March 2, 2024

The 1918 Spanish Flu—The Search for the Virus

Author: The Great Courses
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By Bruce Fleury, Ph.D. for The Great Courses

On Thursday April 3, 1918, President Woodrow Wilson was struck by a coughing spell so severe he had difficulty breathing. The attack was so sudden that Dr. Cary Grayson, Wilson’s White House physician, at first thought that Wilson had been poisoned.

U.S. 39th regiment in Seattle wears masks to prevent influenza. (Image: Everett Historical/ Shutterstock)

Note from the editor:

This is the third article in a series of three that covers the flu of 1918. In this 24-lecture series, “Mysteries of the Microscopic World,” Dr. Bruce Fleury covers the world of bacteria, viruses, fungi, and other organisms, collectively known as microbes.

Even though when this course was produced we were still years away from the first reported cases of COVID-19, it gives context to our current climate to look back on this stage of our world history and witness how it affected the entire world. Below, you can read his lecture in its entirety, and watch the full video.

A President’s Struggle

President Wilson was very ill, with severe diarrhea and a fever over 103 degrees Fahrenheit. He lay in bed for several days, and couldn’t even sit up until the fourth day. George and Clemenceau came to Wilson’s room to continue the talks, but the talks went very poorly. Wilson was gaunt and haggard. He had a pale face and sunken eyes, but he continued to drive himself relentlessly.

Herbert Hoover grew concerned that Wilson had changed after his illness, becoming stubborn and unwilling to listen to advice. Secret Service agent Col. Starling noted that Wilson “lacked his old quickness of grasp, and tired easily.” Wilson became paranoid, insisting that his home was filled with French spies.

He grew obsessed with trivial details, like who was using what official vehicle. Lloyd George refers to Wilson’s “nervous and spiritual breakdown in the middle of the Conference,” attributing it to overwork and harsh criticism by the press. Gilbert Close, Wilson’s secretary, wrote, “I never knew the president to be in as difficult a frame of mind as he is now. Even while lying in bed, he manifested peculiarities.”

And then Wilson suddenly announced a complete change of pace, conceding to Clemenceau virtually every point he had previously fought so hard to make. Later, authorities speculated that Wilson had suffered a mild stroke, ignoring his bout of flu. That stroke is an idea that persists to this day, and for good reason. We don’t normally associate flu with neurological or psychological problems. But the 1918 flu was the exception to the general rule. It left many of its victims with permanent mental damage.

Dr. Charles W. Burr, a specialist in mental complications
from influenza, wrote in 1918 that the typical flu survivor might face some
long-term mental problems. “To make a decision about some trifling matter tires
him, and an important matter requiring any deep thought, for even a short time,
must be put to one side.”

This is a transcript from the video series Mysteries of the Microscopic WorldWatch it now, on The Great Courses Plus.

Did Wilson’s concessions result from his struggle with
influenza? A careful examination of his state of mind before and after the flu
strongly suggests that his illness changed his attitude and behavior
profoundly. Whatever the cause, by caving in to Clemenceau’s harsh treatment of
Germany, Wilson helped to create the conditions that ultimately led to the next
World War.

Adolf Berle, Jr., later to be appointed assistant secretary of state, said in his letter of resignation to Wilson:

“I am sorry that you did not fight our fight to the finish and that you had so little faith in the millions of men, like myself, in every nation, who had faith in you. Our government has consented now to deliver the suffering peoples of the world to new oppressions, subjections and dismemberments—a new century of war.”

What We Learned from the 1918 Spanish Flu

Between adding to the miseries of the First World War, and contributing to the rise of the Second World War, the 1918 flu had a big impact on human history. What if it were to return today? Would we be prepared to fight it?

One of the most fascinating aspects of the 1918 flu turns out to be a detective story, the search in modern times for an intact virus. That search is no idle exercise because in the wrong hands, the virus could make a formidable weapon. But if we can find one, maybe we can figure out why it was so incredibly deadly. And if we can decode its genes, we might find a way to fight it, or any similar virus.

