Black Death and AIDS are global pandemics that have captured the popular imagination, both attracting extravagant hypotheses to account for their origins and geographical distributions. Medical scientists have recently attempted to connect these two great pandemics. Some argue that the Black Death of 1346–52 was responsible for a genetic shift that conferred a degree of resistance to HIV 1 infection, that this shift was almost unique to European descendents, and that it mirrors the intensity of Black Death mortality within Europe. Such a hypothesis is not supported by the historical evidence: the Black Death did not strike Europe alone but spread from the east, devastating regions such as China, North Africa, and the Middle East as much or even more than Europe. Further, in Europe its levels of mortality do not correspond with the geographic distribution of the proportion of descendents with this CCR5 gene. If anything, the gradient of Black Death mortality sloped in the opposite direction from that of present-day genotypes: the heaviest casualties were in the Mediterranean, the very regions whose descendents account for the lowest incidences of the HIV-1 resistant allele. We argue that closer collaboration between historians and scientists is needed to understand the selective pressures on genetic mutation, and the possible triggers for changes in genetic spatial frequencies over the past millennia. This requires care and respect for each other's methods of evaluating data.
In the mid-1990s, it was discovered that possession of the CCR5-Δ32 allele leads ‘to nearly complete resistance to HIV-1 infection’ and AIDS. 1 This genetic mutation shows strong geographical traits: while supposedly absent among Africans, Amerindians and East Asians, it is found in up to 14%, in certain northern populations of Eurasia, and more recently this figure has been estimated to be as high as 18%. 2 Moreover, within Eurasia the frequency of this gene shows a north-to-south cline, with its highest rates in north-eastern Europe. 1–5 Subsequent research has largely sustained these geographical patterns, although geneticists now find that the allele was not wholly absent from non-Eurasian populations, but is also detected in people of African descent. 2,4
In an attempt to explain these findings, it has been suggested that the Black Death may have caused the genetic mutation that conferred protection to Europeans against AIDS. 1 In a survey of CCR5-Δ32 allele frequencies in 38 ethnic populations with 4166 subjects, the absence of the allele outside Eurasia, and a north-south gradient within Europe, were affirmed. Frequencies for Asia were very low (0% for Chinese descendents, 0% for Georgians and 3.4% for Uzbeks—the highest for any area of Asia, unless Russia is assumed to be Asian; no distinction was made between Asiatic and European, or north and south Russia). (A later study showed the same pattern from 71 locations, apparently with distinctions for eastern Europe and northern Asia, but did not tabulate gene frequencies. 2 ) The earlier study by Stephens et al . 1 speculated that this change did not result from genetic drift, but happened abruptly sometime between 275 and 1875 years ago, and that the mutation occurred only once and rapidly increased in population frequency through strong selective pressure: ‘possibly [it was] an ancient plague, the nature of which is currently undetermined’. Yet, despite the uncertainty of the specificity of this genetic mutation to Europe, the authors argued that the Black Death of 1348 was the ‘best’ candidate for the supposed epidemic that set in motion this ‘enormous selective mortality’.
More recently, the genetic mutation has been attributed to smallpox, 2,6 or to a haemorrhagic disease such as Ebola, with the suggestion that the mutation did not result from a single disease strike, but from recurrence over several centuries. 6–10 These claims continue to be made, 9,10 even after new scientific evidence of the allele's more ancient origins and earlier rate of increase, 2,4,5 as well as conflicting historical facts (explored below). Making such connections between epidemics of the past and present, and in particular the Black Death's spread, its character, and its possible association with a specifically European genotype around the fourteenth century, demands careful scrutiny of the historical evidence.
