Stone Knives to Iron Plows

•	Plagues were not always a problem
•	Epidemics couldn’t spread very far when the human race consisted of only scattered nomadic tribes

•	But when we started gathering together to build villages, and raise crops and domesticated animals, we changed our niche and altered our habitat
•	And these changes in ourselves and in our environment forced microbes to adapt or perish 

•	So let’s follow our slow climb from Pleistocene caves to Paleolithic campfires, from Neolithic towns to the towering cities of the ancient world
•	And along the way, let’s consider the many ways in which these changes left us vulnerable to a host of new microbial invaders and microbial strategies

•	Our voyage begins six million years ago on the plains of Africa
•	I want you to close your eyes, and imagine what that world was like

•	Stretching as far as the eye can see is the endless savanna, small islands of trees, separated by stretches of open grassy terrain
•	Grazing animals cross the grassy land in small herds, and if you’re lucky, you might get a glimpse of our primate ancestors, swinging from tree to tree in the remaining forests

•	About four to seven million years ago, vast ice sheets began to spread over North America and Eurasia
•	The tropical African climate became much cooler and drier
•	Dense steamy jungles gave way to open savanna

•	The evolutionary edge now went to those animals adapted for a mixture of arboreal (tree dwelling) and cursorial (ground running) challenges
•	This new environment favored those who could both live in the trees, and cross the open grasslands to forage on more distant tree islands

•	And when you take a closer look at the mammals during this period, not surprisingly, you see a general decrease in the number of arboreal species, and an increase in the number of cursorial species

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Our distant ancestor Australopithecus lived in this mosaic of forest and plain
•	And if you look at its skeletal structure, you see a mixture of arboreal and cursorial adaptations

•	By taking those first few steps onto solid ground, we were already starting down the path that would someday lead to smallpox, typhus, and the Black Death
•	As soon as our bare feet touched the warm soil, we changed both the battlefield and the rules of engagement in our eternal struggle with our microscopic foes

•	Contact with the earth meant contact with an entirely new group of microbes from those we carried down with us from the treetops
•	The soil teems with all kinds of parasites and pathogens - viruses, nematode worms, and flukes

•	Among those hordes of new microbial neighbors were tapeworms, hookworms, anthrax, smallpox, flu, and a host of other human ills that now became a part of our evolutionary heritage
•	For better or worse, our world would never be the same

•	And now, for the first time, we came into close and regular contact with many other ground-dwelling animals, like rabbits, rats, mice, and the ancestors of our domesticated cattle and poultry

•	Hunting new types of prey meant direct contact with new species of microbes 
•	Homo erectus probably picked up tularemia and anthrax from skinning and eating animals like rabbits
•	With our prey came Salmonella, and the parasites that carry hemorrhagic fevers

•	Hunting big game was a big step for us in more ways than one
•	Because many of the animals that would have been easiest to catch would also have been those most easy to catch something from!

•	Like most predators, we must have preyed upon those animals least likely to escape or defend themselves, the very young, the very old, and the very sick
•	So diseased animals became a regular part of the human diet, along with tapeworms, flukes, and Trichinella

•	Why didn’t all these new pathogens wipe out our distant ancestors?
•	Despite all these new microbial challenges, epidemic diseases were still not a significant problem
•	What probably saved us was our small populations – the Earth was a pretty lonely place….

•	At the end of the Pleistocene, the entire human race consisted of only about five million people, scattered in small bands across the surface of the Earth
•	Each band or tribe probably consisted of a dozen or two individuals or less, rarely more than a hundred

•	And each tribe roamed over a huge territory, probably several square miles, with a population density of only about one person per square mile
•	These hunter-gatherers lived off the land, foraging for nuts, berries, roots, grains and seeds, and whatever small prey they could catch

•	You can still find similar nomadic tribes today, in parts of India, Mongolia, and the Arabian desert
•	The nomadic life style favors low birth rates
>	The land can only support a few people
>	It’s hard to carry and raise children when you’re constantly on the move

•	Small nomadic populations could live off the land indefinitely, slowly using up local resources, and then moving on to new areas with fresh supplies
•	Bands rarely crossed paths, and may have even intentionally avoided one another, minimizing the competition between them

