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Few of the monsters that evolution created have  been so successful at hurting us as the variola  

virus, responsible for smallpox. The carnage  it caused was so terrible and merciless that  

it compelled humankind, for the first time,  to act truly globally. It was one of the  

greatest wins of our species over the ancient  powers of nature, all made possible by… cows. 

Variola is a virus, a tiny machine that only  seeks to reproduce itself. Evidence of It has  

been found in Egyptian mummies and in writing  from India and China as old as 3000 years.  

1300 years ago smallpox killed up to a third of  Japan’s population. By the sixteen hundreds, it  

was one of the major causes of death worldwide.  In late 18th century Europe, it killed 400,000  

a year. Every third person who went blind did so  because of this virus. Even in the 20th century,  

a hot second ago in history, it still killed at  least 300 million people. Smallpox is an abusive  

monster that returns over and over and over  again, killing, maiming, and disrupting societies.

How could variola be so incredibly deadly for  so long and how could we have forgotten its  

horror so quickly? In 2023, there are only  two laboratories left where the living virus  

is officially stored for research:  in Koltsovo, Russia and in Atlanta,  

USA. Which is certainly a good idea  because what could possibly go wrong?

Let’s say that through an unfortunate series of  

events the virus got out and you got  infected. What would happen to you?

How Smallpox Kills

Variola is highly infectious and catches a ride  in small droplets you breathe in. Immediately it  

begins to infect the cells that line your throat  and starts killing them to cause chaos. Why?  

To trick your body into giving it  a lift. Whenever cells in your body  

die a violent death, your immune  cells immediately stream to the  

site of infection to help out. In  this case that backfires horribly.

As immune cells begin cleaning up dead  cells, eating viruses and killing infected  

cells , variola infects a crucial cell of  your immune system: Your Dendritic cells,  

intelligence cells that gather information  and leave the battlefield to get help.  

They enter your lymphatic system, a highway  network that spans your entire body and  

connects hundreds of immune bases. In these  bases your heavy defenses are activated and  

should be the last place an enemy would want  to invade, but Variola wants to get here.

For about 12 days, the virus quietly  infects civilian and immune cells,  

jumping from cell to cell infecting more and more  of them. At some point a critical threshold is  

reached and variola starts its attack for real.  Millions of viruses use the lymphatic highway  

to spill into your blood and organs, infecting  your whole body. Suddenly variola is everywhere.

But despite this global attack, your  adaptive immune system is struggling to  

wake up. Your immune cells look for and use  critical transmitters called interferons to  

mobilize the body against viruses. Interferons,  as the name suggests, interfere – significantly  

slowing down virus infections but also quickly  activating millions of anti virus weapons.  

But Variola is able to deactivate interferons,  which stuns the anti virus side of your defense  

system. Other systems would usually help 

• like the complement system, a sort of  

mobile minefield that can destroy viruses but  variola also manages to shut this down too.

And so, with little resistance variola spreads  everywhere and infects billions of your cells  

all over your body. Among the infected are your  capillaries, the smallest blood vessels in your  

body, which die in great numbers. All this death  activates an immune cell that you really don’t  

need right now but that is attracted by death:  The Neutrophil. Normally an efficient killer of  

invaders great and small, it is not very effective  against smallpox. And even worse, Neutrophils  

fight by vomiting deadly chemicals, which  kills even more of your cells. On top of that,  

they order inflammation, fluids streaming from  your blood vessels into your tissue. All over your  

body, as first millions, then billions of your  cells die, you get a rash that only gets worse  

and worse. Pus and cellular junk fills it up as  your body swells up with hundreds of lesions, all  

over your skin and inside, even on your organs,  all filled with billions of variola viruses.

Now the critical phase begins. As you fight  for survival, you burn up in a high fever,  

thousands of battlegrounds drain your blood of  fluid that streams into your tissue and organs.  

