomes."
A study of ancient DNA from Trepenoma pallidum infections published in Nature in January -- which is currently under editorial review because questions have been raised about its data and conclusions -- found a timeline that was earlier and which could have placed the emergence of syphilis-like diseases before people arrived in the Americas, suggesting it would have already been in Europe before Columbus voyaged back.
Kerttu Majander, an archaeogeneticist at the University of Basel who led that study, said the new work shows unprecedented diversity of disease-causing bacteria in the Americas, making it clear Columbus didn't bring them to the Americas. But the question of whether there were already treponemal diseases already in Europe in some form "cannot be really proved or disproved" by this data.
Another outstanding question is why the version of the disease that swept Europe was so severe. Ancient genomes from Europe have shown that Treponema pallidum was present during the late 15th century -- including yaws and syphilis. But the uncertainties around dating the skeletons makes it impossible to know whether these specimens were from before or after Columbus.
Understanding the differences between the subspecies that cause these different, but related diseases is a key question for scientists trying to understand these diseases today.
"This could tell us more about why these diseases (syphilis, yaws, bejel) have such different disease presentations, and if we can find ways to optimise treatment and patient management as a result. The Origins (of syphilis) are only important if they can help answer that question," Mathew Beale, a senior staff scientist who studies bacterial evolutionary genetics at the Wellcome Sanger Institute, wrote in an email. He added that as is so often the case in science, the story is likely far from settled: "It is plausible that each set of new genomes will change things, repeatedly reopening the story."