In hypothesizing that the Black Death of 1348 was the crucial epidemic that caused the genetic shift, Stephens et al . 1 assumed that the plague of 1348 was the same disease ( Yersinia pestis ) as described by Alexandre Yersin in Hong Kong in 1894, and that spread to India and many ports around the world in the late nineteenth and early twentieth centuries. But bubonic plague is not a temperate or European disease; rather it flourishes in the subtropics. As a number of historians and biologists now argue, the epidemiology of medieval and recent waves of plague had little in common. Their modes and rates of transmission, cycles of infection, seasonality, and relationship between host and pathogen were strikingly different. 7,8,11–17
In short, Y. pestis is a disease of rodents in which humans sometimes participate (to paraphrase Robert Koch's succinct definition coined in 1900). For Y. pestis to become a human disease, an epizootic of rodents must first break out. After the pathogen has decimated the rodent population, hungry rat fleas seek other warm-blooded creatures to satisfy their thirst for blood and may turn to man. The transmission is hardly efficient as diseases go. The rat flea must regurgitate the bacillus into the bloodstream of a human host, which occurs successfully in less than 20% of bites. Because of this complex system of transmission, and because rats are homebound creatures, the disease spreads slowly, over ground usually no faster than 12 miles per year. Further, Y. pestis is rarely contagious. In the early twentieth century, physicians in one hospital after another reported to their astonishment that the ‘safest place to be in plague time was within the plague ward’, despite the crowding of relatives around plague-afflicted patients. Moreover, early in the twentieth century, public health workers were able to predict the outbreak of plague in India through its correspondence with the fertility cycle of rat fleas (primarily X. cheopis ). It reached epidemic levels only in coolish, humid conditions (temperatures around 50–75°F and humidity >50%. 11,16
By contrast, the Black Death wreaked fear among contemporaries, not only because of the vast numbers it killed (as high as 78% of some populations), but also because of its speed of transmission, travelling almost as fast per day as the rodent bubonic plague does per annum. Such rapid spread and apparent ready transfer from person to person led physicians and the laity alike by the late fourteenth century to distinguish this Black Death from other ‘slower-moving’ diseases with similar skin lesions such as smallpox. 11,16 Although present in the medical literature, the term ‘contagion’ took on common usage only with the Black Death and its aftershocks in the latter Middle Ages. It could strike and peak at any time of year. Yet in Mediterranean areas such as Florence, Rome, Bologna, Barcelona and parts of southern France from the mid-fourteenth to the early eighteenth century, the Black Death consistently reached its highest mortality rates in mid-summer, at the warmest and driest time of the year, when the fertility cycle of the rat flea (both X. cheopis and C. fasciatus , which is more common in Mediterranean Europe) is at its nadir. 16
Because of its complex mechanism of transmission, Y. pestis has never caused death of the magnitude recorded for the Black Death in 1348. 11,16,17 The highest mortality wrought by bubonic plague in the late nineteenth or twentieth century for any major city in any year was Bombay in 1903, in which <3% of its population was felled. 16,18 Moreover, pneumonic plague has been even less deadly. The Manchurian plagues of 1911 and 1922 are the only ones to have reached epidemic proportions, and neither killed more than 0.03% of the populations infected. 19,20 By contrast, at least a third and perhaps more than half the population of Europe was struck down in one plague only, that of 1347–1352, 17,21 when cities such as Florence lost three-quarters of their residents in four or five months. 16
Yersinia pestis in Europe
There is little evidence to suggest that Y . pestis ever seriously threatened Europe. The worst incidents of this plague were at the beginning of the twentieth century in ports such as Glasgow, Hamburg and Lisbon. Despite great fears that the Black Death had returned, none of these cities lost more than a hundred people. On the other hand, ample evidence indicates that a rat-based bubonic plague had been prevalent in subtropical India, China, and parts of Africa long before Yersin discovered the bacillus in 1894, or the so-called ‘third pandemic’ sprang from its subtropical reservoirs touching several ports in Europe, north America and Australia. Descriptions of diseases, with boils that first struck rats and then spread to humans, fill chronicles and travel reports back to at least the fourteenth century in India, and are widespread in the reports of Western doctors in China in the eighteenth and early nineteenth centuries. Yet no one to date has uncovered a contemporary source from medieval or early modern Europe that describes a disease of buboes preceded or accompanied by the death of rats or any other rodent. 16 Thus historically the bubonic plague ( Y. pestis ) appears to have been prevalent in the very places where the CCR5-Δ32 allele is absent among present-day descendants, manifesting the opposite correlation to that asserted by Stephens et al . 1 ( Figure 1 ). Furthermore, laboratory tests have shown it is unlikely that the CCR5-Δ32 allele protects against Y. pestis . 22,23 Yet despite these wide historical discrepancies and initial experimental results, scientists and the media persist in asserting the positive correlation between bubonic plague in Europe and possession of the HIV-resistant allele.