We are more vulnerable today than our parents were in so many ways. We’ve made all of these great advancements in public health and medical technology, but recent changes in lifestyle and diet have left us a lot closer to the brink, should that deadly flu be unleashed in our lifetime. Think about how quickly the 1918 flu was spread by rail and ocean liner.

Learn how different cells have evolved to distinguish self from non-self, providing the first line of defense against infection.

Our modern network of interstate highways and global airlines would disperse such a viral killer like it a lot faster and more effectively. Our increasingly interconnected global trade system is also more easily disrupted. We are less self-reliant, economically speaking; so a global pandemic might trigger a cascade of economic collapse, leading to shortages of critical items. Our growing reliance on refrigerated and frozen food means that our homes contain a significantly greater amount of perishable items. Remember how Philadelphia’s stores closed down as the flu began to spread?

With a minimum of canned goods and dry food in our pantries, most of us would soon run out. Go back to 1957: A typical American family ate about 90 percent of their meals at home. Their kitchens contained about 20 percent perishable foods, mostly different kinds of fresh fruits and vegetables. The modern American household eats at home only 62 percent of the time, and 48 percent of the food in the typical home consists of perishable food. Said in jest, let’s face it, if McDonald’s and Burger King were to close tomorrow, a significant portion of my immediate family would probably starve to death within a month!

Being more vulnerable means we have to be better prepared; that preparation starts with a better understanding of what made this flu virus so dangerous. But where to begin? Few samples were preserved at the time; people didn’t really know what viruses were, much less how to save them. So how do we find a sample of the deadly virus?

The answer is simple: Look in the lungs of the dead. The U.S. Army had preserved many samples of lung tissue from dead soldiers, soaking them in formaldehyde and encasing them in little squares of paraffin. In fact, the original orders to preserve tissues from diseased military personnel came from none other than Abraham Lincoln. Jeffery Taubenberger of the Armed Forces Institute of Pathology, along with his colleague Ann Reid, began trying to isolate the virus from a scrap of lung tissue that they took from a young soldier.

Meanwhile, Dr. Kirsty Duncan, anthropologist, geographer, and amateur virologist, had become obsessed with solving the mystery. She reasoned that only burial in permafrost would have saved that 1918 virus that long. A four-year search led her in 1997 to a little, frozen cemetery in Spitsbergen, a tiny windswept isle some 600 miles north of northern Norway.

There had been several coal mines on the island active in the early 1900s, operated by the Arctic Coal Company. Duncan knew that the flu had hit Norway, and she wondered if any miners had carried it to Spitsbergen. She finally narrowed her search to the mining town of Longyearbyen, which was a seasonal mining town—you fished in spring, you mined for coal in the winter.

Most of the local records had been destroyed in World War I, but she finally managed to track down some old company diaries held by a local schoolteacher. Using those diaries, she found a cemetery with six young miners from Norway who had died of the flu just after leaving the ship, and were buried in the frozen soil.

As she was assembling an expedition to exhume the bodies, Taubenberger was closing in on the prize. He contacted Duncan, and the two of them collaborated for a while, but they very soon parted company. Duncan found Taubenberger and Reid to be too cautious, too methodical; Taubenberger found Duncan to be much too flamboyant.

Learn how ecological disturbances, both natural and human-made, can benefit harmful microbes.

Things Taubenberger Found

Duncan’s expedition prepared to don moon suits to prevent the release of live virus, but that elaborate exhumation proved a complete bust. The bodies turned out to be buried too close to the surface, and were badly decayed. (Keep an eye out for reruns of Virus, a 1995 NBC TV movie, which is based on a Robin Cook novel and features a fictional “Kirsty Duncan” type, racing to unearth the 1918 bug in order to fight a modern epidemic.)

