The Second Deadliest Virus in the World!

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 million, then billions of your cells die, you get a rash that only gets worse and worse. Pus and cellular junk fill 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 humanities 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 millennia was slain, by us, apes with pointy needles.  Today we live in a time of enlightenment. None of us alive today is 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 vaccine 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.