The Angel of Death

•	In our last lecture, we watched our distant ancestors descend from the trees into a brave new world, filled with new evolutionary challenges
•	We saw how epidemic diseases were born from our change to an agricultural lifestyle, and the rise of the great cities of the ancient world

•	In this lecture, we’ll witness the bubonic plague descend like an angel of death upon the cities of Europe
•	And we’ll learn why one of mankind’s oldest diseases has become one of our newest medical mysteries…

•	It’s hard to imagine something as small as a bacterium in the role of the grim reaper
•	But if you’re small enough to fit on the head of a pin, you’re also small enough to ride on the back of a flea, or safely tucked inside of one…
•	And that’s what vector-borne diseases rely upon

•	Many of our worst diseases are vector-borne diseases, like typhus, malaria, and dengue fever
•	While crowd diseases didn’t become a problem until our populations grew, vector-borne diseases probably plagued us while we were still swinging through the trees…

•	Vectors are organisms that carry microbes that cause diseases
•	Most vector-borne diseases are carried by arthropods, like flies, fleas, ticks, lice, and mosquitoes

•	Many microbes rely on multiple vectors
•	Malaria and dengue fever, for example, can be carried by several different species of mosquitoes

•	Vector-borne microbes evolve differently from other microbes
•	As long as their primary host is healthy, they don’t really need us
•	Extreme virulence isn’t usually a great idea, as microbial strategies go
•	It’s better to have the victim up and about, spreading the microbe far and wide

•	But if a microbe relies on a vector, it’s no problem if the host is bedridden and in agony
•	The vector can easily pick up the microbe from patients who are flat on their backs, plus the victims can’t usually fight back!

•	Vector-borne diseases are like tiny angels of death, swooping down from some invisible realm, turning our hopes and dreams into nightmares, and turning our cities into graveyards
•	Or so it must have seemed to Europeans, when the Black Death fell upon them…

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Prior to the emergence of the plague, Europe was basking in one of the most fruitful, productive, and disease-free periods in its history
•	For reasons we still don’t understand, temperatures were much warmer from about 950 AD to 1250 AD

•	During this Medieval Warm Period, European populations grew very rapidly
•	By the Twelfth Century, the population of Europe had tripled

•	They called it the “monde plein”, the full world – and it was the time when the great cathedrals were built
•	The warm period led up to the Renaissance, the great flowering of European culture

•	But this warm spell was followed by an extended period of damp, chilly weather called the Little Ice Age, which lasted for nearly five hundred years, from about 1350 to 1850
•	Very few people have heard of the Little Ice Age, although it was one of the most important events in human history

•	America is a nation of beer drinkers, for example, because our ancestors couldn’t grow grapes in Northern Europe during the Little Ice Age!
•	Among the many cultural landmarks it led to were sexual privacy, the Stradivarius violin, and the French Revolution… 

•	Sexual privacy became possible because the cold weather led to the invention of chimneys and flues that could share a fireplace on more than one floor, instead of the traditional (and now inadequate) communal hearth

•	This also reinforced the differences between the social classes, because now there was a definite upstairs and downstairs for masters and servants, even in winter
•	The Stradivarius violin may owe its exquisite tone to the densely packed cells in the wood, a response to the cold climate

•	As for the French Revolution…there’s nothing like a few generations of famine to fuel social unrest among the have-nots 
•	How cold did it get?

•	Temperatures were about 4o-5o F colder
•	Cold enough to cause increased snow cover, and to set the glaciers moving south
•	It’s no accident that so many paintings from this period depict winter scenes

•	We don’t fully understand what caused it, but our best theory is that the warm period melted enough ice and snow to change the density of seawater in the North Atlantic 
•	This input of fresh water slowed down or stopped the oceanic conveyor belt, the ocean currents that redistribute equatorial heat to the poles

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The temperate zone got a lot colder…
•	During such periods of global climate change, weather becomes extreme, and unpredictable
•	Severe storms, floods and droughts became more frequent, as the Little Ice Age progressed

•	It became harder and harder to grow crops
•	By the 14th Century, summers in Northern Europe became too cool and damp for grain to fully ripen, and the Great Famine set in
•	Millions starved, and many turned to cannibalism

