BY MIKE MAGEE

This Fall, I am teaching a 4-week course on “How Epidemics Have Shaped Our World” at the President’s College at the University of Hartford. It is, of course a timely topic, but also personally unnerving as we complete a third year under the shadow of Covid-19.

Where does one begin on a topic such as this? Yale historian, Frank M. Snowden, in his book “Epidemics and Society: From the Black Death to the Present”, made his intentions obvious. He would begin with the plaque. Why? His answer, “The word ‘plague’ will always be synonymous with ‘terror’”, and especially references:

Virulence: “It strikes rapidly, causing excruciating and degrading symptoms, and, if untreated, achieves a high case fatality rate (CFR)…of at least 50%.”

Speed: “Its progress through the body was terrifyingly swift. As a rule, the plague killed within days of the onset of symptoms, and sometimes more swiftly.”

Target: “It preferentially targeted men and women in the prime of life (and)…left in its wake vast numbers of orphans, widows and destitute families.”

Reaction: “…communities afflicted with plague responded with mass hysteria, violence, and religious revivals… people sought to assuage an angry god.”

Scapegoating: “Frequently, vigilantes hunted down foreigners and Jews and sought out witches and poisoners.”

One might also argue, as Snowden does, that the plague also launched the field of Public Health which included quarantines, penthouses, masking, and sanitary cordons. But knowledge of causality (Yesinia pests, passed along by common flea from ship rat to humans) and treatment (modern sanitary movement and modern antibiotics) was slow to reveal itself.

But that’s “ancient history.” Not so fast. Last week, Nature published a paper authored by Jennifer Klunk PhD and her associates from McMaster University’s Ancient DNA Centre focused on modern genes that they now believe owe their existence to the Black Plague’s human rampage nine centuries ago.

The Black Death is estimated to have killed 30% to 50% of Europeans between 1347 -1351. But DNA anthropologist, Hendrik Poinar, a colleague of Klunk’s, focused on one nearly forgotten graveyard in London, the East Smithfield graveyard. It was purchased by King Edward III as a plague pit for mass burials, accepting “guests” for a small moment in time between 1348-1349. Later survivors of the plague, who died of other causes, were buried on top of plague victims in 1350 and beyond. The dated samples of DNA included cadavers from before, during, and shortly after the plague event.

The hypothesis: “…this concentrated mass death event could have caused hugely selective pressure on the genetics of the individuals who survived, who would likely have passed down genes that allowed them to survive the plague.”

The findings: 

1. DNA samples were obtained from 318 cadavers in London and 198 cadavers in a Danish cohort. Burial position allowed investigators to pin time of death relative to the plague event. By comparing pre- and post-plague samples, the investigators were able to isolate 35 genes that were more prevalent in those that survived the plague. Cross-referencing with the Danish sampling, they whittled the list down to 4 genetic targets. 
2. One of the four variations was associated with the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene which codes a protein whose purpose is to slice and dice invading viral and bacterial proteins, and post or display them on the surface of macrophages. These “warning flags” allow the protective macrophages to identify what invaders next to gobble up and destroy. The presence of the gene appears to have offered a 40% increased chance of surviving the plague.
3. Modern day humans can have one, two, or no working copies of the ERAP2 gene. Investigators armed with human blood samples from all three varieties then tested them against the Yersinia pests bacteria. As expected, samples with immune cells having two working copies of the ERAP2 gene were most effective in killing Y. pestis.

The hitch:

But possessing this survival gene comes with one important downside. Modern day humans who have the two working copies of ERAP2 are also more likely to inappropriately attack their own living cells. Specifically, rates of Crohn’s Disease, Rheumatoid Arthritis, and Lupus are higher in this cohort than in those without the survival gene variant. The implications are obvious to all, and enough to bring Darwin back from the grave. As University of Arizona population geneticist said, “This is a truly impressive paper. The implications of the potential speed and power of natural selection in immune genes are wild.”

The protective, and potentially autoimmune causing variant, lives on in 45% of modern day Brits. Thus epidemics will continue to shape our world, raising difficult risk/benefit questions along the continuum of infectious disease, immunity, chronic inflammation, and modern day vaccine policy.

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Mike Magee MD is a Medical Historian and the author of “CODE BLUE: Inside the Medical Industrial Complex.”