Meanwhile, Taubenberger had been contacted by a retired pathologist named Dr. Johan Hultin. Hultin had actually beaten Duncan and Taubenberger to the punch by almost 50 years. As a young graduate student in 1949, he had also become intrigued by that elusive 1918 virus and became determined to find it.

In fact, he decided to make the virus the subject of his dissertation. He tracked down a mass grave of 72 flu victims in Brevig Mission, Alaska, in 1951. But the expedition was a failure; he found several bodies, but he was unable to recover any of the virus. Forty-six years later, in 1997, he read an article in Science by Taubenberger and decided to try digging at Brevig, once again. While the world was watching Kirsty Duncan, Dr. Hultin flew back to Brevig. He checked into a local motel and began digging for new samples with his pickaxe.

Most of the bodies that he found were badly decayed, but there was one obese victim dubbed “Lucy” who was fairly well-preserved. Heavy layers of fat around her lungs had protected them and Hultin was able to collect several tissue samples. He sent the infected, frozen samples to the army pathology lab through UPS, the U.S. Post Office, and FedEx. (Those were the days.) This time Hultin was successful; Lucy yielded several viral fragments. Taubenberger used these samples, together with the army samples that he had collected, to sequence several viral genes.

Although we solved one mystery—finding intact genes from the 1918 virus—several mysteries remain unsolved. Why did the flu kill so many young adults? Why were the three waves of flu so closely spaced? Where did it come from? To this day, no one knows why the flu hit young adults so heavily, producing that W-shaped curve we talked about rather than the usual U-shaped curve of mortality. Instead of that normal decline in deaths in young-adult and early-adult stages, the 15- to 34-age groups in the 1918 Flu showed a big spike of mortality.

It may be that the healthy immune systems of those young men and women were their undoing. That’s a novel concept. Can there be such a thing as being too healthy? Remember that the sheer devastation of the lungs of soldiers was comparable to the damage done by mustard gas.

Some doctors think this damage was partly due to a deadly overreaction by the immune system—what we call a cytokine storm. Maybe this cytokine storm was particularly intense in those with the healthiest immune systems. Or perhaps young adults in 1918 had especially high levels of tuberculosis, leaving their damaged lungs ripe for invasion by influenza.

The Three Waves of the Flu

The unbridled virulence of the flu probably contributed to its ultimate undoing. Flu is driven by “herd immunity.” It needs to constantly hop from one population to the next as each host population either dies or acquires resistance. We would expect to see waves of flu spaced several months apart. Major antigenic shifts would be required every two or three years to survive herd immunity.

But the three waves of the 1918 Flu were very close together. Each wave should have been months apart, but in some areas the three waves of the flu were only weeks apart. In a few places, the waves were so close together that it’s hard to say where one ended and the next one began.

In the Northern Hemisphere, the first wave lasted from spring into summer, the second wave from summer to fall, and the third wave from fall to winter. That tight spacing remains a mystery to this day. It lends some support to the argument that that second wave was a hybrid virus or a mutant strain.

A hybrid or mutated flu would be sufficiently different to overcome the partial immunity of survivors of the first wave. Cycles of the 1918 flu are so out of step that many scientists have come to doubt the validity of the whole idea of epidemiological cycles, at least where the flu is concerned. Maybe the patterns formed by the hypermutable virus are just too unpredictable. Or perhaps we are missing a much larger pattern. One hypothesis suggests that H1, H2, and H3 flu strains are “macrocycling,” competing with one another in cycles that can last 68 years or more.

There are three types (three genera) of flu: type A, type B, and type C. Type A is the most dangerous: It infects humans; other mammals, including pigs; and birds. Type B infects humans and seals. Type C infects humans and pigs. Each type can have many subtypes, and each subtype can have several variants. Remember those H spikes and N spikes on the flu virus that we learned about in Lecture 11? There are 16 known subtypes of the H antigen, and nine known subtypes of the N antigen.