•	Thousands of villages disappeared from the map
•	Between 1350 and 1450, Germany alone lost 40,000 towns
•	Guards had to be posted on the gallows throughout the Rhineland, or villagers would cut down the corpses for food

•	Wheat became increasingly expensive – the staple food of all Europe
•	Natural catastrophes began to mount from the fickle weather, like the All Saints Flood in Holland, in 1570, in which over one hundred thousand people drowned

•	Social and political structures broke down, as people tried to figure out why God had abandoned them, and why neither priests nor kings could stop the world from sliding into ruin…
•	They looked for scapegoats, like Jews, or witches, or anyone in authority 

•	As if things weren’t bad enough, the Hundred Years War was soon raging throughout Europe (1337 to 1453)

•	The historian Barbara Tuchman, in her classic A Distant Mirror: The Calamitous 14th Century, calls it one of the worst times to be alive in human history
•	And into this already dismal period came the Black Death, a pandemic that would kill half the population of Europe

•	Bubonic plague is a vector-borne disease, carried by oriental rat fleas
•	It can persist in the wild in many species of rodents 
•	It is an ancient killer…

•	They say that history is written by the survivors, but in the ancient plagues, survivors were few and far between
•	Take the Plague of Justinian, for example, the first recorded pandemic of the bubonic plague…

•	The Plague of Justinian began in 541 AD, and burned through the Roman Empire for over two hundred years
•	It started in Egypt, and spread from Alexandria throughout the known world

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It claimed 10,000 lives a day in Byzantium at its peak, with over 300,000 victims in a single year, a quarter of the city’s population
•	The final death toll, for the Eastern and Western Holy Roman Empire, is estimated at 100 million people!

•	The historian Procopius tells us:
>	Finally, when there was a scarcity of gravediggers, the roofs were taken off the towers of the forts, the interiors filled with the corpses, and the roofs replaced…And after the plague had ceased, there was so much depravity and general licentiousness, that it seemed as though the disease had left only the most wicked.”

•	Most believe that the second pandemic, the medieval outbreak known as the Black Death, arose in Central Asia or China around 1320 to 1340
•	Untold millions of Chinese died of plague, which spread to India and Africa along the Silk Road and ocean trade routes

•	It was a terrible confluence of events for the unsuspecting citizens of Europe
•	The world was finally emerging from the shadow of the collapse of the Roman Empire, and trade and travel once more extended outward, into Africa, India, and the Far East

•	Crusaders crossed the map of the known world by the tens of thousands
•	The old Silk Road was back in use, with stalwart travelers like Marco Polo, in 1271

•	And the Mongol Horde straddled Eurasia, from China to the Black Sea
•	A steady stream of exotic trade goods, and exotic microbes, flowed from Cathay to Constantinople

•	The plague may have entered Europe during the siege of Caffa, when the Khan’s Turkish mercenaries hurled plague-ridden corpses over the walls of the city
•	We’ll learn more about the attack on Caffa in our lectures on germ warfare

•	When the plague hit Caffa, then held by the Genoese, its residents fled in terror, carrying the disease back to Sicily, Genoa, Venice, and other Mediterranean ports
•	Within three years it covered all of Europe and North Africa, reaching Britain in 1348

•	Weakened by generations of famine, crowded into cities fouled by garbage, sewage, and rats, European populations were sitting ducks for the Black Death
•	Populations fell 40 to 60%, with up to 75 to 100 million dead in the 14th Century alone

•	The plague ebbed and flowed throughout Europe for the next three hundred years
•	The last gasp of the Black Death was the Great Plague of London, in 1665-1666, chronicled by Daniel Defoe and Samuel Pepys
•	Between 70,000 and 100,000 people died

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London’s dogs and cats fell under suspicion as plague bearers, and 40,000 dogs and over 200,000 cats were slaughtered
•	Which, of course, only further increased the population of the rats that carried the infected fleas!

