Under the microscope, Yersinia pestis looks nothing special.
It has a fairly standard shape for a bacterium - a sort of short rod with rounded ends - and is relatively poorly motile.
But she is responsible for the disease, which once upon a time exterminated a third of the population of Europe and caused millions of deaths worldwide.
The mere mention of the word bubonic plague evokes both fear and fascination in people, even today.
The disease is now extremely rare in both the US and Europe, largely thanks to lifestyle changes that prevent it from being easily transmitted to humans via infected flies.
Even when this happens, it can be relatively easily treated with life-saving antibiotics.
But these cases still happen.
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Most recently, a man in Oregon, USA contracted bubonic plague from his own pet cat.
That's not something that comes as a huge surprise to evolutionary geneticist Paul Norman, who studies bubonic plague at the University of Colorado, Anschutz.
"There are still small pockets of infection in America," he says.
It still circulates in wild animals such as squirrels and prairie dogs, he adds.
In America, about seven human cases of plague are reported on average, although deaths are much less common - just 14 between 2000 and 2020.
In some parts of the world, such as Madagascar, this disease is much more common.
But although relatively rare compared to the past, the bubonic plague left its mark on the human species and can still be found in the genomes of people living today.
It is considered to be Yersinia pestis visited people for thousands of years.
DNA evidence of bacteria has been found in skeletons from 4.000 years ago.
But in the early 14th century, a strain of this bacterium exploded in Europe as the Black Death.
It is believed to have originated in villages around the Chui Valley in present-day Kyrgyzstan, possibly being transmitted to humans by flies from infected groundhogs before spreading to Europe along the Silk Road trade.
By the 14th century, the Black Death had killed more than 50 million Europeans, according to estimates based on historical writings and testimonies.
More recent studies of agricultural activities at the time show that the price may not have been so dramatic everywhere, as some areas were ravaged by the disease, while others were barely touched.
Over the centuries, however, the plague is estimated to have killed at least 200 million people.
Because plague epidemics were so catastrophic, researchers have long wondered whether they left a lasting imprint on the human immune system.
One particular theory suggests that the Black Death may have been widespread enough in the 14th century to create some form of natural selection.
The idea was that some individuals who survived the plague could pass on to future generations the genetic traits that helped them do this.
"The Black Death put an enormous strain on the human population of Europe," says Norman.
"It was persistent and harmful, and anyone with the slightest advantage in that situation genetically had a better chance to survive," he adds.
But until relatively recently, gathering any data to answer this question was nearly impossible.
Sequencing DNA from the skeletons of ancient plague victims found in mass graves is a difficult process, as scientists often have to work with the tiniest fragments of DNA, many of which are extremely contaminated.
"It's quite common to find that most of the DNA actually came from soil or bacteria that took over the skeleton after the person died," says Pontus Skoglund, a Swedish geneticist who heads the Ancient Genomics Laboratory at London's Francis Crick Institute.
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Experts have discovered, however, one piece of skeleton in which intact human DNA can still reliably be found.
Called the labyrinth of bones, it is in the inner ear and is one of the densest parts of the human body.
"It's the most successful place to extract DNA," says Norman.
"It's a very, very tiny bone, still preserved in the skull samples. Without wanting to be too explicit, you have to drill really deep to get to that bone, whereas something like leg bone is extremely porous and bacteria can get to it much more easily," he explains.
In the last three years, this has brought new insights into who survived past plague epidemics and why.
Regulation of immunity
The human leukocyte antigen (HLA) system consists of a group of genes that encode proteins on the surface of our cells, which play an important role in coordinating the immune response.
A recent study showed that some people, asymptomatic for covid-19, possessed certain HLA variants that acted as a form of natural protection against the virus.
"The role of HLA genes is to identify foreign invasion in the body and direct the immune system to seek out cells infected with pathogen proteins and destroy them.
"Relatively rare variants of these genes can help some people survive the pandemic and if the death toll from covid was much higher, the human population would be left with a much higher frequency of these variants," says Norman.
In 2021, he and colleagues showed that HLA variants played a role in determining who survived medieval plague epidemics.
Researchers analyzed a mass grave of plague victims from the 16th century in the German town of Elwangen, and sequenced the genomes of 36 skeletons.
When they compared them to the DNA of people living in Elvengnen today, they found that the 21st-century residents of the town had subtle differences in various HLA genes, which most likely made their ancestors better able to defend against Yersinia pestis.
Two years ago, an international group of researchers attempted to investigate how the Black Death affected human immunity by collecting genetic samples from the skeletons of around 500 people from cemeteries in London and across Denmark who died before, during and after the 14th-century pandemic.
They observed patterns involving a gene called ERAP2, which encodes a protein known to help human immune cells fight Yersinia pestis and other pathogens.
But one variant of ERAP2 makes a more restricted form of the protein, while the other makes the full one.
The study showed that medieval Londoners and Danes who carried the latter variant of ERAP2 were twice as likely to survive the Black Death.
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By the end of the 14th century, researchers found that 50 percent of examined Londoners and 70 percent of Danes possessed this variant.
However, further analyzes are needed.
Skoglund says researchers need to study the thousands more genomes of individuals who lived across Europe at the time of the Black Death and in the centuries that followed to see if adaptations like the ERAP2 variant became truly widespread and integrated into our DNA.
"Any gene that had a protective effect against this epidemic could get quite a boost in frequency after one such event.
"But that could only happen after a few generations," he says.
Skoglund even wonders whether diseases such as smallpox, which were even more persistent and contagious than the plague, killing hundreds of millions of people, could have had a greater impact on shaping modern immune systems.
But the plague retains a certain fascination, and we can gain valuable information from studying how it affected our distant ancestors.
"Studying how plague evolves and why certain strains were more infectious in terms of mortality is important for understanding the evolution of strains that can become problematic," says Hendrik Poinar, an evolutionary biologist at McMaster University in Ontario, Canada.
Skoglund points to a study he did of plague victims found in Somerset and Cumbria in Great Britain from around 4.000 years ago, when Yersinia pestis had yet to develop the ability to spread via flies.
"We can see in the DNA that the bacteria did not possess a genetic factor that would enable them to transmit this through flies.
"But developing it had drastic consequences for human health, but we can also learn something based on how evolution solved problems in the past, how it came up with biological mechanisms to fight those diseases thousands of years ago. This is of key importance, because we can use this knowledge with vaccines and the development of medicines today," he adds.
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