Moreover, even if we assume that the Black Death and its subsequent late-medieval and early-modern strikes were another disease ‘yet to be determined’, or even a haemorrhagic disease such as Ebola, 7–10 the argument that it provoked the HIV-resistant allele remains unconvincing. It is false to assume that the Black Death of 1348 was peculiar to Europe (including Russia), that these plagues, no matter what their agent may have been, ‘were confined to Europe’ as Duncan and Scott blatantly and erroneously assert. 10 Instead, contemporary European sources point to the origins of this disease from China, India or the steppes of Russia (where frequencies of the CCR5-Δ32 allele are zero or in Uzbek low at 3%). The Black Death arose outside Europe, and certainly devastated non-European populations as much if not more than European ones. 16,24–28 Egyptian chronicles, burials and other archaeological remains point in the same direction. Descriptions of buboes, numbers killed, and mass destruction from Egypt across the Steppes to present-day Uzbekistan, led a historian of plague in the Middle East to surmise that the Black Death and its successive strikes in the fourteenth and fifteenth centuries devastated northern Africa and Asia Minor more severely than Europe. 27,28
Those scientists who believe that the Black Death was Y. pestis (and indeed those who do not) have assumed that the north-south European geographical cline in the frequency of the CCR5-Δ32 allele among present-day descendents parallels the severity of the Black Death in 1348, as well as the recurrence of plagues to the eighteenth century. Thus Sweden (in whose descendents the allele is highest at 14%) or Finland (where some have speculated the CCR5-Δ32 allele may have originated) 2 would have been the area in Europe hardest hit by the Black Death, while Greece and Italy (whose descendents bear the lowest percentages of this allele, of around 5%) would have been hardly touched. Although plague reached Norway and Sweden, 29–32 no evidence (textual, archaeological, or from changes in cultivation) shows the plague invading Finland until 1440, and thereafter it returned only four times, 29 compared with thirty or more strikes for individual towns across much of Italy. Furthermore, the first wave of plague from 1347 to 1353 appears to have skipped over large parts of Bohemia, northern and eastern Europe, and the Netherlands (where allele frequencies are also >10%), and some of these northern zones were only lightly grazed in later medieval plagues. There is good evidence, for example, to suggest that the plague did not strike the textile town of Douai in northern France until 1400, and through the later Middle Ages it killed fewer in the Low Countries (and especially Holland) than in most other places in Europe. 16,31,32
On the other hand, narrative sources and quantitative analysis show that the plague hit the south of Europe hardest. Towns such as Trapani in Sicily were completely deserted after 1348, and from tax and burial records, Tuscany lost the majority of its population in 1348 alone. Similarly, Mediterranean cities such as Genoa and Naples in 1656, after an absence of plague for 120 years or more, again registered the highest mortalities anywhere in Europe killing half or more of these populations, a far higher proportion than of London in its Great Plague of 1665 or of Copenhagen in 1711, where in neither city was more than 20% of its population killed. 16,33,34 Thus it is erroneous to assert that the plague mortalities exhibit a north-south cline: rather the opposite seems to be the case ( Figure 1 ).