•	There are three distinct forms of plague, each more horrible than the last – bubonic, which is the most common form, pneumonic, and septicemic
•	Fortunately, modern antibiotics and vaccines are effective against all three forms of plague

•	Bubonic plague is a disease of the lymphatic system, an important part of the immune system, as we’ll learn in our series of lectures on immunity
•	It starts from 2 to 5 days after infection, with fever, chills, muscle aches, and headaches

•	The lymph glands in the groin, neck, and armpits swell to grotesque proportions, the characteristic plague buboes

•	Delirium, convulsions, coma, and death may quickly follow, with about 40-60% mortality in 2 to 8 days if left untreated
•	Victims are often in extreme pain, thought to be due to the decomposition of their skin while they’re still alive!

•	In pneumonic plague, the disease spreads to the lungs, and can then be spread as an aerosol through coughing and sneezing
•	The symptoms include coughing up blood, progressive pneumonia, and shock
•	The fatality rate is over 90%, and death occurs in as little as 1 to 2 days!

•	In septicemic plague, the bacterium enters the bloodstream, and kills virtually 100% of its victims, most of them in less than a day
•	A bacterial toxin interferes with the normal clotting process, and victims quickly bleed to death internally

•	These clinical descriptions, as terrible as they sound, cannot begin to convey the sheer horror that confronted mankind during the Black Death
•	The poet Petrarch asks: 
>	“Is it possible that posterity can believe these things? For we, who have seen them, can hardly believe them.”

•	The Black Death – the very name conjures up bleakness and despair
•	Those who lived through it called it the Great Mortality, or the Great Pestilence, the term “Black Death” wasn’t coined until 1832

•	Rotting corpses lay where they fell, in streets, in alleyways, in houses….
•	Boccaccio says: 
>	“How many valiant men, how many fair ladies, breakfast with their kinfolk and the same night supped with their ancestors in the next world!”

•	Thieves and looters rejoiced, but only until they caught the disease themselves, from plundering the dead…
•	Many stores were closed and shuttered, and hoarding and profiteering were rampant
•	Healers and priests were scarce, those ministering to the sick were the first to die

•	Corpses were carried away by an endless succession of carts, and tossed into mass graves by the hundreds
•	The constant tolling of church bells was an eerie counterpoint to daily life
•	The only sound more ominous was the silence that fell when no one was left to ring them

•	One survivor writes in the 14th Century:
>	“And I, Agnolo di Tura, called the Fat, buried my five children with my own hands...There was no one who wept for any death, for all awaited death. And so many died that all believed that it was the end of the world”

•	di Tura describes graves so shallow, that dogs dragged out corpses and devoured them – he says:
•	“And in many places in Siena great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night, and all were thrown in those ditches and covered over with earth. And as soon as those ditches were filled more were dug”

•	People looked for scapegoats – Jews were blamed for poisoning the wells and causing the plague
•	The slaughter of Jews was frightening – the city of Strasbourg alone killed 2,000 Jews in 1349, and by mid century, over 200 Jewish communities had been wiped out

•	Quack cures were abundant, and physicians were all but helpless in the face of the plague
•	To avoid direct physical contact, doctors dressed in a morbid “beak doctor” outfit, an early version of a biohazard suit, with a grotesque bird-like mask

•	The long beak was stuffed with crushed flowers, aromatic herbs, and spices partly to cope with the stench of rotting corpses, and partly due to the mistaken belief that the plague was spread by invisible vapors called miasmas
•	We’ll learn more about miasmas in our next lecture, on germ theory…

•	People stuffed their pockets full of dried herbs and flowers for the same reason, as immortalized in the famous children’s rhyme, which many believe dates back to the Plague of London…

•	Ring around the rosey,
A pocketful of posies,
ashes, ashes,
We all fall down! 

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Petrarch, who lost his true love Laura to the plague, laments:
>	 Where are our dear friends now? Where are the beloved faces? Where are the affectionate words, the relaxed and enjoyable conversations? What lightning bolt devoured them? What earthquake toppled them? What tempest drowned them? What abyss swallowed them? There was a crowd of us, now we are almost alone.”

