THE THIRD WAVE
The summer of 1919 saw the pandemic begin to retreat everywhere. Physicians noted an abrupt drop in new cases. “It was like you’d flipped a switch,” an American wrote. Yet the devil virus was unpredictable. In many places, influenza seemed almost gone, only to flare up, retreat, and flare up again. The third wave had begun. Regardless, the trend was clear: flu was loosening its grip. By mid-1920, the pandemic was over.44
Why?
At the time—and also in writings decades later—the pandemic was said to have “run its course.” However, that is not a scientific explanation. The phrase is really an evasion, a way of disguising ignorance of what brought the pandemic to an end. Nothing happens without a cause, and the third wave was no exception. Researchers today believe the pandemic ended for two reasons: one military and political, the other the nature of viruses.
First, the physical environment no longer favored the devil virus. True, armistice celebrations, followed by masses of troops returning home, led to a spike in flu cases. However, the coming of peace also emptied the unhealthy trenches, training camps, and military bases, such as the one at Étaples. What is more, the Treaty of Versailles enabled Germany to resume food imports, ending the famine and increasing people’s ability to resist infections of all sorts.
Second, just as the human immune system can be too robust, triggering a fatal overreaction, viruses can be too virulent—too deadly. Viruses, we recall, are not alive; they exist on the border of life. They do not “want” to harm, let alone kill, those they invade; that would be committing “suicide.” Viruses must reproduce and pass their genes to the next generation. This process involves a delicate balance between their ability to infect new victims and to harm them. If a mutation allows a virus to, say, bypass the human immune system, the virus stands a better chance of reproducing. If, however, a mutation destroys the virus before it reaches new victims, the cycle is broken. That strain of the virus will disappear, and the pandemic it caused will end.
Moreover, the natural process that makes a virus deadly also makes future versions of it milder. Different viral strains, resulting from subsequent mutations, inevitably occur. The devil virus was most unstable, always changing its capabilities. A mutation that makes its effects milder increases its chances of reproducing because it does not kill its host. The 1918 strain of the devil virus was as lethal as it could get; it is hard to imagine it being any worse. Future mutations, then, were bound to make it milder, more like the strains that cause seasonal flu. In other words, it is likely that the milder third-wave virus replaced its deadlier second-wave ancestor. Yet this is not a one-way street, since further mutations can turn a virus back into a mass killer.45
The human immune system, too, undoubtedly helped end the 1918 pandemic. Nobody knows whether an infectious disease can wipe out the entire human race; this has never happened, or you would not be reading these words. If the 1918 pandemic is any guide, humankind survived the worst disease event ever. Though exposed to the devil virus, the vast majority of people did not get sick, and those who did, survived. Having killed the most vulnerable—the very young, the very old, young adults, pregnant women—the virus must have run out of likely victims to infect.
To put it another way, the pandemic behaved like an immense forest fire: it eventually burned out. In nature, forest fires consume anything flammable that gets in their way, areas totaling thousands of square miles of forest, brush, and grassland. If left alone, however, they always run out of fuel. The devil virus consumed “human fuel.” When its fuel ran out, it simply came to a halt. Yet the virus still exists, though mutated into a far milder form. Influenza pandemics struck in 1957 and 1968, bringing death to 2.5 million people in all. Scientists have proven that the viruses causing those pandemics were descended from their 1918 ancestor.46
Many of the people who recovered from the second-wave strain bore its aftereffects for months, even for life. For example, “recovering” poet Robert Frost wondered, “What bones are they that rub together so unpleasantly in the middle of you…? I don’t know whether I’m strong enough to write a letter yet.” Frost was lucky; eventually he wrote some of his best poems. Still, medical records cite survivors who permanently lost their senses of smell and taste. Some suffered from disorders of the heart, lungs, kidneys, and eyes. Former patients hiccupped for days without letup. Others had hallucinations, seeing menacing spiders, snakes, and bats. “Sleeping sickness” plagued a special group of victims, causing them to sleep and sleep yet awaken exhausted.47
Here we may expand Nobel Prize–winning biologist Peter Medawar’s definition of a virus: for humanity, the devil virus was the worst piece of bad news that nature ever wrapped up in protein. What could science do about it?
