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It is an almost humorous understatement to say the Bubonic plague had an enormous negative impact on humanity, but researchers have started to uncover a silver lining we didn’t expect!

Yersinia pestis, the bacterium responsible for bubonic plague, once caused millions of deaths around the world and wiped out a third of Europe’s population.

Even today, the words “bubonic plague” evoke both fear and fascination. Thankfully, the disease is now exceedingly rare in the US and Europe, primarily due to lifestyle changes that make it more complicated to spread to humans from infected fleas. Better still, when it does occur, it can typically be treated with simple antibiotics.

Researchers have long wondered whether plague outbreaks have left any permanent imprint on the human immune system, as they were so catastrophic. In particular, one theory suggests that the Black Death could have created a form of natural selection, with some of the individuals who survived it passing on genetic quirks that helped them do so to future generations.

Gathering data to answer this question has recently been a lot of work. Sequencing DNA from ancient plague victims’ skeletons found in mass burial sites is challenging, as scientists often have to work with tiny fragments of DNA, many of which are highly contaminated.

However, experts have discovered one piece of the skeleton called the bony labyrinth, where intact human DNA can still be reliably found. It lies within the inner ear and is one of the densest parts of the human body. This has helped to yield new insights into who survived past plague outbreaks and why over the last three years.

The human leukocyte antigen (HLA) system is a set of genes that encode proteins on the surface of our cells, playing a critical role in coordinating the immune response. Certain HLA variants acted as a natural protection against Covid-19 for some asymptomatic individuals due to some sort of genetic lottery

In 2021, researchers demonstrated that HLA variants could’ve played a role in determining who survived medieval plague outbreaks. They found that the present-day inhabitants of the German town of Ellwangen had various HLA gene differences that likely rendered their ancestors more capable of fighting off Yersinia pestis. Two years ago, a study showed that medieval Londoners and Danes carrying a specific ERAP2 variant were twice as likely to have survived the Black Death. 

Researchers found that a gene called ERAP2, which helps immune cells fight pathogens like Yersinia pestis, has two variants. People with the full-sized protein variant were twice as likely to have survived the Black Death. By the end of the 14th century, 50% of Londoners and 70% of Danes carried this variant. However, more research is needed to understand whether this adaptation became widespread and integrated into our DNA.

“Any genes that had a protective effect against this outbreak could have had quite a boost in frequency after such an event,” he says. “But this may have only been over a few generations.”

Skoglund even wonders whether diseases such as smallpox, which was even more persistent and virulent than plague, killing many hundreds of millions of people, could have had a more significant impact on shaping modern immune systems.

Studying past plagues can provide valuable insights. Hendrik Poinar from McMaster University believes investigating plague strain evolution is crucial to understanding the development of problematic strains. David Skoglund’s study of 4,000-year-old plague victims in the UK found Yersinia pestis had not yet developed the ability to be transmitted by fleas.

“We can see in the DNA that the bacteria lacked a genetic factor that allows this flea-based transmission,” he says. “But by evolving that, it had a drastic impact on human health. But we can also learn from how evolution dealt with problems in the past, how it came up with biological mechanisms to battle those diseases thousands of years ago. That’s vital because we can use that to help us with vaccines and drug development today.”