Between the first modern Europeans arriving in 1492 and the Victorian age, the indigenous population of the new world dropped by at least 90%.
Not the conquistadores and company -- they killed lots of people but their death count is nothing compared to what they brought with them: small pox, typhus, tuberculosis, influenza, bubonic plague, cholera, mumps, measles and more leapt from those first explores to the costal tribes, then onward the microscopic invaders spread through a hemisphere of people with no defenses against them. Tens of millions died.
These germs decided the fate of these battles long before the fighting started.
Now ask yourself: why didn't Europeans get sick?
If new-worlders were vulnerable to old-world diseases, then surely old-worlders would be vulnerable to new world diseases.
Yet, there was no Americapox spreading eastward infecting Europe and cutting the population from 90 million to 9. Had Americapox existed it would have rather dampened European ability for transatlantic expansion.
To answer why this didn't happen: we need first to distinguish regular diseases -- like the common cold -- from what we'll call plagues.
1) Spread quickly between people.
Sneezes spread plages faster than handshakes which are faster than… closeness. Plagues use more of this than this.
2) They kill you quickly or you become immune.
Catch a plague and your dead within seven to thirty days. Survive and you'll never get it again. Your body has learned to fight it, you might still carry it -- the plague lives in you, you can still spread it, but it can't hurt you.
The surface answer to this question isn't that Europeans had better immune systems to fight off new world plages -- it's that new world didn't have plagues for them to catch. They had regular diseases but there was no Americapox to carry.
These are history's biggest killers, and they all come from the old world.
Let's dig deeper, and talk Cholera, a plague that spreads if your civilization does a bad job of separating drinking water from pooping water. London was terrible at this making it the cholera capital of the world. Cholera can rip through dense neighborhoods killing swaths of the population, before moving onward. But that's the key: it has to move on.
In a small, isolated group, a plague like cholera cannot survive -- it kills all available victims, leaving only the immune and then theres nowhere to go -- it's a fire that burns through its fuel.
But a city -- shining city on the hill -- to which rural migrants flock, where hundreds of babies are born a day: this is sanctuary for the fire of plague; fresh kindling comes to it. The plague flares and smolders and flares and smolders again -- impossible to extinguish.
Historically in city borders plagues killed faster than people could breed. Cities grew because more people moved to them than died inside of them. Cities only started growing from their own population in the 1900s when medicine finally left its leaches and bloodletting phase and entered its soap and soup phase -- giving humans some tools to slow death.
But before that a city was an unintentional playground for plages and a grim machine to sort the immune from the rest.
So the deeper, answer is that The New World didn't have plagues because the new world didn't have big, dense, terribly sanitized deeply interconnected cities for plages to thrive.
OK, but The New World wasn't completely barren of cities. And tribes weren't completely isolated, otherwise the newly-arrived smallpox in the 1400s couldn't have spread.
Cities are only part of the puzzle: they're required for plages, but cities don't make the germs that start the plagues -- those germs come from the missing piece.
Now, most germs don't want to kill you for the same reason you don't want to burn down your house: germs live in you. Chromic diseases like leprosy are terrible because they're very good at not killing you.
Plague lethality is an accident, a misunderstanding, because the germs that cause them don't know they're in humans, they're germs that think they're in this.
Plagues come from animals.
Whooping cough comes from pigs, and does flu as well as from birds. Our friend the cow alone is responsible for measles, tuberculosis, and smallpox.
For the cow these diseases are no big deal -- like colds for us. But when cow germs get in humans thing things they do to make the cow a little sick, makes humans very sick. Deadly sick.
Germs jumping species like this is extraordinarily rare. That's why generations of humans can spend time around animals just fine. Being the patient zero of a new animal-to-human plague is winning a terrible lottery.
But a colonial-age city raises the odds: there used to be animals everywhere, horses, herds of livestock in the streets, open slaughterhouses, meat markets pre-refrigeration, and a river of literal human and animal excrement running through it all.
A more perfect environment for diseases to jump species could hardly be imagined.
So the deeper answer is that plagues come from animals, but so rarely you have to raise the odds and with many chances for infection and give the new-born plague a fertile environment to grow. The old world had the necessary pieces in abundance.
But, why was a city like London filled with sheep and pigs and cows and Tenochtitlan wasn't?
This brings us to the final level. (For this video anyway)
Some animals can be put to human use -- this is what domestication means, animals you can breed, not just hunt.
Forget a the moment the modern world: go back to 10,000BC when tribes of humans reached just about everywhere. If you were in one of these tribes what local animals could you capture, alive, and successfully pen to breed?
Maybe you're in North Dakota and thinking about catching a Buffalo: an unpredictable, violent tank on hooves, that can outrun you across the planes, leap over your head head and travels in herds thousands strong.
Oh, and you have no horses to help you -- because there are no horses on the continent. Horses live here -- and won't be brought over until, too late.
It's just you, a couple buddies, and stone-based tools. American Indians didn't fail to domesticate buffalo because they couldn't figure it out. They failed because it's a buffalo. No one could do it -- buffalo would have been amazing creature to put to human work back in BC, but it's not going to happen -- humans have only barely domesticated buffalo with all our modern tools.
The New World didn't have good animal candidates for domestication. Almost everything big enough to be useful is also was to too dangerous, or too agile.
Meanwhile the fertile crescent to central Europe had: cows and and pigs and sheep and goats, easy pests animals comparatively begging to be domesticated.
A wild boar is something to contend with if you only have stone tools but it's possible to catch and pen and bread and feed to eat -- because pigs can't leap to the sky or crush all resistance beneath their hooves.
In The New World the only native domestication contestant was: llamas. They're better than nothing, which is probably why the biggest cities existed in South America -- but they're no cow. Ever try to manage a heard of llamas in the mountains of Peru? Yeah, you can do it, but it's not fun. Nothing but drama, these llamas.
These might seem, cherry-picked examples, because aren't there hundreds of thousands of species of animals? Yes, but when you're stuck at the bottom of the tech tree almost none of them can be domesticated. From the dawn of man until this fateful meeting humans domesticated maybe a baker's dozen of unique species the world over, and even to get that high a number you need to stretch it to include honeybees and silkworms. Nice to have, but you can't build a civilization on a foundation of honey alone.
These early tribes weren't smarter, or better at domestication. The old world had more valuable and easy animals. With dogs, herding sheep and cattle is easier. Now humans have a buddy to keep an eye on the clothing factory, and the milk and cheeseburger machine, and the plow-puller. Now farming is easier, which means there's more benefit to staying put, which means more domestication, which means more food which means more people and more density and oh look where we're going. Citiesville, population lots, bring your animals, plagues welcome.
That is the full answer: The lack of new world animals to domesticate, limited not only exposure to germs sources but also limited food production, which limited population growth, which limited cities, which made plagues in The New World an almost impossibility. In the old, exactly the reverse. And thus a continent full of plague and a continent devoid of it.
So when ships landed in the new world there was no Americapox to bring back.
The game of civilization has nothing to do with the players, and everything to do with the map. Access to domesticated animals in numbers and diversity, is the key resource to bootstrapping a complex society from nothing -- and that complexity brings with it, unintentionally, a passive biological weaponry devastating to outsiders.
Start the game again but move the domesticable animals across the sea and history's arrow of disease and death flows in the opposite direction.