In 1996 scientific researchers tracked down descendants of the people who had survived the plague at Eyam, looking for a genetic mutation which could explain why so many people who had been exposed to the plague bacteria had not sickened. Within the novel, ‘Three: A Tale of Brave Women and the Eyam Plague‘ by Jennifer Jenkins, we encounter several survivors (I won’t mention them by name until later in the post to allow those who have not finished the book to still engage with this post about something epidemiologically fascinating!) but for the people at the time they had no real ways of knowing why some of them survived while the rest of their families and neighbours perished. What was it about these particular individuals, exposed to Yesinia pestis as much as the next person in Eyam, yet never sickening and/or seeming to recover? Could their genes have contributed to their survival and secured inherited disease resilience for their ancestors, detectable even in the modern day?
What the researchers discovered after taking DNA samples from the descendants of Eyam’s plague survivors was a high prevalence of the delta-32 mutation of the CCR5 chemokine-receptor locus on human chromosome 3, a genetic mutation known to prevent infection with HIV. The deletion in the gene results in a loss of function at the surface of the CCR5 receptor protein. In the case of HIV, the virus does not recognise the mutated protein and cannot bind to the site and enter the cell to infect it.
Study of the delta-32 mutation by scientists hoping to cure HIV has revealed that those with one copy of the mutation were resistant to HIV and those with two copies of the mutation were immune to HIV. A study of test subject Steve Crohn produced results where even with 3,000 times the amount of HIV usually needed to cause HIV infection, Crohn remained unaffected by HIV. The genetic mutation acted as a blocking mechanism, preventing the virus from binding with his white blood cells.
Yesenia pestis invades cells in a manner similar to HIV, effectively hijacking the white blood cells that are sent to eliminate it. Once inside, they then travel with the cell to the lymph nodes, where they break out and attack the body right in the central part of the immune system. It is incredible to think this was the microbiology taking place in the body of George Viccars, our Patient X, on that fateful day when he sickened following the arrival of the plague-infected cloth from London. As Mary Cooper nursed him, the plague bacteria was arriving in George’s lymph nodes, reproducing and creating the fateful buboes. What scientists believe is that the delta-32 mutation, likely found in Mary herself as she nursed George, her two sons and her husband to their grave but never sickened herself, may have prevented plague bacteria from ever entering the host’s white blood cells.
Scientists speculated that the presence of this genetic mutation in Eyam survivors’ descendants, found only in the populations of North Europe, was responsible for preserving the lives of the 1665-1666 survivors and then ensuring its passing on to subsequent generations through increased prevalence down to selection pressure (where an event that kills off a significant number of individuals greatly increases the chances of the surviving individuals’ genes being passed on). Despite sharing environmental factors- and in many cases, kinship- with plague victims, it is likely that the recessive genetic mutation of the survivors’ DNA gave them a selective advantage, whilst sadly not always having been passed on to their children (the mutation requiring two copies to be most effective). The loss of children and the survival of parent(s) during the Eyam plague seems to support this theory of a guardian recessive gene providing a mystical immunity that would have been unfathomable to Eyam’s residents at the time. Once the genetic mutation was established through the survival of those carrying delta-32, it would have been like a photocopier machine, replicating for centuries within a close-knit community where people tended to marry locally, if not from the immediate community.
There is ongoing speculation over the likely population size of Eyam at the time of the plague epidemic, with estimates ranging from 350-887. people The higher estimate creates a minimum death rate of 30% and the lower estimate puts that figure at 80% mortality. The wiping out of whole families might appear to support the latter figures. The parish records show that the number of burials for the plague year was ten times higher than the village’s yearly average and double that of the five-fold increase seen during the same time period in London, which was also ravaged by plague.
Eyam’s survivors made up 10% of the collective families who were affected. They were of both genders and all ages. They survived sometimes when literally nobody else from their family did. All this pointed towards a recessive pattern of protection from a mutated gene. It was present in 14% of the descendants of Eyam survivors that were tested. Joan Plant, for instance, could trace her mother’s lineage back ten generations to surviving siblings, Frances and Margaret Blackwell. Margaret is the topic of conversation between Emmott and Mary Cooper in the novel because she appears to survive the plague’s clutches by drinking a pitcher of bacon fat! There is a good chance that unlikely cure is a red herring and what is most likely is that both she and her brother inherited a recessive gene from both parents, giving them a genetic advantage over Yesinia pestis. The parents, with only one genetic mutation each, would still have succumbed to the disease.
Delta-32 mutation is found exclusively in Caucasians. Testing in native Africans, East Asians and Indians yielded no trace of the genetic abnormality. In fact, the levels of delta-32 detected in Eyam was matched only be areas of Europe known to have been impacted by plague during the 1300s, when bubonic plague wiped out 30-40% of Europe’s population, and areas of the USA which were settled by European plague survivors and their descendants. Scientists believe the mutation originated 700 years ago due to selective pressure ,which would correlate with the arrival of the most severe plague pandemic on the continent.