This is a detective story. Here was a mass murderer that was around 80 years ago and who’s never been brought to justice. And what we’re doing is trying to find the murderer.
—Dr. Jeffery K. Taubenberger, 1998
THE SEARCH BEGINS
With the passing of the third wave, the great pandemic all but vanished from the news. This is not surprising, since forgetfulness is a very human quality, a way of setting aside bad experiences, allowing oneself to go on with living. Historian Alfred W. Crosby confirms this. While glancing at the Readers’ Guide to Periodical Literature for the period from 1919 to 1921, he made a startling discovery: thirteen inches of column space devoted to references to baseball stories, but only eight inches to stories about influenza. Moreover, few of the leading college history textbooks even mentioned the pandemic, and those that did gave it only a few brief sentences. It was as if humanity were suffering from amnesia, blocking out a painful experience over which it had no control. That is why Crosby titled his classic 1976 book America’s Forgotten Pandemic: The Influenza of 1918.1
Similarly, biographies of leading physicians barely touch on the tragedy. When Victor Vaughan wrote about the war years in his autobiography, A Doctor’s Memories, he dismissed the flu outright: “I am not going into the history of the influenza epidemic. It encircled the world…flaunting its red flag in the face of science.” The coauthors of William Welch’s biography gave a mere three paragraphs of a 539-page book to this monumental disaster. After ranking it among the “most destructive epidemics of military history,” they abruptly changed the subject. For both Vaughan and Welch, as for so many other physicians, the pandemic highlighted the failure of scientific medicine, to which they had devoted their adult lives. It was a stunning letdown after the advances of the previous half century.2
For others, however, forgetfulness was not a plan for the future. As one physician observed, the pandemic was “an appalling demonstration of man’s hopelessness and ignorance.” But it was also a challenge that science dared not ignore.3
There were those who tried to meet the challenge, even as the pandemic raged. Medical researchers set out in various directions. In seeking the cause of influenza, at first most accepted the findings of a German scientist named Richard Pfeiffer. In 1892, Pfeiffer had discovered a bacillus, a rod-shaped bacterium, in the lungs of flu patients. Here, he announced, was the villain. In 1918, doctors doing autopsies found “Pfeiffer’s bacillus” in microscope studies of lung tissue from dead soldiers. Believing the bacterium caused influenza, they prepared vaccines to jolt the immune system into action. The vaccines’ failure, however, proved that the bacillus did not cause influenza. We now know that the devil virus simply made it easier for normal throat bacteria to infect the lungs.4
Joseph Goldberger, an American physician and epidemiologist employed by the U.S. Public Health Service. (Date unknown) Credit 83
Meanwhile, Dr. Joseph Goldberger (1874–1929), a U.S. Public Health Service researcher, followed another research path. Goldberger wanted to know how influenza really spread. In pursuing this aim, he experimented on healthy men, a method now illegal in the civilized world.
On November 18, 1918, exactly a week after the armistice, Goldberger visited D
eer Island Prison in Boston Harbor. The prisoners were sailors serving time for offenses such as desertion, theft, fighting, and striking a superior. As the doctor looked on, guards lined up a batch of prisoners, surly, tattooed fellows with an attitude. Goldberger explained that he needed fifty men for “certain influenza experiments.” The only requirement: they must not have had influenza that year. Prisoners who volunteered, and lived, would get a pardon, be allowed to return to regular duty at full pay, and have their records wiped clean. “Volunteers,” a guard bellowed, “one step forward.” Sixty-seven, not fifty, men decided they would be better off with a few days of the flu than years in a navy prison.5
A boat took them to nearby Gallops Island, a quarantine station with a large influenza ward. Goldberger then tried everything he could think of to infect his human guinea pigs. He swabbed and sprayed pure Pfeiffer’s bacillus into their noses, throats, and eyes. He injected them with blood and a soup of all sorts of bacteria taken from flu patients’ noses and throats. For good measure, he exposed each man to two seriously ill patients. The men had to let patients breathe, cough, and sneeze into their faces—they even lay in bed with them for hours. The result? Nobody caught the flu, for reasons still unknown, and, as promised, the men were released. “Perhaps,” Goldberger said in conclusion, “if we have learned anything, it is that we are not quite sure what we know about the disease.”6
Not quite sure! That put it mildly. Everything about influenza remained mysterious, and perhaps unknowable, in 1918. What caused the infection? Where did it come from? How did it attack? How did it spread? Why did it go away? Could it ever return? Ahead lay decades of painstaking research to make the devil virus reveal its secrets.
