(This video is no longer available for streaming.) Can we better prepare for future flu pandemics by resurrecting the 1918 flu virus? This microbe, recovered from tissue samples of World War I soldiers, is perhaps the deadliest pathogen in human history. In this NOVA scienceNOW video segment, meet microbiologists working in the trenches to (very carefully) reconstruct a virus that killed up to 50 million people worldwide.
PBS Airdate: November 21, 2006
NEIL DEGRASSE TYSON: With winter come fears of the flu, and sometimes the flu can be deadly, especially the bird flu. You've all heard of it. It's a virus that people catch from birds like chickens. It's already killed hundreds of people.
Fortunately, this bird flu does not spread easily from person to person, but if it evolves a way to do that, we could be in big trouble.
Correspondent Chad Cohen met up with folks who are trying to stop that from happening by taking a closer look into our past, at the most deadly viral outbreak ever.
CHAD COHEN (Correspondent) : Whatever scary things are lurking in the back of your freezer, I'll venture a guess you've got nothing on Terrence Tumpey. Getting into his deep freeze, at the CDC in Atlanta, is like prepping for a spacewalk.
Frozen inside, sits a tiny vial of what might be the deadliest pathogen in history, a virus that hadn't been seen in almost 90 years, the 1918 flu—until Tumpey brought it back from the dead.
IAN WILSON: 1918 was the worst pandemic we've seen for any virus, and this killed, probably, at least 50 million people worldwide.
CHAD COHEN: In 1918, flu took three times as many lives as all of World War I.
IAN WILSON: So the question is, "Why was it, in 1918, so different? Why did it cause so many excess deaths, compared to other pandemics?"
CHAD COHEN: And could a flu that deadly strike again?
We do know where all flu viruses get their start: in the digestive tracts of birds.
TERRENCE TUMPEY: They just happily co-exist there, not causing disease, for the most part, in wild birds.
CHAD COHEN: But every once in a while, an ordinary bird flu changes.
TERRENCE TUMPEY: It's a mistake in nature. These viruses actually get out and infect other hosts.
CHAD COHEN: Hosts, like people. That's what scientists think may have happened in 1918.
IAN WILSON: The thought was that, in 1918, the virus did cross the species barrier and directly infect humans.
CHAD COHEN: That's one theory, at least. And when a virus that begins in birds gains the ability to pass from human to human, infecting our lungs, spreading through coughs and sneezes, no one's immune because it's never been around before. And that's when a pandemic occurs.
We're hearing a lot, recently, about the threat of a new pandemic, the avian flu. It's quite lethal, transmitted through close contact with birds, to people who work and live near birds.
TERRENCE TUMPEY: Fortunately this virus has not figured out how to efficiently transmit itself from human to human.
CHAD COHEN: Infected people, in other words, cannot infect other people.
The question is will they ever be able to? And if so, how? And when this virus does strike, why does it kill?
Terrence Tumpey believes he can find the answers by experimenting with a flu that transmitted and killed very well, the 1918 virus.
TERRENCE TUMPEY: By having this in hand, we can actually try to understand better how these pandemic flu viruses work.
CHAD COHEN: There was just one small problem: the 1918 virus hadn't been around for nine decades.
JEFFREY K. TAUBENBERGER (Armed Forces Institute of Pathology) : No one had ever been able to study the 1918 virus, this horrible killer virus, because there were no isolates.
CHAD COHEN: No living samples. But biologist Jeffrey Taubenberger, searching through preserved tissue samples of World War I soldiers, was able to recover the 1918 flu's genetic code. Somewhere, buried within, are instructions that gave it the ability to kill. But where?
TERRENCE TUMPEY: Unfortunately, when you look at the genetic sequence, the blueprint of this virus, there's no smoking gun that tells us that this particular virus is lethal.
CHAD COHEN: Tumpey couldn't find an answer by simply reading a recipe for the 1918 flu virus, he needed to experiment with the real thing.
TERRENCE TUMPEY: We felt like it was important to actually reconstruct this virus.
CHAD COHEN: That's right, he said, "reconstruct," rebuild the 1918 flu from scratch, one of the most lethal viruses we've ever known.
Using Taubenberger's recipe and a technique called reverse genetics, scientists at the Mount Sinai School of Medicine added all the chemical building blocks in the right order and the right amounts, and it worked.
They created a living 1918 virus so nasty that when Tumpey exposed lab mice to it, they were all dead in just three days.
TERRENCE TUMPEY: I was quite surprised. I didn't anticipate that they would die that quickly. That was very quick.
CHAD COHEN: And it was just what happened to humans in 1918. Unlike normal flu strains, which can only infect high in the respiratory tract, the 1918 virus attacked tissue deep in the lungs, as well, and that's a vulnerable spot.
TERRENCE TUMPEY: ...the delicate areas of our lung tissues, causing this extreme inflammation, resulting in death.
CHAD COHEN: The 1918 flu so badly inflamed those areas of its victims' lungs that many died through suffocation. And, as it happens, that's just how the avian flu kills, too.
TERRENCE TUMPEY: Those are important characteristics and similarities among the 1918 virus as well as the avian virus.
CHAD COHEN: So, these two deadly viruses attack similar parts of the lungs, but that still doesn't answer the biggest question: "Will the avian flu ever transmit from people to people like the 1918 virus did?"
