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The 1918 pandemic infected over 500 million people, but the virus that caused it didn't stop in 1918.

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You can head to D-R-I-N-K-L-M-N-T dot com slash scishow for a free sample pack of electrolyte drinks with any order. [ intro ] The year is 1918. Folks are driving their brand-new Model-T hand-crank vehicles, everyone still wears hats all the time, and don’t even think about having a zipper for your trousers.

But lurking on the horizon is a looming threat that will remain to plague humanity for the next hundred years: the H1N1 influenza virus. The 1918 influenza pandemic is the most deadly pandemic of the last century. In just two years, the disease infected 500 million, amounting to one third of the humans alive at the time, and killed at least 50 million in total.

Because of this, we’ve spent decades studying exactly what happened, why this virus was so deadly, and what we can do to prevent it. And we’ve found something unexpected: This virus didn’t just cause one pandemic. The H1N1 virus of 1918 can, directly or indirectly, be connected to at least three other pandemics.

So let’s take a tour through the last hundred years of virology history and explore the many evolutionary steps leading us from 1918, to 2009, and beyond. But first, a little background on this weird group of viruses called influenza. There are three main types of influenza virus that can infect humans, which are helpfully called influenza A, B, and C.

There’s also influenza D, which so far has only ever been found in cattle and pigs. Influenza A type viruses can infect humans and many other animals, while influenza B infects humans and seals, and influenza C predominantly infects humans. A and B both spread seasonally during the winter season of your respective hemisphere, and because of this, both types are included in the annual flu shots. -- But for the purposes of this video, we’re really only worried about influenza A, since influenza A viruses are the only ones that have become pandemics – so far, anyway.

Within the larger groups of influenza viruses, there are many smaller groups or isolates. These isolates are all genetically distinct from one another. They’re similar enough to be considered the same virus, but can be different enough that the proteins on their surfaces, known as antigens, show substantial variation.

They can cause different symptoms as well. Since your immune system recognizes those surface proteins, antibodies that fight one strain of flu might not work well against another. Influenza A viruses get their names based on the two major antigens on their surfaces, called hemagglutinin and neuraminidase, or HA and NA for short.

That’s the simple version. I won’t go into how many headaches were had over viral nomenclature while this script was in development These two proteins are what allows influenza to infect a cell: HA binds with receptors on the outside of the host cell, and NA breaks down the cell membrane to let the virus inside - and then lets it back out again. Once inside, the virus uses the cell’s guts to produce more viral particles to continue to spread in the host organism.

But the host’s immune system can use these spiky proteins as well. The host can develop antibodies that recognize that specific surface protein, and those antibodies will neutralize the threat and prevent the virus from replicating. In turn, the virus will slowly develop mutations in the shape of its surface proteins, which helps it go undetected by the host’s immune system.

And thus, the perpetual game of viral cat and mouse continues for all time. We name kinds of influenza A viruses based on what type of HA and NA protein they have - so, H1N1 or H3N5, or so on. So far, we’ve documented 18 HA types and 11 NA types that can go into influenza A, but not all of these infect humans.

Though they’re all the same protein at the level of what they ultimately do, an HA or NA earns itself a new number if it’s more than 50% different genetically from its predecessor protein. This also means that one H1 may behave a little differently than another H1, if their genetic sequences are a little different but not a lot different. Like anything else with a genome, the flu can evolve.

The slow accumulation of gene mutations that can potentially happen every time a virus replicates is called antigenic drift. Because these changes occur gradually, our immune systems can generally recognize these viruses enough to provide some protection. Though, it’s also the reason we have to keep getting seasonal flu shots.

It’s also not the only kind of genetic change we see in flu viruses. All of the influenza viruses are zoonotic, meaning they can spread between different species of animals, including humans. But only influenza A hops around enough to register as a major concern.

Influenza B and C aren’t able to evolve as rapidly as influenza A can, partly because A does a ton of host-hopping. Influenza A viruses can infect swine, birds, bats, cats, horses, seals, and even whales. This also means it will jump between susceptible species every once in a while.

This gives rise to the perfect conditions for what’s called antigenic shift. See, there’s no rule saying a host can only be infected by one version of the flu at a time. If two or more viral strains infect the same host organism and meet up in the same cell, they can swap segments of their genomes in a process called reassortment.

It’s kind of like when a few kids get together to swap Pokemon cards on the playground - only instead of a shiny Charizard, one of them ends up with a new combination of proteins that our immune systems won’t recognize. Maybe a bad trade for us, but potentially a great trade for the virus. Not always, since it’s random, but sometimes the virus lucks out.

