Scientists sequence the full Black Death genome and find the mother of all plagues

By Ed Yong | October 12, 2011 1:00 pm

This is an updated version of an old piece, edited to include new information. Science progresses by adding new data to an ever-growing picture. Why should science writing be different?

The road of East Smithfield runs through east London and carries a deep legacy of death. Two cemeteries, established in the area in the 14th century, contain round 2,500 of bodies, piled five deep. These remains belong to people killed by the Black Death, an epidemic that killed between 30 and 50 percent of Europe in just five years. It was one of the biggest disasters in human history and seven centuries on, its victims are still telling its story.

In the latest chapters, Verena Schuenemann from the University of Tubingen and Kirsten Bos from McMaster University have used samples from East Smithfield to reconstruct the full genome of the bacterium behind the Black Death. This species – Yersinia pestisstill causes plague today, and the modern strains are surprisingly similar to the ancient one.

Compared to the strain that acts as a reference for modern plague, the ancient genome differs by only 97 DNA ‘letters’ out of around 4.6 million. Y.pestis may not be the same bacterium that butchered medieval Europe 660 years ago, but it’s not far off. Indeed, Schuenemann and Bos found that all of the strains that infect humans today descended from one that circulated during the Black Death. Even now, people are still succumbing to a dynasty of disease that began in the Dark Ages.

The Black Death is supposedly the second of a trilogy of plague pandemics. It came after the Plague of Justinian in the sixth to eighth centuries, and preceded modern plague, which infects some 2,000 people a year. But some scientists and historians saw features in the Black Death that separates it from other plague pandemics – it spread too quickly, killed too often, recurred too slowly, appeared in different seasons, caused symptoms in different parts of the body, and so on.

These differences have fuelled  many alternative theories for the Black Death, which push Y.pestis out of the picture. Was it caused by an Ebola-like virus? An outbreak of anthrax? Some as-yet-unidentified infection that has since gone extinct? In 2000, Didier Raoult tried to solve the debate by sequencing DNA from the teeth of three Black Death victims, exhumed from a French grave. He found Y.pestis DNA. “We believe that we can end the controversy,” he wrote. “Medieval Black Death was plague.”

Raoult was half-wrong. The controversy did not end. Some people argued that it’s not clear if the remains came from Black Death victims at all. Meanwhile, Alan Cooper analysed teeth from 66 skeletons taken from so-called “plague pits”, including the one in East Smithfield. He found no trace of Y.pestis. Other teams did their own analyses, and things went back and forth with a panto-like tempo. Oh yes, Y.pestis was there. Oh no it wasn’t. Oh yes it was.

In 2010, Stephanie Haensch served up some of the strongest evidence that Y.pestis caused the Black Death, using DNA extracted from a variety of European burial sites. Schuenemann and Bos bolstered her conclusion by taking DNA from bodies that had been previously exhumed from East Smithfield, and stored in the Museum of London. “We sifted through every single intact skeleton and every intact tooth in the collection,” says Bos. They extracted DNA from 99 bones and teeth and found Y.pestis in 20 of them.

Schuenemann and Bos took great care to ensure that their sequences hadn’t been contaminated by modern bacteria. Aside from the usual precautions, they did all of her work at a facility that had never touched a Y.pestis sample, they had the results independently confirmed in a different lab, and they found traces of DNA damage that are characteristic of ancient sequences. They also failed to find any Y.pestis DNA in samples treated in exactly the same way, taken from a medieval cemetery that preceded the Black Death. Finally, it’s clear that the people exhumed from East Smithfield did indeed die from the Black Death – it’s one of the few places around the world that has been “definitively and uniquely” linked to that pandemic.

Even though they had its DNA, deciphering the ancient bacterium’s genome was difficult. The DNA was so heavily fractured that Schuenemann and Bos only managed to extract enough from four of their teeth. They lined up the fragments against a modern plague genome, and looked for overlaps between the remaining stragglers. In the draft that they’ve published, every stretch of DNA has been checked an average of 28 times.

By comparing this ancient genome with 17 modern ones, and those of other related bacteria, Scheuenemann and Bos created a family tree of plague that reveals the history of the disease. They showed that the last common ancestor of all modern plagues, lived between 1282 and 1343 before it swept through Europe, diversifying as it went. The East Smithfield strain was very close to that ancestral strain, differing by only two DNA letters.