Well, first, let's back up a little bit. How does flu infect us in the first place?
So this is what flu looks like under a microscope?
TERRENCE TUMPEY: Electron microscope, yeah.
CHAD COHEN: An actual flu virus, but for our purposes, let's represent a virus by this unpleasant fellow.
For all his nastiness, he isn't all that complex. In fact, he only has eight genes. We, by comparison, have more than 20,000.
We're going to look at two of these eight flu genes: one, because it's responsible for getting the virus into a cell, and the other, for getting it out again.
Flu gets into cells with the "hemagglutinin" gene.
IAN WILSON: So, in order to penetrate cells, you could imagine that the hemagglutinin was sort of like a key.
CHAD COHEN: A key, which we'll refer to simply as "H." And that key unlocks the cell, so that the virus can get inside.
TERRENCE TUMPEY: If it gets into your cell, it will take over the machinery of the cell and start making more copies of itself.
CHAD COHEN: But now the virus has a problem. These copies are stuck to that cell. That's where the other gene comes in. It's called Neuraminidase, or "N," for short.
TERRENCE TUMPEY: Neuraminidase is critical for release.
CHAD COHEN: Getting back out?
TERRENCE TUMPEY: Getting back out.
CHAD COHEN: The virus copies use N to cut themselves free. And now each of them, armed with their own Hs and Ns, are off to infect more cells.
In birds, there are 16 different kinds of H genes and nine N genes. Every flu is some combination of these. Humans have only caught a few.
The Hong Kong flu, which killed nearly a million people when it broke out, in 1968, gets in with H3 and out with N2. So it's called H3N2. In 1918, the virus, which killed 50 million people, was H1N1. Now there's the avian flu that's got everyone so worried, and it has a new combination of Hs and Ns: H5N1.
The avian flu's H key, or hemagglutinin gene, can open the lock between birds and people, that is, transmit from birds to humans. But it still cannot open the lock between people and spread from one person to another—yet.
But here's the problem: once it's in our bodies, the hemagglutinin gene can change. It's as if it can fit the lock, but it can't turn it, which would be great, if it stayed that way. But a virus's genetic recipe constantly changes, or mutates, as scientists like to say. And if just the right changes take place in the hemagglutinin gene, those changes could open the lock, allowing it to spread between people.
But exactly what are those changes?
Going back to Taubenberger's recipe for the 1918 virus, Ian Wilson and his colleagues at the Scripps Research Institute found the answer to what the 1918 virus may have needed to spread between humans. They pinpointed two changes, or mutations.
IAN WILSON: Only two mutations were sufficient to change the virus's hemagglutinin to adapt to human receptors.
CHAD COHEN: So could those same two mutations in the avian flu's hemagglutinin gene allow it to spread between humans also?
To find out, they tried those same two mutations.
IAN WILSON: To our surprise, we found that, in fact, we couldn't very easily change it with the mutations that occurred in 1918. So that suggests that it might actually be a little bit more difficult, and it might take a little bit more time, for an H5N1 virus to be able to adapt to human lung cells.
CHAD COHEN: And that's good news. The Scripps team believes the H5N1, or avian, flu doesn't seem to adapt easily, so that people can infect other people.
Back at the CDC, Tumpey is taking a different approach to find out why these viruses are so deadly. Instead of experimenting with tiny variations in a flu gene, Tumpey is testing entire genes. He's looking at each of the 1918 virus's eight genes, one by one by one, to see which ones caused it to be so lethal and which ones should be the target of new antiviral drugs. He started with that H key gene.
He took one from his 1918 virus and put it in an ordinary seasonal flu.
TERRENCE TUMPEY: ...a contemporary influenza strain that doesn't kill, and, all of a sudden, it was lethal.
CHAD COHEN: And when he did the reverse, took the H key from an ordinary flu and put it on a 1918 virus...
TERRENCE TUMPEY: The virus was no longer lethal; it didn't cause disease.
CHAD COHEN: So all signs seem to point to the H key, or H.A., as scientists call it, as being, at least partly, responsible for lethality.
TERRENCE TUMPEY: Well, there's something very intriguing about the H.A.
CHAD COHEN: So intriguing that, now, Tumpey is planning to do something pretty radical: put the hemagglutinin gene from the 1918 flu virus into the avian flu virus, to see if he can create an avian flu virus that can spread from person to person.
You want to combine H1, 1918, with H5? What's going on there?
TERRENCE TUMPEY: I think it will be important, as a set of experiments to understand how H5N1 works. And by mix-and-matching it with genes from a virus that actually did that quite well, the 1918 virus, we are hopeful that we can figure that out.
I think, from a scientific point of view, this is the only way to understand how these pandemic viruses work.
CHAD COHEN: Tumpey is one of the few people in the world who has the clearance to work with a live 1918 flu virus.
TERRENCE TUMPEY: So if we can figure out how to slow it down, studying this virus as a model virus, then perhaps we'll advance our knowledge on the avian H5N1 virus as well. Maybe we can figure out how to stop it.
CHAD COHEN: If Terrence Tumpey has his way, the virus that took so many lives in the past may help prevent another from taking more lives in the future.
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This material is based upon work supported by the National Science Foundation under Grant No. 0229297. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.
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- Image credit: (1918 virus in mouse lung) From Tumpey et al., Science, 310(2005), used with permission of AAAS