The virus is more likely to jump from one host species to another when those two species are in close contact frequently. That said, the virus needs to do more than just make the jump once. It also needs to be infectious enough to spread in its new species host once it gets there.

Which means that while it doesn’t happen all at once, or every flu season, novel pandemic influenzas are out there cooking, and purely due to chance they’ll probably keep rearing their heads every couple of decades. Which is exactly the scenario we found ourselves in, way back in 1918… Scientists aren’t sure where in the world this virus first made the jump from animals into humans, but we do know that it spread fast. The first reports of an unusual flu virus came from Kansas, USA, in March of 1918.

Just one month later it was reported in France and Spain, and the virus soon swept the globe. So the virus didn’t actually originate from Spain, even though this flu is often called the “Spanish flu”... in English-language history texts, anyhow. It’s a misnomer based on a quirk of history: Spain was neutral in World War I, and therefore placed way fewer restrictions on its press at the time.

So all the coverage was coming from there… just not all of the infections. This is just one of many reasons it’s considered bad practice to name diseases after places these days, at least within common parlance. Official names of virus strains might have place names for keeping-track-of-them reasons, but for the rest of us, it can just feed into stigma.

But anyway, back to 1918. While people had dealt with seasonal flu outbreaks long before 1918, this flu outbreak was unusual because of who got the sickest. Most flu seasons, the people that are most vulnerable are the elderly and the very young - basically, those with weaker immune systems. causing many of them to develop bacterial pneumonia and other fatal or debilitating complications.

At the time, people had no idea why this flu season was so virulent and so deadly, especially among the young and healthy. Actually… we’re still not totally sure, but we have some thoughts. The one of most interest to us right now is that the 1918 flu virus was really different from flus that had circulated in the preceding 20 to 40 years.

In particular, the flu viruses that had been most common between 1880 and 1900 are thought to have been strains with H3 proteins, not H1. And it’s likely that the kind of flu that is circulating when you’re young makes a lifelong impression. The flu you’re exposed to when you’re young seems to induce a degree of lifelong immunity.

This idea is called original antigenic sin. Basically, the idea is that once your immune system learns how to make antibodies against the flu, it never really figures out how to change the blueprint. In fact, each subsequent exposure to any flu virus will still cause the immune system to develop further protections against the original flu strain, even when that’s not the one you’d just encountered.

Which is fine… until the predominant type of flu changes, leaving you vulnerable. So that’s what some researchers think happened in 1918. The 20 to 40 year olds had immune systems primed against the seasonal flu of the time, but were blindsided by this brand new H1N1 strain.

So where did this H1N1 flu come from? H1 strains of flu had been around in humans for decades before the 1918 outbreak, but N1 was only present in animal reservoirs, mainly swine. Human H1 made the leap to pigs, bumped into some of their N1 viruses along with some avian influence, and made a really, really infectious baby.

That H1N1 strain crossed back into humans, and was able to spread among them as well. This is also supported by the fact that 1918 flu pandemic in humans was concurrent with a flu pandemic in swine, which we don’t talk about as much as the one in humans, because we’re just a little biased. What’s more, the 1918 H1N1 flu transferred back into swine, and became one of the primary strains of flu found in pigs for decades to come.

But the real kicker is that ever since the crossover of H1N1 influenza A into humans in 1918, at least some of the genes from the 1918 flu virus have been circulating in basically every flu pandemic we’ve had. After the 1918 flu pandemic, we seemed to be doing pretty well as far as pandemic influenza viruses were concerned, but nothing lasts forever. Once we got to 1957 we had a new influenza on the block, but it turns out that it wasn’t actually very new at all.

Between 1918 and the 1950’s, there still wasn’t a clear understanding of what the 1918 flu was. It took until the 1930’s to identify that viruses existed at all, let alone that they were what caused the flu. Even then, researchers weren’t convinced a little old influenza virus capable of going pandemic like that.

That is, until 1957, when they saw it happen. The influenza pandemic of 1957 isn’t as famous as that of 1918, largely because it wasn’t as deadly. This influenza virus was first observed in China and likely made the leap from avian sources into humans somewhere in that region.

While the 1957 flu was an H2N2 virus, we know from sequencing its genome that a lot of its other surface proteins came from the 1918 pandemic strain of H1N1. Some of its other proteins, called polymerases, were descended from those in the 1918 human flu viruses. And these polymerases are what helps the virus get so good at replicating in a host cell, and transmitting to new hosts too.