•	When the plague subsided, rather than turn towards the Church and thank God for sparing them, many people had the opposite reaction
•	As Matteo Villani tells us, “They believed that those whom God’s grace had saved from death … would become better conditioned, humble, virtuous, and Catholic; that they would guard themselves from iniquity and sins, and would be full of love and charity, one towards another. But no sooner had the plague ceased, than we saw the contrary; they forgot the past as though it had never been, and gave themselves up to a more shameful and disordered life than they had led before. They dissolutely abandoned themselves to the sin of gluttony, with feasts and taverns, and delights of delicate foods; and again to games of hazard and to unbridled lechery. And the common folk would no longer labor at their accustomed trades, but demanded the dearest and most delicate foods for their sustenance; while children and common women clad themselves in all the fair and costly garments of the ladies dead by that horrible death.”

•	The third pandemic began in China about 1890, and has since claimed 15 million lives
•	This time, the microbe finally circled the globe, entering the United States through Chinese workers in San Francisco
•	It’s still endemic in the American Southwest!

•	When the plague returned for its third visit, however, we were prepared
•	As we’ll learn in our next lecture, we were finally aware of the true nature of disease, and the proponents of germ theory were eager to hunt down this ancient enemy

•	The race was on to discover the microbe that caused the plague
•	A Japanese team headed by Dr. Shibasaburo Kitasato took an early lead 
•	But a young doctor named Alexandre Yersin was the first to confront mankind’s medieval nemesis

•	Yersin was a young Swiss medical student, who became a French citizen in order to study in Paris, at the Hotel Dieu Hospital
•	While doing an autopsy on a rabies victim, he accidentally cut himself
•	He rushed to the nearby Pasteur Institute, and asked Pasteur for help

•	Pasteur asked his chief colleague, Emile Roux, to try his new rabies vaccine on Yersin
•	Roux was impressed with the young medical student, and a lifelong friendship began between Roux, Yersin, and Pasteur
•	Roux even helped Yersin write the dissertation for Yersin’s medical doctorate

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Yersin continued to work at the Institute, teaching a class in microbiology, and when plague struck in China, Pasteur asked Yersin to investigate
•	Pasteur persuaded the French authorities to send Yersin to Hong Kong in 1894

•	But the British ruled Hong Kong, and they supported Dr. Kitasato, a colleague of Robert Koch
•	Kitasato had all the advantages – a team of Japanese specialists, a gleaming and well-stocked laboratory, the latest Zeiss microscopes…

•	When Yersin arrived at the Hong Kong city hospital, he found that every door was closed
•	The hospital director refused to give him space for a laboratory, and wouldn’t even let him take samples from the hospital’s plague victims!

•	After pleading with the governor of Hong Kong, Yersin forced the hospital director to give him an office, which turned out to be a small table in a corner of a dimly-lit hallway, with barely enough room for a microscope and a few rat cages

•	Yersin took matters into his own hands, and with the help of a local priest, Father Vigano, he built a grass hut right next to the hospital, to serve as his laboratory!

•	He bribed two British soldiers working in the hospital morgue, to let him take samples from the buboes on corpses
•	He rushed back to his hut with his samples, and soon identified and isolated the bacterium, using it to infect two guinea pigs with the plague

•	He named the bacterium Pasteurella pestis, though it was later renamed Yersinia pestis, in his honor (Kitasato is recognized as its co-discoverer)

•	Yersin continued to work night and day on the plague, and soon discovered an effective antiserum 
•	He later opened a branch of the Pasteur Institute in Vietnam, which became his adopted country, and devoted himself to the health and welfare of the Vietnamese people

•	He lived a rich and rewarding life, collaborating with Roux on the discovery of the diphtheria toxin, introducing rubber plantations to Indochina, and helping to found the Hanoi Medical School

•	His home in Nha Trang is now a museum, and his tomb has become a local shrine
•	His tombstone reads – “Benefactor and humanist, venerated by the Vietnamese people”

•	Although Yersin solved one mystery, he was left with another that was equally puzzling
•	How was the plague transmitted from rats to humans?
•	Yersin couldn’t help but notice the dead rats that lay everywhere throughout the city, even in the hospital corridors!

