So, the Black Death.

Pretty exclusively a “back then” thing, right? But if you’re descended from  the European, Middle Eastern, and North African populations that experienced  the plague, and you’re dealing with an autoimmune disease, for you it  could be a “right now” kind of thing.

That’s because evidence is emerging  that gene variants that were beneficial as one of history’s worst  plagues was killing off millions… well, those variants aren’t so hot now. So here’s how the Black Death and  other plagues wrote themselves into our genes and why that turned  out to be such a double-edged sword. [♪ INTRO] So let’s start with a brief history lesson. History’s most notable outbreak of  bubonic plague, aka the Black Death, happened in Europe in the fourteenth century.

It’s thought that a ship arrived in  Sicily with rats already infected with the causative agent of  the plague, Yersinia pestis, and the rats quickly spread  the disease all across Europe. Victims often died within  a week, and the death toll quickly rose to over 25 million people. In a 2022 article from the journal Nature,  an international team of researchers hypothesized that, with a death toll that  high, this likely acted as a gigantic natural selection event, where  the survivors likely had some genetic advantage over those who died.

And to investigate this they did what any good research team would:  they went grave robbing. Or more appropriately, grave sampling. Working with museums who had  access to a handful of cemeteries, the researchers were able to get DNA samples from several hundred people who died  before, during, or after the plague.

Notably, however, these gravesites  were from London and Denmark, so even though the Black Death ravaged  the Middle East and North Africa as well, this study focused only on Europeans.   Their goal was to see if there  were specific gene variants that were more common in the surviving population than in the pre-plague population. To find those “plague please spare me” varieties. As a quick refresher, many  genes come in multiple flavors that can have slightly different effects.

The same gene might come in  regular, diet, or cherry vanilla. And we call those variants  or alleles of that gene. Of all 20,000-ish genes in the human genome, the researchers focused on a pool of  about four hundred immune-related genes.

Which, admittedly, is still a lot of genes. But now they could analyze these  few hundred genes to find ones whose frequency changed  significantly pre to post plague, and specifically ones that became more common, since that would mean they  had some protective effect. All of this narrowing down left  them with four sections of DNA that likely helped the survivors, well, survive.

And one gene in particular  sparked their curiosity. They identified two versions  of a gene called ERAP2, one that seemed to end up expressing  a lot more of that gene’s product (and so presumably doing  more work) than the other. And when the team dug a little  deeper, they did indeed find that these two flavors of ERAP had a  difference in how they functioned.

One variant produced an A type of ERAP2, which coded for full length, healthy proteins. The other was associated with a B type of ERAP2, which produced protein  products that cut off too soon, causing the cell to degrade them. So rest in pieces, ERAP2 type B proteins.

Research has already shown that ERAP2  is important for helping to train other immune cells, clearing pathogens, and  modulating inflammatory responses. Knowing that, the researchers  hypothesize that the type A variant leads to more ERAP2 protein,  and thus better immune training. Essentially, the variant would  have helped the immune system more efficiently identify plague bacteria  while also limiting inflammation.

The scientists estimate that  people who had two copies of the type A variant were 40%  more likely to survive the plague. That’s a pretty huge advantage considering how it wiped out nearly half of Europeans. But while this might sound like a win for  all of humanity, that’s not the full story, because that same protective version of ERAP2 has also been associated with  something else: Crohn’s disease.

We don’t know exactly how it’s involved, but it might be that immune training  function going a bit too paranoid. And when you back up to that  bracket of four variants the researchers had originally identified  as protective against the plague, a different one is associated  with autoimmune diseases like lupus and rheumatoid arthritis. So our genetic superheroes are suddenly  looking more like double agents.

The vigilant immune variants that  kept the plague bacterium in check are a little too trigger-happy  and turning on our own bodies. And this isn’t unique to the  genes identified in this study. It’s a well documented phenomenon  known as antagonistic pleiotropy.

Pleiotropy means that a gene  has more than a single effect, and the word “antagonistic”  highlights how these effects may be at odds with each other. So the ERAP2 type A variant would be  an example of antagonistic pleiotropy: it may spare you from the plague, only to harm your descendants  with an autoimmune disease. A study done in 2023 sought to discover how much antagonistic pleiotropy has affected us.

They surmised that this double-edged  sword may be more common than previously thought, creating  an evolutionary tradeoff between infectious disease protection on the  one hand, and autoimmunity on the other. And they did this by looking at  10,000 years of genomic data. When examining all this data, a trend  appeared: the more fit our genes became in protecting us against infectious diseases, the more vulnerable we became  to autoimmune diseases.

They could even identify specific variants,  such as one that increases the risk of inflammatory bowel disease or IBD  while decreasing the risk of infection with noroviruses, or a separate one  that is associated with protection against COVID-19 instead while  also increasing the risk of IBD. And the researchers don’t  think this is a coincidence. They tried to pinpoint when  selective pressures started favoring these genetic variants, and they found  that most of these changes have occurred since the start of the Bronze Age, around  4500 years ago depending on the region.

This was a time when people were  coming together to live in cities, traveling more, and raising more livestock. All of this would have exposed  people to more pathogens, which led to selection for these  infectious disease-protective traits, that just so happen to increase  vulnerability to chronic diseases. Plus, this link does make sense.

When faced with infectious diseases,  we might want a strong immune response, something that ERAP2 helps with in various immune cells when exposed to the Black Death. But when that immune response gets too strong, it can end up harming us,  like with Crohn’s disease. Which means a very, very long history of disease and survival is written into our DNA.

It’s a curious balancing act, and it shows that the difference between a beneficial  and a harmful trait is razor-thin. But it also shows us that we can keep surviving, and adapting to whatever comes next. Now 14th century victims of the  plague would definitely have benefited from knowing more about subjects  like bacteria… or basic hygiene.

But at least you can learn more about  them thanks to our spinoff podcast, SciShow Tangents, which has  episodes about both of those things. Tangents is a lighthearted, lightly  competitive podcast made by the same minds as those behind SciShow, and 100% of episodes are guaranteed to contain at  least one fact about butts. If that sounds good to you, you can check out Scishow Tangents wherever you get our podcasts. [♪ OUTRO]