This raises some questions about the plague of Justinian. The team think that it was either the work of an entirely different microbe, or it was caused by a strain of Y.pestis that is no longer around and likely left no descendants behind. It was the supposed second pandemic – the Black Death – that truly introduced Y.pestis to the world. This global tour seeded the strains that exist today.

By the time it hit East Smithfield, the plague was already changing. Schuenemann and Bos found that one of their four teeth harboured a slightly different version of Y.pestis, which was three DNA letters closer to modern strains than the other ancient ones. Even in the middle of the pandemic, the bacterium was mutating.

In the intervening centuries, Y.pestis has changed but not by much. None of the few differences between the ancient and modern genomes appear in genes that affect how good the bacterium is at causing diseases. None of them can obviously explain why the Black Death was so much more virulent than modern plague. “There’s no particular smoking gun,” says Hendrik Poinar, who was one of the study’s leaders.

That’s somewhat anticlimactic. In August, Poinar told me: “We need to know what changes in the ancient [bacterium] might have accounted for its tremendous virulence… There is really no way to know anything about the biology of the pathogen, until the entire genome is sequenced.” Now that the full genome is out, it seems to offer precious few clues.

Instead, the team thinks that a constellation of other factors might have made the Black Death such a potent pandemic. At the time, medieval Europe went through a drastic change in climate, becoming colder and wetter. Black rat numbers shot up, crops suffered and people went hungry. “It’s hard to believe that these people living in 1348 London weren’t being infected by various viruses,” says Poinar. “So you probably had an immune compromised population living in very stressful conditions, and they were hit by Y.pestis, maybe for the first time.” They were both physically and culturally unprepared. Their immune systems were naive, they didn’t know what the disease was, and they didn’t know how to treat or prevent it.

In later centuries, it was a different story. Medical treatments helped to cope with the symptoms and affected people were quickly quarantined. Today, we have antibiotics that help to treat plague, and these would be effective against the Black Death strain. We have evolved too. People who were most susceptible to plague were killed, which probably left the most resistant survivors behind. Next, Poinar wants to look at the DNA of people buried in pre-plague and post-plague cemeteries to see if the Black Death had altered our own genome.

Sequencing the Black Death genome may not tell us about why it was so deadly, but it still reveals how the bacterium evolved. Now, Schuenemann and Bos can look at how Y.pestis transformed from a bacterium that infects rodents to one that kills humans and how it evolved over time. That knowledge could be very important, especially since plague is rebounding as a “re-emerging” disease.

The Black Death strain is the second historical pathogen whose genome has been sequenced and certainly the oldest (the first was the 1918 pandemic flu). There are many others to look at, including the Justinian plague strain, and historical versions of tuberculosis, syphilis and cholera.

In the meantime, the East Smithfield bodies have told their story and Bos and Schuenemann are letting them rest. They were very careful with the teeth that they yanked DNA from, and they are now returning these samples to the Museum of London. Having yielded their secrets, they’ll be stuck back into their old skeletons.

Reference: Bos, Schuenemann, Golding, Burbano, Waglechner, Coombes, McPhee, DeWitte, Meyer, Schmedes, Wood, Earn, Herring, Bauer, Poinar & Kruase. 2011. A draft genome of Yersinia pestis from victims of the Black Death. Nature http://dx.doi.org/10.1038/nature10549

Schuenemann, Bos, deWitte, Schmedes, Jamieson, Mittnik, Forrest, Coombes, Wood, Earn, White, Krause & Poinar. 2011. Targeted enrichment of ancient pathogens yielding the pPCP1 plasmid of Yersinia pestis from victims of the Black Death. PNAS http://dx.doi.org/10.1073/pnas.1105107108

PS Oddly, the team’s new paper, where they publish the full Black Death genome, somewhat refutes their first one, where they had only sequenced fragments. Previously, they identified two mutations in the ancient DNA that weren’t seen in any other strain. But those two mutations aren’t there in the full genome, and it now seems that they were a mistake. Ancient DNA can be chemically damaged so that Cs change into Ts. That’s probably what happened in the previous study. Schuenemann and Bos are more confident that their new sequences are correct. They treated their samples with a method that repairs the C-to-T changes, and they went over every bit of DNA 30 times.

