When the bubonic plague arrived in London in 1348, the disease devastated the city. So many people died, so quickly, that the city's cemeteries filled up.
"So the king [Edward III], at the time, bought this piece of land and started digging it," says geneticist Luis Barreiro at the University of Chicago. This cemetery, called East Smithfield, became a mass grave, where more than 700 people were buried together. "There's basically layers and layers of bodies one on top of each other," he says. The city shut down the cemetery when the outbreak ended.
In the end, this bubonic plague, known as the Black Death, likely killed 30 to 50% of people in parts of Europe and the United Kingdom. That's a mortality rate that's at least 200 times higher than the one estimated for COVID, Barreiro points out.
"We all think that COVID-19 was insane and completely changed the world and our societies," Barreiro says. "COVID has a mortality rate of about 0.05% – something like that. Now try to project – if it's even possible – a scenario where 30 to 50% of the population dies."
Now a new study, published Wednesday in the journal Nature, shows that the Black Death altered more than society: It also likely altered the evolution of the European people's genome.
In the study, Barreiro and his colleagues found that Black Death survivors in London and Denmark had an edge in their genes – mutations that helped protect against the plague pathogen, Yersinia pestis. Survivors passed those mutations onto their descendants, and many Europeans still carry those mutations today.
But that edge comes at a cost: It increases a person's risk of autoimmune diseases. "The exact same genetic variant that we find to be protective against Yersinia pestis is associated with an increased risk for Crohn's disease today," Barreiro says.
The study demonstrates how past pandemics could prepare the human immune system to survive future pandemics.
"The evolution is faster and stronger than anything we've seen before in the human genome," says evolutionary biologist David Enard at the University of Arizona, who wasn't involved in the study. "It's really a big deal. It shows what's possible [for humans], in terms of adaptation in response to many different pathogens."
In the study, Barreiro and his team set out to answer a simple question: Did the Londoners, who survived the Black Death, carry a mutation – or even mutations – in their genome that protected them from the disease?
But to answer that question, they had to do something that almost sounds like wizardry: They had to extract DNA from people who died of the plague 700 years ago.
That's where the East Smithfield cemetery becomes so important. Because London officials used this cemetery only during the Black Death, from about 1348 to 1349, scientists know the age of the bodies buried there with extreme precision. And Barreiro and his team could analyze DNA from people who died during three specific time points: before the Black Death, during it and afterwards.
Then they looked specifically at genes involved with the immune system to see if any mutations correlated with survival during the plague. The team also ran a similar experiment with DNA extracted from people buried in Denmark.
When they combined the two experiments, the researchers hit the jackpot.
They found not one, but four mutations that likely gave Londoners an advantage during the Black Death. And the advantage was quite substantial. One mutation, which occurred in a gene called ERAP2, gave people a 40% advantage of survival against the plague.
That's the biggest evolutionary advantage ever recorded in humans, Enard says. And the advantage arose lightning fast, he says, over the course of a few decades.
Before this study, the strongest example of natural selection in humans was the rise of lactose tolerance in Europeans, Enard says. That evolved over the course of thousands of years and still offered only a few percentage points of advantage in terms of survival.
The ERAP2 gene helps to launch a major arm of the immune response earlier on in an infection. People who carry a mutation in the ERAP2 can likely kill invading pathogens more quickly than those without this mutation, Barreiro and his team found. The mutation likely enhances an inflammatory process that helps clear out an infection.
But too much inflammation can become problematic, says paleogeneticist Maria Avila Arcos at the National Autonomous University of Mexico. "If your immune system is super strong, then that can lead to autoimmune diseases. That's kind of the balance."
Indeed, several mutations that protect against the Black Death, including ERAP2, also increase the risk of autoimmune diseases, such as rheumatoid arthritis, today.
Avila Arcos says the new study has a big limitation: It focuses only on a very narrow population, essentially Londoners and people who lived in Denmark at the time. But the Black Death struck many different groups across Europe, Asia and North Africa. "There might be way more cellular mechanisms people used to cope with this devastating outbreak," she says. "But we're just seeing the mechanisms shared across the English and Danish."
By limiting the scope of research to only one small population, the study's findings could also be misinterpreted by the popular media to confirm racist misconceptions about European immunity, says medical historian Monica H. Green, who's studied the Black Death for 15 years.
"There's a general idea, found in a lot of these popularizing essays, books and so forth, that Europeans are immunologically superior to every other population on the planet precisely because Europe has had this long history of exposure to all these diseases, like the Black Death," she explains. "Basically, if Europeans survived, that automatically means that they're the superior race."
She's concerned the findings of this new study will reinforce this idea because there's no data on other populations, such as people in Asia or northern Africa.
"If there's not comparable genetic work on these populations," she says, "then the racists are going to come along and interpret these new findings in any way that they want."