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He made the critical connection between the rats and the plague, but couldn’t figure out how it was actually spread
•	That task fell to Paul-Louis Simond, a young French colonial army doctor, who proved that the oriental rat flea, Xenopsylla cheopis, was the culprit

•	Simond noticed that only those who handled freshly killed rats caught the plague – perhaps the rat fleas were jumping ship!
•	His laboratory made Yersin’s grass hut look like a palace!
•	He lived in a tent, in the middle of India’s rainy season, with almost no equipment

•	Simond had to figure out a safe way to recover freshly killed fleas without handling the rats
•	He solved the problem with a paper bag and a bucket of soapy water
•	He patiently waited for the rats to die of plague, then quickly dropped them into the bag, using long forceps

•	He held the bag underwater, then carefully cut it open to let the soapy water kill the fleas!
•	He later worked out a remarkably clever apparatus to show that uninfected rats could be infected with plague without direct contact, by picking up fleas jumping from dead rats

•	The bacteria multiply in large numbers inside the flea, forming balls that block the fleas midgut, so that it can’t properly feed
•	The ravenous fleas bite harder, while trying to clear their gut by regurgitating concentrated wads of bacteria

•	So each bite delivers thousands of bacteria to infect the next rat
•	A nice example of host manipulation, a microbial strategy we’ll discuss later in more detail

•	The ongoing third pandemic has been relatively mild
•	Several cases of plague are reported every year, but it never spreads very far
•	Part of the reason may be the changing relationship between rats and humans

•	Rats are scarcer that they used to be, even in poor countries
•	Rats are actually an exotic species in Europe, travelers from the Orient…

•	Rats first appeared in European cities around 400-1100 AD
•	Rattus rattus, the black rat, was the first, followed around 1550 by hordes of brown rats, Rattus norvegicus, the so-called Norway rat (it’s really an Asian species)

•	Brown rats are large and aggressive, and quickly displaced the black rat 
•	Brown rats can carry quite a few nasty surprises, typhus, trichinella, a type of jaundice, even a form of equine flu
•	But while brown rats can suffer from plague, the oriental flea prefers the black rat

•	Black rat populations used to build up to frightening levels in Europe
•	But modern rat populations are much smaller, even in poor nations, and are dominated by brown rats

•	Today’s rats are also more domesticated, and tend to stay in one house or neighborhood
•	The plague never spreads beyond the local rodent population

•	And therein lies a mystery….
•	If all three pandemics of plague are the same disease, why don’t contemporary accounts of the Black Death mention large numbers of dead rats?
•	Some do, but many do not….

•	And how do you explain the fact that plague spread even in the cold weather of the Little Ice Age, when rat and flea populations should have been at a low ebb
•	Plague even swept through Iceland, which had no indigenous rats

•	Was the Black Death the same disease as the bubonic plague, or was it something entirely different?
•	That theory was proposed in 1984 by Graham Twigg, who also pointed out that the mortality rate, rapid spread, and epidemic cycles of the Black Death aren’t consistent with the pattern of modern outbreaks

•	He suggested a form of anthrax as the cause of the Black Death – others have suggested an Ebola-like virus
•	The discovery in 2000 of Yersinia pestis DNA from the teeth of 14th Century plague victims, seemed to settle the matter

•	In 2009, however, an Oxford team examined 121 similar teeth, and were unable to find any trace of the bacterium, supporting the theory that the Black Death was a different disease

•	But the issue may have been finally settled in October of 2010, by an international team sampling several mass graves of plague victims all across Europe
•	They found widespread evidence of Yersinia pestis infection

•	This still doesn’t explain the absence of rats in many plague-infested areas, or the inconsistencies in the descriptions of symptoms or epidemiological patterns
•	Many people are still convinced that the Black Death and the bubonic plague are two different diseases…

•	And so we’ve traced the history of the worst vector-born disease of all time, the Black Death
•	The Medieval Warm Period allowed for a rapid increase in European population density

•	But the bad weather of the Little Ice Age led to a collapse in agriculture, and generations of famine and malnutrition helped to make medieval Europe especially vulnerable to the deadly clutches of the plague

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We’ll look at many other examples of how both natural and man-made changes to the environment have encouraged the spread of microbes
•	The Black Death also illustrates that vector-borne diseases can be especially virulent, for reasons we’ll discuss later on

•	One of the most terrifying aspects of the plague must have been not knowing what was killing you…
•	In our next lecture, we’ll learn how we gradually became aware of the existence of the mysterious and invisible realm of microscopic creatures