Finally, Novembre, Galvani and Slatkin 2,6 have asserted that smallpox was the disease that provoked Europe's genetic shift, and maintained its near-unique selective advantage in resisting HIV. But like others who have failed to review the global history of diseases, they neglect the fact that smallpox originated outside Europe, and that there is no evidence that Europe suffered more from it than other parts of the world in medieval, early modern or modern history. Quite the contrary, the New World from the sixteenth century on (when Galvani and Slatkin assume that smallpox was exerting its selective pressure on European populations 6 ) suffered far more. 25 The earliest descriptions of smallpox (and the last reported naturally occurring cases) came from outside Europe: from India and Somalia, respectively. 25,35
A historical and scientific synthesis
To understand the significance of the geographical distribution of the CCR5-Δ32 allele, historians and geneticists need to consider epidemics or conditions that were specific to Europe and which show a north-south cline rather than point to diseases such as bubonic plague ( Y. pestis ), typhus, smallpox, and others whose origins were in the tropics or subtropics. They must be clear and confident of their respective data, and when seeking geographic and demographic associations must be able to define with precision the disease genotypes and phenotypes at different times and places. Molecular methods may be powerful, if properly used. They can be applied to past generations as well as to present-day populations.
Geneticists, archaeologists and physical anthropologists are revising the conclusions drawn in the late 1990s; they are now finding ancient DNA with the mutant gene CCR5-Δ32 in skeletal remains in northern Europe as early as 2900 years ago. 36 Some have estimated its age at 5075 years, and have argued that ‘the high frequency of the allele cannot be attributed solely to a strong selective event within the past millennium’. 5 Moreover, samples from graves in Lübeck (northern Germany) show no difference in percentages of the allele in those who died before and after the Black Death of 1348. 36,37 On the basis of these findings, along with a specific knowledge of the character of the Black Death (whatever disease it was) and its geographical distribution, there is no connection between plague and the HIV-resistant allele.
There are, of course, many examples of one disease conferring protection or vulnerability to another. Sickle-cell anaemia and malaria is a classical instance of two diseases sharing the same geographical distribution, leading to hypotheses to explain their coincidence. 38,Helicobacter pylori and protection from diarrhoeal disease is another. 39 The historical record of diseases can point to ones that were largely confined to Europe and exhibited a north-south cline, such as ergotism. 40 Lactose tolerance is much commoner among European descendents than from those elsewhere in the world; yet within Europe there is a wide range of allele frequencies, showing a distinct north-south cline: Scandinavian descendents are at the top with 100% tolerance, while those from Sicily and Greece are at the bottom with as little as 29%. 41–43 Moreover, the long-term estimates of the emergence of the CCR5-Δ32 gene correspond roughly with those for lactose tolerance (LCT) in Europe. 43 In genetic time, both developed through selective pressures remarkably quickly. Perhaps these parallels should be explored further with more detailed samples of CCR5-Δ32 from Africa and other non-European zones, to distinguish between regions populated by ancient herdsmen with lactose tolerance and zones with low frequencies. Considering Africa as a single zone, as is presently the case with CCR5 studies, constitutes a blunt instrument (as crude, if not more so, as considering Europe as a single homogenous genetic entity). While the largest sample of CCR5-Δ32 genotypes now derives from only 71 regions worldwide, studies of LCT comprise 952 geographic areas, with many thousands of humans genotyped.
The exciting correlations discovered by geneticists and epidemiologists between present-day genotypes in human populations, and varying levels of resistance to diseases, now demand a new cooperation between scientists and historians. Together, they can explore the connections between events, environment, biological change, and possible selective pressures that have occurred in the historical (and not just the pre-historical) past. While the methods and data used by these scholarly communities differ, care and respect for each other's analytical traditions, methods of evaluating data, and sources cannot be neglected by either.
We are grateful to Jean Hyslop for help in composing the figure.