•	With no way to store or preserve food, we had to keep moving to stay alive
•	So we were never in one place long enough to build up trash heaps or pollute the ground or the water with our sewage

•	And because we had to carry our worldly goods on our backs, material possessions were few, limited to those items most essential for day to day survival
•	With game abundant, there was no need to domesticate animals

•	In this idyllic environment, our ancestors may have suffered occasional outbreaks of diseases like flu or smallpox
•	But such outbreaks were self limiting
•	Once the disease had burned through the local tribe, it had nowhere else to go and would become locally extinct

•	Diseases like measles, smallpox, and the bubonic plague are crowd diseases
•	They require large interbreeding populations to sustain themselves

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Only diseases carried by animals like flies or mosquitoes, or diseases able to persist in the soil for long periods of time, like anthrax, would have caused serious problems for early man –

•	Animals that carry diseases are called vectors – we’ll talk more about vectors later on…
•	As the Old Stone Age, or Paleolithic, gave way to the New Stone Age or Neolithic, human settlements were gradually increasing in size and in number
•	Advances in hunting, fishing, and agriculture enabled our ancestors to form larger and more permanent camps

•	After 15,000 years of slow and steady growth, the human population took a BIG leap about 10,000 years ago
•	We went from 7 or 8 million in 10,000 BC to ~ 100 million by 5,000 BC
•	This is a remarkable 10 fold increase in human population

•	So dust off your thinking cap…what could have caused it?
•	I’ll give you a hint – we started doing something different, something really major that we still do today…
 
•	The Neolithic population boom probably marks humanity’s transition to a radically different life style
•	We changed the kind of animal we were, going from nomadic hunter-gatherers, like our primate ancestors, to settled farmers

•	Ecologically speaking, that’s a very big step
•	It is a change in our fundamental human niche – our functional role in the ecosystem - and we are one of the few species ever to accomplish it

•	Over the course of thousands of years, we gradually began to rely less and less on what we could hunt and gather, and more on what we could grow for ourselves
•	The Agricultural Revolution was perhaps the most significant event in human history

•	It allowed us to build up large urban settlements, that would become not only the basis of the great civilizations of antiquity, but also served as a breeding ground for many of our worst microbial foes
•	It encouraged us to build a network of trade routes, which spread microbes as well as trade goods and ideas

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Civilization also created a wealth of new microbial habitats
•	The need to store food in granaries, for example, gave a big boost to populations of rats, mice, and other disease 
•	Rats owe us, big time! – Our civilization is the best thing that ever happened to them! 

•	Our trash heaps became a rich new food source for legions of rodents, flies, and other disease vectors
•	Our water supplies became increasingly contaminated with human and animal wastes, opening up a new strategic pathway for diseases like cholera

•	Deforestation for settlements, cropland and pastureland changed the landscape
•	Many of these changes favored the emergence of diseases like the plague 

•	Our new found wealth and settled lifestyle allowed us to accumulate material possessions – clothing, furniture, bedding
•	And our clothing and bedding provided new environments for diseases carried by ticks, fleas, lice and bedbugs

•	Our new found civilization came with a big price…
•	Neolithic man was shorter and less healthy than Paleolithic man, and didn’t live as long

•	Late Mesolithic skeletons are less robust, and about two inches shorter than Paleolithic skeletons
•	Life expectancy dropped as much as ten years from the Paleolithic to the Neolithic

•	Somewhere around the Bronze Age, about 6,000 years ago, the population density of the human species became high enough for a new type of population regulation to kick in
•	Remember in our last lecture when we talked about extrinsic population regulation?