The key scientific question is this: what caused the genetic mutation to be so prevalent in the residents of Eyam in the first place? For many scientists, the likelihood is not plague itself but smallpox. Smallpox is another virus that cannot infect someone with the delta-32 mutation. There is no evidence that Eyam had suffered a smallpox epidemic prior to the plague epidemic of 1665 and parish records only began in 1630, relatively near to timing of the plague epidemic in the village. For some scientists, Yesinia pestis causing the 1665-1666 epidemic is up for discussion, with some feeling it was an unknown virus and not plague bacteria at all that caused the huge death toll in the village, arguing that quarantine should not have stopped plague and that spread was too rapid for a flea-borne illness. However, my recent blog post on epidemiology in the Eyam plague, drawing upon the work of Whittles and Didelot (2016), explains how the later summer peak was most likely due to human-to-human infections and not rodent-to-human infections.
In a 2005 study, Hummel found that a CCR5-D32 DNA mutation was present in skeletal remains found in graves in Germany and Italy from up to 2,900 years ago, indicating that this mutation likely arose before the massive plague pandemic of the 14th century. Scientists also point out that the CCR5 receptor is not used by Yesenia pestis and that mice with the mutation still died of plague when they were infected, meaning unless the progress of the disease is markedly different in humans compared to mice, for some scientists the presence of the delta-32 mutation was only coincidental.
Haemochromatosis- known colloquially as ‘Bronze Diabetes’ because of the way it can darken the skin and cause hypoglycaemia- is caused in Europeans by 2 major alternative forms of the genes ( known as ‘alleles’), C282Y and HD63. When testing, scientists found the prevalence of individuals carrying the C282Y allele in the Trent and Sheffield area (so, in geographical proximity to Eyam) to be between 12.7-14%. The H63D mutation was carried by 25.9%. This was consistent with the 20% survival to 80% mortality rate when the population of the village of Eyam is taken to be 350 at the start of the plague epidemic. No figures exist for the presence of C282Y in Eyam itself (come on scientists, this needs investigating!) but the Sheffield results suggest it would be approximately the same frequency as the detected delta-32 mutation.
Haemochromatosis causes an excessive amount of iron to be pumped out of the intestinal cells and into the body, as well as out of macrophages (mobile white blood cells). Many pathogens actually depend on iron for growth and this includes our friend, Yesenia pestis. In fact, excessive iron can significantly impair the immune system. Plague bacteria depends on the iron they absorb from white blood cells in order to reproduce, so the virulence and reproductive capabilities of the disease would be greatly depleted in a person whose iron was being leached out of their cells due to ‘Bronze Diabetes’. This would lead to a reduction in buboes formation and a greater ability to resist the plague’s takeover of the immune system, making bubonic plague survivable by such individuals. I am reminded of the Brad Pitt movie, World War Z, where the zombie-creating virus will simply pass over someone who is already sick with a systemic disease. Could a deficiency of iron in white blood cells have saved some of our Eyam survivors?
There is a high prevalence of C282Y mutation in Europe, the battle ground of the Black Death in 1347, which produced a 30-40% death rate. The highest prevalence of this mutation can be found in Belgium, France and England, as well as other parts of North Europe where the highest incidences of plague occurred. The role of the H63D mutation is currently less-well understood. I would also raise the question as to whether incidence of mutation is matched with survivors of the London plague outbreak, and whether the quarantine of the village led to a greater replication of these mutations due to selective pressure.
[*Spoiler Alert- only read on if you have finished reading the novel]
Could CCR5-D32 or a combination of C282Y/H63D mutations have been the reason for the survival of some of the characters from the novel?
Elizabeth Hancock survives the plague even after nursing and burying her husband and six of her children. Could she have had the delta-32 mutation?
William Mompesson repeatedly visits the sick and assists the dying yet he never sickens, despite losing his wife Catherine and throwing himself upon her lifeless body. Could this have been because he had ‘Bronze Diabetes’?
Marshall Howe, the village’s self-appointed sexton, apparently sickens with plague only to recover, believing himself to be invincible but ultimately bringing the pathogen into his home, where it killed his wife and child who presumably did not have the guardian gene mutation.
And then we come to Emmott. How I wish she had been blessed with the genetic mutation that might have seen her reunited with Rowland, living in the house built for them by the villagers and raising the children she dreamed of having. But alas, it appears perhaps only Joseph, her youngest and only surviving sibling, may have been the only Syddall given that particular genetic gift. Whatever caused some of Eyam’s population to survive when others perished is yet to be emphatically discovered by scientists, but what we do have is a lasting testimony to the bravery of both those who lived and those who died.
This blog post is indebted to the following studies: