Nearly seven centuries after the Black Death devastated Europe, scientists are investigating whether its survivors passed down an extraordinary inheritance.

The possibility is unsettling because genetic defenses against a medieval killer might also influence modern inflammatory diseases.

Buried beneath London’s streets, ancient human remains have helped researchers investigate one of evolution’s most consequential questions.

Did the deadliest pandemic in medieval Europe permanently reshape the immune defenses carried by later generations?

And could a genetic advantage that once saved lives become a disadvantage under entirely different modern circumstances?

The answers remain scientifically contested, but the evidence reveals a fascinating relationship between infection, inheritance, and human survival.

To understand that relationship, the story begins in London during the devastating plague outbreak of 1348 and 1349.

Within months, the city confronted a catastrophe that overwhelmed ordinary burial practices and shattered established social routines.

Churchyards could no longer accommodate the dead arriving from households across a densely populated and increasingly frightened city.

Authorities responded by establishing emergency cemeteries, including an extraordinary burial ground near the Tower of London called East Smithfield.

Unlike ordinary medieval graveyards, East Smithfield was closely associated with the initial catastrophic outbreak of the Black Death.

Its relatively narrow burial period would eventually make the cemetery exceptionally valuable for researchers studying historical disease.

Bodies were placed in organized burial arrangements, reflecting an extraordinary effort to manage death amid overwhelming public suffering.

The people buried there represented individual lives, families, occupations, and experiences that written historical records rarely preserved.

Their identities largely disappeared, but portions of their biological histories remained protected inside bones and surviving teeth.

Nobody responsible for those medieval burials could have imagined that future scientists would eventually examine their genetic material.

The catastrophe itself was part of a pandemic that transformed societies across Europe, Asia, and North Africa.

In Europe, estimates suggest the Black Death killed approximately thirty to fifty percent of the population across affected regions.

Such extraordinary mortality disrupted agriculture, commerce, religious institutions, political relationships, and the foundations of everyday family life.

Entire communities experienced repeated losses, while surviving relatives struggled to maintain households and bury those they loved.

The devastation was particularly frightening because people lacked modern knowledge about bacteria, transmission, and effective medical treatment.

Medieval explanations frequently involved religion, corrupted air, environmental conditions, and theories inherited from earlier medical traditions.

The disease could progress rapidly, leaving communities with little opportunity to understand why some people survived and others died.

For generations, historians examined the pandemic primarily through chronicles, economic records, burial sites, and demographic evidence.

Modern genetics eventually introduced another possibility: studying both the microorganism responsible and the people who encountered it.

That opportunity depended on technological advances capable of recovering extremely damaged genetic material from centuries-old human remains.

Ancient DNA rarely survives as complete chromosomes that researchers can examine as easily as modern laboratory samples.

Instead, it generally appears in fragmented sequences, mixed with environmental microorganisms and vulnerable to contamination during excavation.

These limitations once made recovering reliable genetic information from medieval plague victims seem extraordinarily difficult, perhaps impossible.

Nevertheless, researchers recognized that teeth could preserve important biological traces unavailable from many other skeletal tissues.

The protected structures within teeth sometimes retain genetic remnants from microorganisms circulating through a person’s bloodstream before death.

Those traces provided an extraordinary opportunity to investigate the identity of the pathogen responsible for the Black Death.

During excavations conducted between 1986 and 1988, archaeologists recovered hundreds of skeletons from the East Smithfield cemetery.

The remains became part of scientific collections, available for investigations using methods that continued improving over subsequent decades.

Researchers eventually examined genetic material preserved in selected teeth from individuals buried during the medieval epidemic.

In 2011, an international scientific team reconstructed the genome of the bacterium responsible for the Black Death.

That organism, Yersinia pestis, remains capable of causing plague infections in certain parts of the modern world.

The ancient genome provided decisive molecular evidence connecting the medieval pandemic to the bacterial species already associated with plague.

It also opened the possibility of comparing historical bacterial strains with those responsible for more recent outbreaks.

However, identifying the killer raised another question that would prove even more challenging to investigate scientifically.

If the bacterium killed such an enormous proportion of Europe’s population, might surviving individuals have possessed biological advantages?

The answer mattered because survival could potentially influence which inherited genetic variants became more common in subsequent generations.

Natural selection occurs when inherited characteristics influence reproductive success, allowing particular genetic variants to increase across populations.

A catastrophic epidemic could theoretically create unusually powerful selection pressures if genetic differences substantially affected the likelihood of survival.

Yet proving that ancient epidemics produced specific genetic changes requires much more than observing differences between surviving populations.

Researchers must distinguish natural selection from migration, random genetic drift, population structure, and technical errors involving ancient DNA.

These difficulties would become central to the scientific controversy surrounding the Black Death’s possible genetic legacy.

Before the most famous genetic investigation, bioarchaeologist Sharon DeWitte examined skeletal evidence from victims buried at East Smithfield.

Her work investigated whether health conditions before infection influenced an individual’s risk of dying during the epidemic.

Skeletal indicators of physiological stress provided clues about earlier illness, malnutrition, and difficult conditions experienced during life.

The findings challenged the simplistic assumption that plague mortality was distributed equally across every member of society.

People already experiencing physiological frailty appeared more vulnerable, although even otherwise healthy individuals could die from infection.

This distinction suggested that the pandemic’s terrible effects depended partly on differences between the people it encountered.

DeWitte also investigated demographic patterns in populations living after the Black Death and identified evidence of improved survival.

However, improved conditions following the epidemic could have contributed substantially to those apparent changes in health and longevity.

The pandemic produced labor shortages that altered wages, access to resources, and economic relationships across surviving communities.

Some workers gained bargaining power, while certain households benefited from changes in land availability and material circumstances.

Consequently, longer lives after the plague could not automatically demonstrate that genetic selection had produced healthier populations.

The challenge was separating biological inheritance from the enormous social and environmental transformations following medieval population collapse.

That question eventually attracted geneticists interested in determining whether the Black Death influenced immune-related genetic variation.

An international research collaboration included scientists associated with McMaster University and the University of Chicago, among other institutions.

Researchers including Jennifer Klunk, Tauras Vilgalys, Hendrik Poinar, and Luis Barreiro investigated genetic changes around the pandemic.

Their approach relied on comparing individuals who lived before, during, and after the devastating fourteenth-century outbreak.

Rather than relying exclusively on one location, the researchers incorporated historical human remains from London and Denmark.

This geographical comparison was important because similar genetic patterns in separate populations could strengthen an evolutionary interpretation.

The investigation initially involved hundreds of archaeological samples, although only a portion yielded sufficient genetic information for analysis.

Ultimately, the published research examined usable ancient DNA from 206 individuals belonging to the sampled European populations.

The researchers concentrated on genetic regions related to immune function, alongside comparison regions without equivalent known immune roles.

Their central hypothesis was that an extraordinarily lethal infectious disease could produce detectable changes in immune-related genetic variation.

If particular immune variants improved survival, those variants might appear more frequently in populations after the epidemic.

The difficulty involved establishing whether observed changes were sufficiently unusual to rule out alternative demographic and statistical explanations.

Despite these challenges, the team reported intriguing differences at several genetic locations associated with immune system activity.

One especially prominent candidate involved a gene known as ERAP2, which participates in processing proteins for immune recognition.

ERAP2 helps trim protein fragments that cells can present to components of the immune system responsible for detecting threats.

This process contributes to how the body recognizes infected cells and coordinates responses against certain invading microorganisms.

Different inherited variants can influence whether cells produce a full-length, functional version of the protein encoded by ERAP2.

In simplified terms, some genetic combinations support production of the complete protein, while others alter its normal expression.

The researchers proposed that these differences might have mattered when medieval Europeans encountered the bacterium responsible for plague.

Their findings appeared in the scientific journal Nature in October 2022, attracting considerable international attention and public discussion.

The study reported a particularly strong candidate signal near ERAP2 when comparing historical genetic variation across sampled populations.

Researchers then explored whether the gene influenced how living human immune cells responded to the plague bacterium.

Laboratory experiments used immune cells derived from modern donors to investigate differences associated with the relevant genetic variants.

Some cells carrying the functional version of ERAP2 demonstrated a greater ability to restrict or eliminate intracellular plague bacteria.

These findings provided biological evidence that variation in ERAP2 can influence cellular responses to Yersinia pestis infection.

That experimental result was important because genetic differences observed in ancient skeletons cannot independently explain their functional consequences.

The researchers also reported differences in immune signaling, suggesting that ERAP2 variation influences several aspects of inflammatory responses.

Their historical analysis proposed that individuals carrying certain protective genetic combinations may have experienced substantially better survival odds.

One widely discussed estimate suggested approximately forty percent greater survival likelihood for a particular ERAP2 genetic combination.

However, that figure was a model-based historical inference rather than a directly observed survival rate among medieval individuals.

The researchers could not identify which specific people survived the Black Death simply by examining their inherited genes.

Nevertheless, the proposed advantage was remarkable because modest biological differences can matter enormously during catastrophic infectious outbreaks.

The investigation suggested that the medieval pandemic might have favored immune responses particularly effective against a dangerous bacterial pathogen.

But the possible protective advantage was only half the reason this discovery generated such extraordinary public interest.

The other half involved an unexpected connection between the same genetic region and a serious modern inflammatory disease.

ERAP2 variation has been associated with susceptibility to Crohn’s disease, a chronic condition affecting the digestive system.

Crohn’s disease involves persistent immune-mediated inflammation that can damage intestinal tissue and seriously interfere with everyday functioning.

Symptoms can include abdominal pain, diarrhea, fatigue, weight changes, and complications requiring specialized treatment or surgery.

The disease develops through complex interactions involving genetic susceptibility, immune regulation, environmental exposures, and other biological factors.

No single inherited variant can reliably explain why one person develops Crohn’s disease while another remains unaffected.

Yet the association introduced a compelling evolutionary question about the potential consequences of strong immune defenses.

Could an immune response useful against devastating infections also contribute to excessive inflammation under different environmental conditions?

That possibility illustrates an important principle: biological adaptations can involve trade-offs rather than producing universally beneficial characteristics.

A protective response against one threat may have different consequences when the body’s environment or exposures change.

Evolution does not necessarily produce immune systems optimized for comfort, longevity, or disease prevention under every imaginable circumstance.

Instead, natural selection generally favors inherited characteristics that improve reproductive success within particular historical environmental conditions.

An immune response advantageous during repeated lethal epidemics might therefore remain imperfectly suited to different challenges encountered today.

Still, this evolutionary interpretation requires caution because the proposed historical selection involving ERAP2 remains a disputed scientific conclusion.

The association between ERAP2 and Crohn’s disease does not establish that medieval plague epidemics caused modern autoimmune illness.

Nor does it mean everyone possessing a particular ERAP2 variant will eventually experience intestinal inflammation or another disease.

Most importantly, the genetic history of inflammatory illness cannot be reduced to one medieval pandemic or single gene.

Scientists recognize that inflammatory diseases involve numerous contributing factors, many of which remain incompletely understood despite extensive research.

Modern genetics identifies statistical associations that require careful interpretation, especially when environmental conditions influence whether susceptibility becomes illness.

The historical hypothesis remains interesting precisely because it connects laboratory observations with broader questions about long-term evolutionary change.

However, other researchers soon challenged the strength of the evidence supporting unusually powerful selection during the Black Death.

Geneticists including Iain Mathieson and David Reich participated in a detailed reassessment of the original historical analysis.

Their criticism questioned whether the statistical patterns were sufficiently strong to demonstrate natural selection at the reported locations.

They also examined technical issues involving allele frequency estimation, sample limitations, and comparisons across historical population groups.

Ancient DNA studies are particularly vulnerable to uncertainty because surviving genetic fragments represent incomplete information about larger populations.

Differences between sampled burial groups can sometimes reflect chance, population movements, or biases in preserved archaeological material.

The critics argued that appropriate statistical adjustments substantially weakened the original evidence for selection involving immune genes.

They also disputed whether ERAP2 displayed a convincing historical frequency change in the available ancient genetic data.

Their formal critique appeared in Nature in February 2025, alongside a detailed response from the original research collaboration.

The exchange demonstrated that striking biological findings can remain controversial even after publication in prestigious scientific journals.

The original investigators defended their interpretation using additional analyses, statistical checks, and evidence from laboratory experiments.

They maintained that their findings continued supporting ERAP2 as an especially plausible candidate for selection during the pandemic.

The critics, however, argued that the evidence remained insufficient to identify specific variants confidently favored by the epidemic.

These positions share an important distinction between demonstrating a gene’s biological function and establishing its precise evolutionary history.

Laboratory experiments can show that ERAP2 influences immune responses without proving medieval plague changed its population frequency.

Likewise, historical frequency changes require careful analysis before researchers can confidently attribute them to one particular infectious disease.

The controversy therefore concerns the strength of evolutionary inference, not whether the Black Death devastated medieval populations.

It also does not eliminate the broader biological possibility that major infectious epidemics influenced inherited human immune characteristics.

Instead, the debate reveals how difficult reconstructing natural selection becomes when researchers depend on fragmented centuries-old genetic evidence.

Larger archaeological datasets and more complete ancient genomes could eventually clarify whether ERAP2 experienced substantial pandemic-related selection.

Future studies may also identify alternative genetic regions that influenced survival or immune responses during historical plague outbreaks.

Meanwhile, other investigations have explored possible genetic consequences of repeated epidemics in populations with different ancestral backgrounds.

Research involving European Roma populations and neighboring communities has examined similarities in immune-related genetic adaptations across distinct ancestries.

Such comparisons raise questions about whether shared historical environments could produce overlapping evolutionary responses despite different origins.

However, assigning those similarities specifically to plague remains challenging because other infections also affected historical European populations.

Tuberculosis, smallpox, and numerous additional pathogens imposed biological pressures that could influence immune-related genetic variation over time.

Consequently, genetic patterns associated with disease resistance may reflect multiple interacting historical forces rather than isolated catastrophes.

An additional dimension of the story concerns the plague bacterium itself, which also evolved across successive historical pandemics.

Researchers have investigated how ancient strains of Yersinia pestis differed genetically from other historical and contemporary bacterial populations.

The organism did not remain biologically unchanged throughout the centuries separating medieval epidemics from modern scientific investigations.

In 2025, researchers published evidence involving changes in the copy number of an important bacterial virulence gene.

That gene, called pla, contributes to biological processes that help Yersinia pestis establish dangerous infections in mammalian hosts.

The investigation examined evidence of reduced pla copy numbers in certain strains from later historical pandemic periods.

Laboratory research found that reduced expression associated with these genetic changes could decrease mortality in experimental bubonic plague models.

Importantly, the same attenuation was not observed across every experimentally studied form of plague infection in mice.

These findings suggest that changing bacterial virulence may have influenced the pathogen’s persistence under particular ecological circumstances.

However, reduced laboratory mortality does not establish that medieval plague became uniformly less dangerous across entire populations.

Disease severity depends on bacterial characteristics, transmission routes, host vulnerability, environmental conditions, and multiple interacting biological mechanisms.

Researchers have proposed that reduced virulence might sometimes favor persistence when susceptible animal hosts become increasingly scarce.

A pathogen that preserves opportunities for transmission can potentially gain an evolutionary advantage under certain ecological constraints.

But bacteria do not consciously choose strategies, and evolutionary explanations should never imply deliberate intentions or purposeful planning.

Instead, genetic variation and differential reproductive success can gradually alter pathogen populations across many generations and environments.

This produces another fascinating contrast between the human immune system and the microorganisms challenging it throughout history.

Both populations can change through evolution, but their interactions involve complex pressures that rarely produce simple outcomes.

The Black Death consequently provides an extraordinary opportunity to examine the relationship between historical disease and evolutionary biology.

Its consequences extended beyond immediate mortality, influencing economic relationships, settlement patterns, labor systems, and demographic development.

Some of those consequences are firmly documented, while proposed genetic effects require further investigation and careful interpretation.

Modern infectious diseases provide additional reminders that inherited genetic differences can influence individual vulnerability to particular pathogens.

Research during the COVID-19 pandemic identified associations between certain inherited genomic regions and the risk of severe illness.