Blood clotting appears all over your body while  floods of toxins from dead cells build up and can  

cause organs to fail. Your lungs fill up with  fluid, making it harder and harder to breathe.  

One of two things happens now: Either your immune  system wrestles back control – heavy weapons have  

been dispatched, killing infected cells, cleaning  up the thousands of infections one by one,  

killing variola wherever it can be found so  you can slowly begin to recover. The immune  

system will forever remember variola, making  you immune forever. Or, you die, overwhelmed  

by the infection and your immune system’s  panicked reaction to the body wide infection.

About a third of people who contract  smallpox don’t survive. And if you survive,  

you are very likely branded by scars and  may even lose your eyesight or hearing.

For thousands of years this terrible disease  ravaged the world, leaving death and destruction,  

traumatized and maimed survivors. Until  one day, humanity said: “enough”.  

Why don’t we have smallpox anymore?

Smallpox is one of the worst diseases  humanity has ever known. A murderous,  

family destroying, life ruining monster.  There was nothing you could do for the  

infected – but people noticed that  if you survived, you were immune.  

So out of desperation, they came up with a  dangerous practice of variolation: Take scabs  

from an infected person that had a mild case of  smallpox, let them dry out and grind them to a  

fine powder. Then blow the powder up the nostril  of a patient or scratch their skin with it. If  

things went well, they only got a mild version of  smallpox and gained immunity against the disease.

Variolation probably worked because it introduced  the variola in a part of the body the virus wasn’t  

prepared for, disabling most of its nasty  tricks. And because the inoculation was  

left to dry out, that damaged the virus  so it could not cause the full disease.

Unfortunately 2-3% of all patients still died  because they got the smallpox or suffered  

other diseases as a result of treatment. Still,  smallpox was such a horrible and to some degree,  

unavoidable disease that people took the  risk, for themselves and their children.  

Variolation spread around the globe,  while Variola continued to kill millions.

A victory over the virus only became a real  possibility when scientists realized that  

it was not necessary to variolate with the  real smallpox disease, but much safer to use  

material from cowpox, a variant that affected,  surprise, cows. A truly revolutionary step – and  

only a few years later, this led to one of  humankind’s most outstanding achievements:  

Vaccinations. The innovation was simple –  instead of using the real virus to train  

the immune system, use a related virus, cowpox,  that was only mild but also gave you immunity.

Still, it would take another 200 years, countless  individuals fighting the monster where they could,  

delivering vaccines to the most remote places  on earth. All the while the disease ravaged on,  

killing over 300 million people  in the 20th century alone.

In 1966 the World Health Organization decided  that humanity had to come together in a final,  

major effort. A global “smallpox news  network,” based on residents in hotspots, was  

created – tackling local outbreaks of the virus.  Cases were encircled, vaccines given, preventing  

further spread. Smallpox only infects humans,  so if we stopped the human transmission chain,  

we would starve the virus. The last naturally  occurring infection was in 1977, and in 1980,  

just shy of 200 years since the first vaccine  was used, Smallpox was declared eradicated.

Variola, the scourge of humanity, was dead.  No more children would be killed by it,  

no more mothers or brothers or uncles or  cousins. It is hard to convey to people  

around today what an incredible win this was.  One of the cruelest, most dangerous monsters  

that has hunted us for literally millenia  was slain, by us, apes with pointy needles.  

Today we live in a time of enlightenment.  None of us alive today are haunted by the  

specter of smallpox. This light is not  natural; it was set in the sky by the  

sheer will of humankind wanting to be  safe from the monsters haunting us.  

But because we live without them, we forget  that they ever existed and that they are real.  

That the diseases might reawaken, or  new ones might be brewing in jungles,  

wet markets or laboratories,  ready to strike us once more.  

We forget what an incredible gift vaccines  are and how hard we had to battle to get them

We are still protected by the light but it is  cooling each and every day, and we owe it to those  

who will come after us to make sure it doesn’t go  out. We killed one monster. We can do it again.

This video was supported by Open Philanthropy.

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