•	Limiting factors act as a feedback loop to keep populations in balance with their environment
•	Another perspective on limiting factors is to consider how they relate to the density of a population

•	Notice I said density, not size or numbers… population density is numbers per unit area
•	5,000 bunnies in a 10,000 acre field is not a dense population, but those same 5,000 bunnies would be tail to tail in a one acre meadow 

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Sometimes limiting factors act without regard to population density – we call these factors density-independent limiting factors
•	It doesn’t matter whether there are 5 deer or 5,000 deer in a woodlot - if it burns to the ground they’re all toast (well, technically, barbeque…)

•	What we think of as the forces of nature – fires, floods, tornados, hurricanes – are essentially density-independent
•	Sometimes, however, the degree of regulation is directly correlated with population density – we call these factors density-dependent limiting factors

•	Remember our bottled water analogy from last time? 
•	The intensity of the competition for limited bottles of water will depend to a large degree on the density of the population in the store
•	Competition is an extrinsic, density-dependent limiting factor

•	Resources often act as a density-dependent mechanism
•	An obvious example is food supply
•	Food limits population growth in direct proportion to population density

•	Even more subtle than extrinsic limiting factors are limiting factors that act from inside the population - intrinsic limiting factors
•	These are changes in an individual’s reproductive physiology, or their reproductive behavior, that reduce population size in response to factors like over crowding

•	A.E. Newsome did a wonderful experiment, back in 1971, that shows how this works
•	He started with 6 mice, and a limited supply of food, sheaves of oats…
•	(Describe data…)

•	So as population densities exploded, and the food started to run out, fewer and fewer mice were in prime breeding condition
•	This is a great example of intrinsic population regulation, regulation that occurs within each individual

•	Now, let’s see if you’ve got it straight - Are these limiting factors extrinsic or intrinsic, density dependent or density independent?
>	Forest fires (extrinsic, independent)
>	Food (extrinsic, dependent)
>	Predators (extrinsic, dependent – search time, encounter rate, brood size etc…) 
>	Microbial diseases and parasites – think carefully…

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Microbial diseases and parasites are extrinsic, density-dependent limiting factors
•	Think of someone sneezing in a nearly empty room – and that same person sneezing in a crowded office
•	Many microbial strategies rely on densely packed populations to disperse themselves

•	Once human populations became organized into crowded cities, microbial pathogens could exploit our new vulnerabilities
•	The results were measles, smallpox, typhus, plague, syphilis, scarlet fever, a long and growing list of epidemic diseases that would shape our subsequent history 

•	Crowd diseases depend on dense populations of hosts to sustain them
•	Studies of measles, for example, suggest that you need a minimum urban population of about 5,000 people to sustain it

•	As the cities of ancient Egypt, Mesopotamia and Greece reached this critical threshold, epidemics became a part of human history
•	It is often difficult to tell precisely what these diseases were

•	There were few survivors to chronicle these savage epidemics, and the descriptions of symptoms are often lacking in sufficient detail
•	But the few descriptions that have survived of ancient plagues are truly chilling

•	Thucydides wrote in his History of the Peloponnesian War what may be the first descriptions of a pandemic, the Plague of Athens, around 430 BC

•	Athens was at war with Sparta, the second year of the Peloponnesian War
•	The Spartan army was advancing on Athens, which was ill prepared to fight back

•	The Spartan army was fierce and well-trained, and way too powerful for the Athenians, whose military strength lay in their superior navy – not too much use in this case
•	Rather than face them head on, the Athenians retreated behind their wooden city walls, and settled in for a long siege

•	As the Spartan army drew closer and closer, thousands of refugees streamed into the crowded city, creating the perfect conditions for an epidemic
•	Thucydides tells us that the epidemic started in Ethiopia, then passed through Egypt and Libya and into Greece

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The oracle had warned them that this was coming – a long time ago…
•	Thucydides says:
•		“In their troubles they naturally called to mind a verse which the elder men among them declared to have been current long ago: ‘A Dorian war will come and a plague with it.’ ” 

•	No one knows what microbe was responsible - the candidates include typhus, plague, smallpox – even Ebola!
•	The loss of digits to gangrene strongly suggests typhus, but it’s also possible that more than one pathogen was to blame

•	Thucydides himself fell ill, and describes the symptoms in these words: -- “Externally the body was not very hot to the touch, nor pale in its appearance, but reddish, livid, and breaking out into small pustules and ulcers. But internally it burned so that the patient could not bear to have on him clothing or linen even of the very lightest description; or indeed to be otherwise than stark naked. What they would have liked best would have been to throw themselves into cold water; as indeed was done by some of the neglected sick, who plunged into the rain-tanks in their agonies of unquenchable thirst; though it made no difference whether they drank little or much.”