Some investigated variants originated through ancient interbreeding between modern human ancestors and Neanderthals tens of thousands of years ago.

Those findings revealed that genetic inheritance from distant prehistoric populations can influence responses to diseases emerging much later.

Nevertheless, associations with infection severity must be interpreted alongside age, vaccination, medical conditions, and environmental circumstances.

Genetic predisposition generally changes probabilities rather than determining an individual’s future with complete biological certainty or inevitability.

The same principle applies to ERAP2 and the possible relationship between historical plague resistance and inflammatory disease.

Possessing a particular variant does not reveal whether an ancestor survived plague because of that genetic characteristic.

Nor can consumer genetic information independently establish a person’s likelihood of developing Crohn’s disease without appropriate clinical interpretation.

Medical risk assessment requires broader evidence, including personal history, symptoms, family background, and professionally validated diagnostic information.

The scientific significance of ancient DNA lies primarily in revealing population histories rather than offering deterministic personal predictions.

That distinction matters because compelling historical narratives can easily exaggerate the certainty of complex genetic research findings.

The idea that ancestral survival carried a hidden biological cost is powerful, but it remains a developing hypothesis.

Researchers must still determine which evolutionary changes occurred, how strongly infections influenced them, and whether effects persist today.

Even established genetic associations can change in importance depending on environmental exposures and interactions with other inherited variants.

Modern inflammatory disease patterns therefore cannot be explained simply by claiming that medieval survival created contemporary medical problems.

Changes in diagnosis, healthcare access, microbial exposures, diet, and environmental conditions may influence observed disease patterns today.

Scientists continue examining how these factors interact with inherited susceptibility to produce immune responses that sometimes become harmful.

The immune system itself is not a single defensive weapon but an extraordinarily intricate network of specialized biological processes.

Its protective functions include recognizing dangerous organisms, coordinating inflammation, eliminating infections, and preventing unnecessary damage to healthy tissues.

Maintaining balance between defense and restraint is essential because inadequate responses and excessive inflammation can both cause harm.

ERAP2 belongs within this complicated machinery, contributing to protein processing rather than independently controlling every aspect of immunity.

Its possible evolutionary history therefore represents one piece of a much larger story about human biological adaptation.

The medieval victims buried at East Smithfield could never have known their remains would help illuminate these scientific questions.

Their teeth preserved evidence connecting a historical catastrophe with advances in microbiology, genetics, archaeology, and evolutionary medicine.

Their skeletons also remind researchers that every statistical observation originated from an individual who experienced real human suffering.

The losses of 1348 and 1349 cannot be reduced to a laboratory experiment or evolutionary calculation.

Families disappeared, livelihoods collapsed, and communities confronted immense uncertainty without the scientific knowledge available to contemporary medicine.

Yet centuries later, those same historical remains continue contributing to investigations with implications extending far beyond medieval history.

What began as an effort to identify an ancient killer became an investigation into the biological inheritance of survival.

The original ERAP2 research proposed a striking explanation linking protection against plague with susceptibility to inflammatory intestinal disease.

Subsequent criticism established that the proposed historical selection cannot yet be treated as an uncontested scientific fact.

Both developments matter because scientific understanding advances through experimentation, independent analysis, disagreement, and increasingly rigorous evidence.

The unsettling possibility is not that human DNA contains a hidden curse inherited directly from medieval survivors.

It is that characteristics beneficial under one set of conditions may carry different consequences in another environment.

Whether the Black Death specifically produced that trade-off through ERAP2 remains an important unanswered evolutionary research question.

What is certain is that humanity’s biological past continues shaping the questions scientists ask about health today.

The people who survived ancient epidemics passed their genetic inheritance onward, alongside countless other influences accumulated across generations.

Some inherited characteristics may have improved survival, while others may contribute to vulnerabilities under particular modern circumstances.

Understanding those relationships requires evidence that separates fascinating possibilities from conclusions supported by reproducible scientific research.

The Black Death remains a reminder that infectious catastrophes can transform societies and potentially influence populations across generations.

And the most compelling discovery may ultimately concern how survival, evolution, and disease remain connected across extraordinary stretches of time.