Q J Med 2006; 99:497–503
doi:10.1093/qjmed/hcl076
Review
The Black Death and AIDS: CCR5-32
in genetics and history
S.K. COHN, JR and L.T. WEAVER1
From the Department of History (Medieval Area) and 1Division of Developmental Medicine
(Child Health), University of Glasgow, Glasgow, UK
Summary
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.
Introduction
In the mid-1990s, it was discovered that possession
of the CCR5-32 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 CCR5-32 allele frequencies in 38 ethnic
populations with 4166 subjects, the absence of the
Address correspondence to Professor S.K. Cohn, Jr, Department of History (Medieval), 10 University Gardens,
Glasgow G12 8QQ. email: [email protected]
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!
498
S.K. Cohn, Jr and L.T. Weaver
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.
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 450%.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
The Black Death and AIDS
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 CCR5-32
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 CCR5-32 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
499
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 CCR5-32 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 presentday 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
CCR5-32 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 CCR5-32 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
410%), 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
500
S.K. Cohn, Jr and L.T. Weaver
Figure 1. Population frequencies of the CCR5-32 allele (upper section: black 410%, dark grey 6–10%, pale grey <6%)
and Black Death mortalities 1346–53 (lower section: black 450%, dark grey 25–50%, pale grey <25%) in Europe. Based on
data from Stephens et al.1 For computer-simulated maps, see Novembre et al.2
The Black Death and AIDS
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 Slatkin2,6 have
asserted that smallpox was the disease that provoked
Europe’s genetic shift, and maintained its nearunique 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 populations6)
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 CCR5-32 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 CCR5-32 in skeletal remains
501
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 CCR5-32 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 CCR5-32 from Africa and other nonEuropean 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 CCR5-32 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
502
S.K. Cohn, Jr and L.T. Weaver
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.
Acknowledgements
We are grateful to Jean Hyslop for help in
composing the figure.
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