Flus prior to 1957 are designated subtype H1N1, so the 1918 Flu was H1N1. The 1957 pandemic was caused by a new subtype H2N2, which left 2 million people dead. The 1968 Hong Kong flu was H3N2, and it left 1 million dead in its wake. We think that both the H2N2 and H3N2 subtypes are a mixture of bird and pig flu genes.

The molecular evidence suggests that the 1918 flu was H1N1, a novel strain of bird flu which later spread to swine and humans. There are no known records of epidemics among poultry at that time, but ironically, bird flus are usually asymptomatic for birds—they carry it, but don’t suffer from it. In the wild, we think ducks are the natural reservoir.

We’ve taken samples of avian flu from preserved wild birds in museum collections, and they turn out to be very similar to the ones we collect today. But the 1918 flu—well, that’s a different kind of avian flu.

Learn how a few hundred genes can easily make more than 100 million different antigen receptors, specific to any foreign invader that enters the body.

Flu is rather unusual in that new subtypes of flu tend to drive all old subtypes into extinction. Only one subtype at a time usually exists in humans, and usually only one variant. The reason may be that each new subtype provokes a general immune response to the flu virus that gives partial immunity against a variety of other variants of the flu, including older strains. So when the older strains finally cycle back into fresh populations, the door may be already closed.

Modern-Day Flu Panic

The 1976 swine flu was an H1N1 variant, which is why it caused an international panic. Nobody likes to get a flu shot, but in 1976, a record 40 million of us lined up to do just that. Private David Lewis, a fresh recruit at Fort Dix, New Jersey, was the first to die of the flu; he collapsed in the middle of a 5-mile hike. Flu had been spreading through the barracks for weeks, but no one up to that point had died from it.

Only four of the many flu victims at Fort Dix had that unknown swine flu virus, and of those four, only Private Lewis died. But because the fatal flu turned out to be H1N1, it revived fears of the 1918 pandemic and that was enough to push the red panic button.

Once the military released the story about the Fort Dix outbreak, the press ran wild, exhuming all of the horror stories of the 1918 pandemic. That publicity prompted the U.S. Health Service to call for a mass vaccination with a little-tested vaccine. Many people died or experienced severe medical problems after getting their flu shots.

Was it merely a coincidence, or was the vaccine actually dangerous? By May of 1980, over 3,917 lawsuits had been filed, seeking over $3.5 billion in damages. Three hundred people died of the flu vaccine according to the lawsuits, but only Private Lewis is known to have died of the flu. If nothing else, that 1976 swine flu scare prepared us for another epidemiological nightmare. A modern outbreak or a terrorist attack with weaponized flu would require a similar scheme of mass inoculation.

In 1997, an explosive outbreak of avian flu broke out in Hong Kong. This was a new strain of bird flu called H5N1. The sheer savagery of this new virus led to renewed urgency to understand that doomsday flu. One and a half million chickens were slaughtered to stop the disease from spreading. Six out of 18 infected people died.

That outbreak could have been the beginning of a serious new pandemic, but rapid quarantine and the destruction of every single chicken in Hong Kong stopped it in its tracks. H5N1 is currently the most dangerous type of flu in circulation. Many experts think that if this bird flu ever manages to fully cross over into humans, it would kill untold millions of people.

The H5N1 mortality rate now stands at 59 percent. In March 2005, H5N1 broke out in Vietnam, Indonesia, and North Korea, adding still more victims. Since 1997, 295 people have died from H5N1. The full designation is HP AI A(H5N1)—the HP standing for highly pathogenic. This form of flu is epizootic, which means it occurs in non-human species.

It is also panzootic, which means that it infects many different species of animals. Although it hasn’t evolved yet to efficiently cross over to humans, all the danger signs are there: It’s lethal, it’s spreading very rapidly through avian populations, and it has already caused sporadic human infections. Flu expert Robert Webster says:

“This virus right from scratch is probably the worst influenza virus, in terms of being highly pathogenic, that I’ve ever seen or worked with. Not only is it frighteningly lethal to chickens, which can die within hours of exposure, swollen and hemorrhaging, but it kills mammals from lab mice to tigers with similar efficiency.”