•	“For the disorder first settled in the head, ran its course from thence through the whole of the body, and even where it did not prove mortal, it still left its mark on the extremities; for it settled in the privy parts, the fingers and the toes, and many escaped with the loss of these, some too with that of their eyes. Others again were seized with an entire loss of memory on their first recovery, and did not know either themselves or their friends.”
•	 It came and went for four long years, killing a quarter of the city’s inhabitants

•	Thucydides says: “The bodies of dying men lay upon one another, and half-dead creatures reeled about the streets.” 
•	Over 1,000 tombs dating to this time were uncovered in 1995, along with a mass grave containing 150 bodies

•	The Athenian army was devastated, losing 4,400 infantry and 300 cavalry to the plague
•	The decimated army never truly recovered, and Athens eventually lost the war, its weakness setting the stage for the rise to power of the Macedonians, and later the Romans

•	Among the casualties was the Athenean ruler Pericles
•	His death, and the decimation of Athens’ citizenry, contributed to end of the Golden Age of Greece and the decline of the dominance of Greece in the Mediterranean   

•	In the wake of the plague, social order completely disintegrated, and lawlessness prevailed
•	Thucydides tells us: -- “There were other and worse forms of lawlessness which the plague introduced at Athens. Men who had hitherto concealed what they took pleasure in, now grew bolder. For, seeing the sudden change,--how the rich died in a moment, and those who had nothing immediately inherited their property,--they reflected that life and riches were alike transitory, and they resolved to enjoy themselves while they could, and to think only of pleasure. Who would be willing to sacrifice himself to the law of honour when he knew not whether he would ever live to be held in honour?”

•	“The pleasure of the moment and any sort of thing which conduced to it took the place both of honour and of expediency. No fear of Gods or law of man deterred a criminal. Those who saw all perishing alike, thought that the worship or neglect of the Gods made no difference. For offences against human law no punishment was to be feared; no one would live long enough to be called to account. Already a far heavier sentence had been passed and was hanging over a man's head; before that fell, why should he not take a little pleasure?” 

•	The plague was most likely smallpox, which broke out again in the Plague of Antonine in 165-180 AD
•	Roman troops sacked the rebellious city of Seleucia (near Baghdad) and brought the disease home with them

•	The physician Galen gives us an accurate description that leaves little doubt that smallpox was the culprit in the Plague of Antonine, though some think that typhus was to blame, the early symptoms are similar to smallpox
•	Whatever the cause, mortality ran from 30% to 50%

•	The common belief was that the gods were punishing the Romans for plundering the Temple of Apollo when they sacked Seleucia
•	The plague depopulated much of the Empire, triggering a social and economic decline that lasted for over a century

•	It also claimed the lives of two Roman emperors, Lucius Verus, and Marcus Aurelius Antoninus, for whom the plague is named
•	As Marcus Aurelius lay dying, he said: “Weep not for me; think rather of the pestilence and the deaths of so many others.”

•	The Plague of Antonine marked a turning point in the history of the Roman Empire
•	Decimated by plague, Roman legions couldn’t stem the growing tide of barbarian invasion in the West, and couldn’t defend their territories in the East – they just didn’t have the manpower

•	The great Plague of Cyprian, another outbreak of smallpox, swept through Egypt and into Europe about 250 AD and lasted for over 20 years
•	At its peak, it claimed 5,000 victims a day in the city of Rome alone

•	 “Afterwards there broke out a dreadful plague, and excessive destruction of a hateful disease invaded every house in succession of the trembling populace, carrying off day by day with abrupt attack numberless people, everyone from his own house. All were shuddering, fleeing, shunning the contagion, impiously exposing their own friends, as if with the exclusion of the person who was sure to die of the plague, one could exclude death itself. “ (Pontius of Carthage)

•	Hieronymus writes that the human race was “all but destroyed, and the earth returned to desert and forest”
•	It was during the Plague of Cyprian, incidentally, that the custom arose of wearing black during mourning 

•	The sheer savagery of these ancient plagues is hard for our modern minds to grasp
•	But beneath the horror, beneath the human misery and suffering, a new balance of nature was emerging