BREAKTHROUGHS
Medical researchers, driven by curiosity and their wish to settle scores, moved on several fronts. Even in the midst of the pandemic, they began to document it. Over the years, they amassed a vast array of official reports, detailed studies, articles in medical journals, personal accounts, graphs, and statistical tables. These would provide a factual basis, a jumping-off point, for future research. Even a failed experiment had value, because it ruled out an approach, pointing researchers in other, more promising directions.
The first breakthrough came in February 1933. Scientists Wilson Smith, Christopher H. Andrewes, and Patrick P. Laidlaw of England’s National Institute for Medical Research set out to find the cause of the disease in a special way. They washed the throats of flu patients with a sterile liquid, then passed the liquid through filters with such tiny pores that bacteria, if present, could not get through. Finally, they put the filtered liquid into the noses of laboratory mice and guinea pigs, none of which got sick.
The researchers then repeated the experiment with two ferrets, relatives of the weasel with sharp teeth and short tempers. Not only did the ferrets get the flu, so did other ferrets in cages nearby. The team reported it had found “the primary infective agent in epidemic influenza,” which it called an airborne virus. Three years later, another English scientist, C. H. Stuart-Harris, got the flu after a ferret sneezed in his face. Harris was thrilled because this proved beyond doubt that the virus reached humans through the air. At about the same time, Richard E. Shope, an American researcher, proved that pigs could get the virus, probably from their human handlers. But what was a virus—really? And what did a virus look like? Only a better microscope could reveal the answers.7
Though microscopes had vastly improved since the 1600s, the most powerful glass-lens devices enlarged objects only 2,000 times at best. It took a revolution in technology to reveal submicroscopic objects. That happened in the late 1930s, with the electron microscope. A German invention, this device focuses a beam of electrons—charges of electricity arranged around the nucleus of atoms—on an object. It then projects the resulting image onto a screen magnified up to 10 million times. The electron microscope gave birth to the science of virology. Instead of merely knowing that flu viruses existed, now researchers could see them in every detail, study them, and learn how they worked. But the viruses they saw were merely the current strain, not the devil virus of 1918, which had vanished, burned out during the third wave.
A student using an early scanning electron microscope. (1974) Credit 84
By the early 1940s, virologists had identified the protein spikes that enable the flu virus to stick to a cell’s outer wall, penetrate it, and then allow the next viral generation to break out. In 1944, at the height of the Second World War, a team led by Oswald T. Avery Jr. at New York’s Rockefeller University Hospital, one of the nation’s chief research institutions, proved that certain genes are made of DNA. Later research revealed that flu virus genes consist of RNA.
The year 1944 also saw the first effective flu vaccine. Then as now, drug companies grew active viruses in their laboratories by implanting them in fertilized chicken eggs, an ideal growing medium. Once injected into an egg, a droplet of virus multiplies until, after a few days, it has become a teaspoonful of new viruses. At that point, technicians remove them, deactivate them chemically, filter out any impurities, and package them for use by health professionals. It takes 150,000 chicken eggs to make a 250-gallon batch of deactivated flu virus. Supplying America with enough vaccine for a normal flu season requires scores of batches and millions of eggs.8
It takes between four and six months to manufacture flu vaccines. These, however, are imperfect and cannot always prevent the disease. Nevertheless, the immune system “sees” the invader as foreign, and its memory cells spring into action against a virus related to a previous year’s strain. So even if infected, patients have milder symptoms and a shorter recovery time.