Image: Skeletons from the Museum of London;

Comments (12)

  1. PSP

    One of the most fascinating topics, and best posts I’ve seen recently. Kudos, and thanks.

  2. Gil

    Has there been research to see if a phage or plasmid could be responsible for the differences in mortality between strains?

  3. @Gil – Yes! That was in their earlier paper but got lost in the edit. Here’s what I wrote about it last time:

    Many of the Y.pestis sequences came from a plasmid – a ring of DNA that sits apart from the bacterium’s main genome. This one, known as pPCP1, is responsible for many of the features that set Y.pestis apart from its close relatives and contains many of the genes that allow it to grow in human hosts, and spread to new ones. However, pPCP1 wasn’t responsible for the unique nature of the Black Death – the Smithfield sequences were no different to those of modern strains.

  4. Michelle

    Fascinating. What is scary is that we don’t know what our current climate changes will yield, especially with people in such complete denial!

  5. Rich

    It’s worth mentioning that human European habitations were infested with rodents and fleas during that time period which is uncommon today even in poor households thanks to modern construction standards.

    Also, some Europeans kept dogs which also could harbor the disease vector [fleas]. In contrast, cultures west of Europe were less likely to have flea problems and also more likely to have cats which also reduce flea problems by their rodent hunting activites. Oddly, cats were ‘taboo’ in Europe as pets for a very long time. Most likely just because they didn’t have functional farming uses, and also due to superstition.

    One way to think of the scenario is to imagine malaria not existing, but mosquitos still being endemic to India let’s say. Suddenly, if malaria comes from afar or gains virulence factors and makes its way into the mosquito population, well then the endemic would be much more lethal as it swept through the Indian population due to a lack of resistance. Similarly, fleas didn’t harbor pestis, then suddenly they did, bam. Sure, the weather could have played a factor. It was likely to be a perfect storm, but we can’t ever know for sure.

  6. Sean

    Also, they had the human flea, Pulex irritans in greater numbers than modern populations. This is indeed a bridge vector for plague.

  7. Justin Gaines

    “PS Oddly, the team’s new paper, where they publish the full Black Death genome, somewhat refutes their first one, where they had only sequenced fragments. Previously, they identified two mutations in the ancient DNA that weren’t seen in any other strain. But those two mutations aren’t there in the full genome, and it now seems that they were a mistake. Ancient DNA can be chemically damaged so that Cs change into Ts. That’s probably what happened in the previous study. Schuenemann and Bos are more confident that their new sequences are correct. They treated their samples with a method that repairs the C-to-T changes, and they went over every bit of DNA 30 times.”

    —That’s not proper logic. A great deal of genetic diversity can be present in a small sample–mutations are common in bacteria, and two mutations between any two or more bacteria is fairly likely. The sample most likely consists of more than one individual bacterium.

  8. Except they went over their old samples with their new method and they couldn’t replicate their old sequences. So, no, this isn’t due to genetic diversity. They were wrong the first time. They explicitly say they were wrong the first time.

  9. Yes, these kind of mistakes are common in ancient DNA, and the lead author on this paper is something on an expert in DNA damage patterns, having previously worked on the Neanderthal and Denisova genomes. Cool to see further applications of ancient DNA studies beyond hominins.

    Regarding the spread of the black death a recent paper claimed that rats were probably not solely or primarily responsible because of the lack of discovering huge numbers of rodent corpses and that the speed at which the epidemic grew was just to fast to have been spread by anything other than human contact. I’m not sure how strong their evidence is but perhaps it’s a case of ‘scape-rats’.

  10. Ken

    I tried to briefly cover this paper on my own site that also deals with plague, except the authors from Northwestern believe the Black Death version may have been more virulent due to mutations in its sRNA. I don’t know much about sRNA so I didn’t write much of a post on it, but I figure you could probably understand it a bit better and might find it interesting.

    http://www.pnas.org/content/108/37/E709

  11. I wish they would explain this a bit further. Do they mean that it’s hard to objectively confirm that these deaths and burials were due specifically to the plague

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