But the really gnarly ones tend to come from H1 lineages. So this happenstance meeting of an H2 line with H1’s polymerases resulted in a strain of H2N2 flu with the highly infectious punch of H1N1 flus. And This happened again just a decade later , with a new flu pandemic in 1968.

This new flu was an H3N2 virus carrying that same N2 protein that was so closely related to our H1N1 friend of 1918, as well as that handy-dandy polymerase. The 1968 pandemic was first spotted in Hong Kong, and spread widely. But oddly enough, it didn’t seem to behave in the same way everywhere it went.

The death rate was much higher in the US than it was in western Europe, and rather than spreading like wildfire, this pandemic spread more like molasses. This may have been due to previous exposure to the N2 antigen, which was pretty much the same between 1957 and 1968. Past exposure could have conferred at least partial protection from the 1968 outbreak, or at least slowed it down.

This pandemic may have also done us a favor: The 1968 flu became so widespread t hat it completely outcompeted the H2N2 virus from 1957, and that strain of flu is now extinct. And H3N2 still gets the last laugh , as it’s now one of the two lineages of seasonal flu that hits us every year. Now finally, it’s time to close the loop on a little foreshadowing I set up earlier.

Remember how I said that the 1918 H1N1 influenza hopped into swine. It stayed in circulation among swine for nearly a century, and eventually branched into two lineages: North American and Eurasian. These two swine lineages remixed in Mexico, where they also recombined with a human-circulating H3N2.

That virus was itself a triple assortment of avian, swine, and human flus. That tortured combination of reassortments produced 2009’s H1N1 “swine flu” outbreak. And the 2009 flu pandemic possessed more echoes of its 1918 ancestor than just the name.

Like in 1918, this flu strain was most severe in young adults, since H1N1 flus of this subtype hadn’t been circulating for a few decades. Indeed, the 1968 flu pandemic may have been a source of protection for older folks in 2009. Because the H1N1 flu of 2009 contained genes from the H3N2 flu of 1968, people aged 65 and older had been exposed to this flu as children and were protected as adults due to original antigenic sin.

Fortunately this flu outbreak was much less deadly than any of its flu pandemic ancestors, thanks in part to medical advances like vaccines and a better understanding of how to prevent the spread of viruses from person to person. So what have we learned? Was the 1918 flu a super-virus unlike anything before or since?

Is it doomed to keep coming back to haunt us again and again? Well, sort of. We do know that it hit a perfect storm of novelty and infectiousness, but we also know that a lot has happened since in the world of influenza viruses.

And understanding how it has contributed to later outbreaks of flu can help us predict who’s going to be affected, and how much. Twice now we have seen the influence of the original antigenic sin in influenza outcomes, which is leading some researchers to look towards this aspect of our immune responses as a potential way to engineer more effective, universal influenza vaccines. It’s been over ten years since swine flu, and other than a few scares here and there, we haven’t had another pandemic… of the influenza variety.

And while the 1918 flu could strike again, it may also give way to a successor. Since 2003, all eyes have been on a strain called H5N1, or sometimes “bird flu” in the popular press, and it doesn’t seem to be all that closely related to pandemic H1N1 at all, having come from both wild and domestic birds. H5N1 is in a group of influenzas called highly pathogenic avian influenzas, or HPAIs.

H5N1 has been seen in humans here and there, but only in zoonotic transfers and no sustained person-to-person spread – yet. The key word in "highly pathogenic avian influenza" is "avian" – it's really infectious but so far, only in birds. Knock on wood.

If H5N1 were to adapt to spread between mammal hosts, or reassort with a different strain that can do so, there’s concern that it would spread incredibly quickly. There have been only four cases of H5N1 reported in humans from 2019 to 2022, probably in part due to measures meant to keep COVID-19 in check. That said, it is extremely harmful to birds.

Some closely related HPAIs have mortality rates in affected birds of more than 90%. So because our birds are under threat, this ends up affecting the price of poultry and eggs at the supermarket. No minor concern given the price of everything else these days.

But, keeping a close eye on the strains of flu that are in circulation now, in both humans and animals, is key to keeping us prepared, just in case. See, we know now with the benefit of hindsight that the ‘57 and ‘68 flus tipped their hands before they became a real problem. We understand now what elements of the 1918 flu have helped it stick around and spread between people.

Which means we can keep an eye out for those same elements poking their noses above ground. Maybe? And it makes keeping an eye on H5N1 a really good idea.

But even if it’s the new kid on the block that muscles out the various 1918-derived strains eventually, that 1918 flu has had one heck of a run. I guess sometimes you can teach an old virus new tricks. And if that virus has taught us anything, it’s that you can always refresh and go at it again.

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