However, flu viruses never stop mutating. Because they constantly drift and shift, the current year’s vaccine may give little, if any, immunity to the mutations in the next year’s virus. As a result, drug companies must constantly change the makeup of their vaccines. Usually, a vaccine is “trivalent,” a mixture of what researchers think will be the coming year’s three most common viral strains.
Two agencies tell drug companies what strains they must include. Since 1948, experts from the World Health Organization (WHO), an agency of the United Nations, have monitored flu viruses throughout the world. WHO teams track mutations of known strains, looking for signs that they are dangerously close to becoming able to jump from human to human. The other agency, the Centers for Disease Control and Prevention (CDC for short), a branch of the U.S. Department of Health and Human Services, also monitors flu viruses. The agencies’ cooperation is an important milestone. Throughout history, people never had warning that a major killer disease was on the way. Now they do. Every February, WHO and CDC virologists hold a “flu meeting” to check their findings and select the strains the drug companies should include in the following year’s vaccine. Because it takes six months to make enough vaccine for the seasonal outbreak, companies need to get an early start.
Since 2002, physicians have relied on two weapons to fight the flu virus after it invades lung cells. Sold under the trade names Tamiflu (a pill) and Relenza (an inhalation mist), these drugs act like Krazy Glue. When the protein spikes of next-generation viruses try to tear open an infected lung cell, the drugs clump the viruses together on the cell’s inner surface. Immobilized and trapped, the viruses cannot infect nearby cells, and the infection is halted in its tracks. The only drawback is that, for these drugs to work, a person must take them no more than forty-eight hours after symptoms appear. Yet no one knows how long the drugs will continue to be effective. Owing to its constant mutations, the flu virus is likely to find a way to neutralize the drugs, just as bacteria eventually “learn” to resist antibiotics. Change rules nature; nothing stays the same forever. In virology, change also guarantees researchers lifelong employment.
Tamiflu, the trade name of oseltamivir, an antiviral medication used to treat and prevent influenza. Credit 85
HUNTING THE 1918 KILLER
Given the ever-changing flu virus, scienti
sts are certain another pandemic is inevitable. Pathologist Jeffery K. Taubenberger, whom we will soon get to know better, puts it this way: “The problem is, it happened before….And a lot of people ask me, What’s the chance of another pandemic like 1918? The answer is, I have no idea. But if you ask me what the chance of another flu pandemic of some kind is, I’ll tell you. It’s one hundred percent. And I’d like to be ready, wouldn’t you?”9
Being ready requires knowledge of the long-gone devil virus. What made it unique? What made it so lethal? As mutations create new viral strains today, researchers can look for genetic similarities to those in the 1918 strain. “And if you find a virus that’s got them,” says Taubenberger, “hey, heads up. This is Bad Virus.”
Pathologist Jeffery K. Taubenberger was the first to sequence the genome of the influenza virus that caused the 1918 epidemic. (Date unknown) Credit 86
It may be impossible to prevent a pandemic, but it may be possible to prepare to fight one by making a vaccine before it gets going. Yet there is a problem—a very serious one. Flu viruses are extremely fragile; they decay almost immediately after a victim dies. Luckily, finding the virus’s remains became the mission of a unique man.10
His name is Johan Hultin. In 1949, the twenty-four-year-old took a break from his medical studies to earn a doctorate in microbiology, the science of microscopic organisms. A citizen of Sweden, Hultin enrolled at Iowa State University, which has a first-rate program of study. The following year, he overheard a visiting virologist discuss the 1918 pandemic. So far, the visitor said, nobody had found a trace of the killer virus. The best way to find one, he suggested, was to take lung samples from victims buried in permafrost, ground so frozen that it never thaws, most likely in Alaska. Hultin was fascinated. “I heard that, and my God, then I knew. That was the subject for my PhD. That was it,” he later told an interviewer.11
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