A multi-billion-dollar international effort is currently underway to study H5N1 and to prepare for a possible, future outbreak. Why do so many strains of flu continue to originate in Asia? The most likely explanation is the large number of people living in close proximity to domesticated pigs and birds, which is a recipe for a new pandemic. Between 1968 and 2004, China went from 5.2 million pigs to 508 million pigs, and from 12.3 million poultry to 13 billion poultry.

A Retrospective on the 1918 Flu

Was the 1918 flu an Asiatic flu? Some think it might have begun as an avian virus in China. Many agree that the killer flu, or a very close relative, caused mild local epidemics in 1916–1917. The likelihood of Kansas is usually thought of as the 1918 flu’s point of origin in humans, but a recent paper by John Oxford claims that it first erupted in a massive field hospital complex in Étaples in northwest France in the winter of 1915–1916. Symptoms were very similar to those of the subsequent pandemic.

Was the 1918 flu a swine flu or an avian flu? Taubenberger was originally certain that the 1918 flu virus came from American pigs, but his latest research demonstrated that it was, in fact, an avian flu. Flu expert Robert Webster claims that it was definitely swine flu, and probably circulating in mammals for some time before 1918.

Taubenberger remains unconvinced, pointing out that swine flu was not described by veterinarians prior to 1918. Gavin Smith, in a 2009 paper in Nature, hypothesized that the virus was a blend of avian flu and swine flu. Pigs can catch both human and avian flu, and that makes them a veritable viral blender. The 1918 Flu might have been part pig, part bird, and part human.

H1N1 has become one of the most common causes of respiratory disease in pig farms in North America, hence, that “swine flu” designation for H1N1, despite the fact that it may ultimately come from birds. The 2009 swine flu epidemic was an H1N1 subtype, like the 1918 flu, which is one reason why doctors overreacted so strongly to that outbreak. Initial analysis of the 2009 swine flu pandemic indicated a higher mortality rate for young adults, just like the 1918 flu, and once again caused by extreme cytokine storms.

In 2004, a team of scientists from the University of Wisconsin at Madison took two genes from the 1918 flu virus—the ones that code for the H and N spikes—and stitched them into the genes of mice. They created special strains with both genes, or with just the 1918 H or N genes. The spliced N gene, by itself, proved to be relatively benign—nothing special.

The mutated H binding protein proved to be one of the primary factors that made the 1918 flu so incredibly virulent. That same team, in 2008, found a key set of three genes from the 1918 virus that allowed it to target cells in the lungs, rather than just the usual upper respiratory cells that flu viruses would ordinarily attack.

In 2005, Taubenberger’s team announced that they had finally decoded the entire genome of the 1918 flu. They used the army specimens, preserved in paraffin, and fragments recovered from Hultin’s “Lucy,” and concluded that it was an avian virus that had found a new host in humans. Whether pig, bird, human, or a combination of all three, if that 1918 flu does return, we may be prepared for it this time.

Terrence Tumpey’s team, in 2006, spliced genes from the 1918 bug into a modern virus—a living virus. He then tested an experimental DNA vaccine that had been developed by the National Institutes of Health (NIH) and found it to be effective against the live reconstructed 1918 virus. Mice who were infected with the lab bug all died. All of the 10 vaccinated mice survived.

We’ve seen mankind on both the winning side and the losing side in our age-old struggle with microbes: We conquered the germ of laziness but we were decimated by the 1918 flu. There’s a very good reason why we’ve managed to survive the evolutionary arms race so far: Our highly evolved immune system gives us a deadly weapon to use against our microscopic rivals.

This is the third article in a series of three about the 1918 flu pandemic.
Read part one here.
Read part two here.

Read more