•	It’s no accident that epidemic diseases seem to wax and wane throughout history
•	It reveals an interesting evolutionary relationship between us and our microbial competitors

•	The rapid course of epidemics betrays their evolutionary Achilles’ heel
•	Many microbes can’t survive for long outside of a living body

•	Epidemic diseases infect everyone in the population in a relatively short period of time
•	The victims either die or recover – and those who recover now have immunity

•	The disease can’t recur until a new population builds up, either through births or through immigration, or until the microorganism mutates in a way that hides it from the immune system once again

•	The pattern that results from all this is a series of population cycles between host and pathogen
•	The microbe quickly uses up all its available hosts, and has to travel to another population in order to survive

•	Meanwhile, the host population gradually recovers, and builds up its numbers
•	Eventually, enough susceptible people build up for the disease to return for another round of infection

•	That’s why we call diseases like measles, chickenpox, and German measles (Rubella) childhood diseases
•	More accurately, they prey on naïve populations

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I got so many types of measles as a child, the doctor once told my mother I was probably immune to every kind of measles known to man
•	Consider the incidence of measles in New York City…It spikes up and down in a very regular pattern, every couple of years

•	The explanation for the pattern of childhood diseases came, appropriately enough, from a gentleman named Peter Panum, a Danish medical health officer
•	He was sent to the Faroe Islands in 1846 to investigate an outbreak of measles

•	The islands had been free of measles for 65 years, until a Danish carpenter arrived with a fresh case
•	Within 6 months, 6,000 of the 7,782 islanders were infected
•	Panum noted that the elderly survivors of the previous epidemic in 1781 didn’t catch measles – immunity to measles was for life

•	The pattern of measles in New York City is a lot like the classic predator-prey dynamics of the Canada lynx and snowshoe hare, whose populations rise and fall in a very regular way
•	They form a series of what are called predator-prey cycles, regular oscillations up and down, in their relative numbers

•	We have excellent data on these population cycles, going back nearly 200 years, which might seem odd, considering that ecology didn’t exist until the early 20th Century
•	Can you figure out who would have been scrupulously collecting population data about the lynx and the hare that long ago?

•	It wasn’t a scientific motivation, but an economic one
•	The data come from the Canadian fur trade, from pelts sold to the Hudson’s Bay Company!

•	Each cycle is roughly the same – the population of the hares starts to rise, followed shortly by a parallel increase in the number of predators
•	More prey means more predators survive and make more predator babies 

•	As the population of the lynx increases, it eventually begins to depress the population of its prey, and as hare populations begin to drop, so do populations of the lynx
•	Eventually the hare populations start to recover, as fewer and fewer lynx are around to hunt them, and the cycle begins again… 

•	Now substitute a microbial disease for the predator
•	When it hits, everyone either dies or recovers
•	Those who recover have immunity 
•	As time passes, those with immunity gradually die off or move away

•	New individuals are born or move in who lack immunity
•	The disease returns, and once more rages through the population

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The measles cycle in NYC is unusually short, only about 2-3 years – pop quiz …can you tell me why the NYC measles cycle is so short?  ………….
•	New York City has a very high immigration rate, and quickly builds up a new population of susceptible hosts

•	Disease cycles can be very complex, with many factors involved
•	Tuberculosis, for example, was nearly eliminated from developed nations after World War II – we came so close…

•	Improved nutrition, better housing, isolation of victims, vaccinations, antibiotics - TB nearly lost its host population
•	But TB today is alive and well 
•	WHO, the UN’s World Health Organization, reported 1.7 million deaths from TB in 2009, that’s 4,700 people per day! 

•	Why is TB still a deadly killer?
•	Chalk that one up to the AIDS epidemic, which has left millions of people with crippled immune systems, people who are now highly vulnerable to TB and other diseases, creating a new population of vulnerable host

•	Today, the world’s population stands at over 6 billion and is rapidly increasing
•	By 2025, it could reach 8.5 billion people!
•	By 2025, India will add about 600 million people
•	Nigeria will add 200 million people
•	China will add another 357 million

•	That’s a massive increase in numbers, especially for a species as destructive as our own
•	Our growing population will have a tremendous effect on our environment, creating a wealth of new opportunities for microorganisms