Pale Rider: The Spanish Flu of 1918 and How It Changed the World

by Laura Spinney

  One of the reasons that scientists had such difficulty believing that a virus had caused the pandemic was that, unlike many of the opportunistic bacteria that invaded the lungs of patients already infected by flu, and no matter what nourishing gel they offered it, they weren’t able to grow it in a dish. ‘Grow’, in this sense, means persuade it to produce more copies of itself. As we know, however, a virus can’t reproduce outside a host cell. For a virus to enter a host cell, protein structures on its surface, called antigens, must first bind to receptors on the cell’s surface. The two have to fit pretty well, like a lock and key, but when they do, a cascade of molecular events is unleashed that allows the virus to pass inside the cell (an antibody works by attaching itself to one of those same antigens, so preventing it from attaching itself to the host receptor). Once inside the cell, the virus requisitions the cell’s reproductive machinery to manufacture new copies of its components. These are then assembled into new viruses that break out of the cell, killing it in the process, and proceed to infect new cells. In humans, the flu virus invades cells lining the respiratory tract, damaging that lining as the cells die. The result is the symptoms of flu.

  In 1931, the same year that Shope identified a virus as the cause of swine flu, American pathologists Alice Woodruff and Ernest Goodpasture succeeded in growing a virus in a fertilised chicken’s egg. This was the result of their observation that chicken eggs could become infected by a disease of poultry called fowlpox, which is caused by a virus. Their achievement meant that viruses could now be grown in large quantities in the laboratory, free of contamination by bacteria. That in turn meant that scientists could study them tranquilly, outside epidemics, and begin developing vaccines against them. The first flu vaccine was produced by a Russian, A. A. Smorodintseff, in 1936. He took a flu virus and grew it in an egg, then extracted the offspring of the virus that replicated least well and grew them in another egg. He repeated this process thirty times, until he had a virus that didn’t replicate very well at all–another way of saying that it was mild–and this he injected into people. The first human guinea pigs experienced a barely perceptible fever but were protected against reinfection with flu.

  Smorodintseff’s vaccine was given to Russian factory workers with the goal of reducing absenteeism due to respiratory disease. The same kind of vaccine was used for the next fifty years in the Soviet Union, and more than a billion Russians received it. But it only protected against influenza A, and it had other limitations too–not least that the virus could continue to reproduce in the recipient and potentially recover its virulence. Later, scientists found that they could stop it replicating by treating it with the chemical formaldehyde. Though much larger quantities of it were required, the ‘inactivated’ virus still provided protection against reinfection.

  Vaccines were developed that protected against more than one flu type–so-called polyvalent vaccines–and by 1944 the American troops arriving in Europe to fight the Second World War had received the first mass flu vaccine containing inactivated viruses of more than one type. One of those who had worked on it was Jonas Salk, the man who would become famous as the inventor of the polio vaccine (and whose name, in the 1950s, would be better known to Americans than that of their president). His fascination with viruses began in the early twentieth century, when the world’s virologists–some of them in his native New York–were trying to solve the mystery of the Spanish flu.

  By the 1940s, therefore, scientists had classified flu, they had introduced it to all manner of unsuspecting animals, they had even–in a tribute to human ingenuity–developed vaccines against it. But even after all doubts had been silenced as to the existence of the flu virus, it remained a mythical beast–something like a leprechaun, or the Higgs boson before it was outed in 2012–because nobody had ever seen it. It belonged to that category of creature that, in a premonitory article written in 1903, Émile Roux had labelled êtres de raison, or theoretical beings: organisms whose existence can be deduced from their effects, though they have never been detected directly.4

  The problem was that, even with the help of an optical microscope, there was a limit to the tininess of objects that could be seen. Essentially, it was impossible to see anything smaller than the wavelength of visible light. Red blood cells were visible, as were some of the bacteria that infected them, but not a virus, which is smaller. Two Germans, Max Knoll and Ernst Ruska, broke through that barrier in the early 1930s, when they invented the electron microscope. An electron, like a photon of light, behaves as both wave and particle, but its wavelength is hundreds of times shorter than that of a photon. The flu virus was visualised for the first time in 1943, twenty-five years after Dujarric de la Rivière risked his life to prove it existed.

  It is of medium size, as viruses go, and close to spherical (though sometimes it can be shaped like a rod): a tiny bead of protein encircling an even tinier kernel of genetic information. The whole is enclosed by a membrane, on top of which sits that all-important antigen, called haemagglutinin, or H for short. H looks like a lollypop. Its stalk projects down into the membrane while its round if convoluted head is presented to the outside. In fact, some flu viruses–including the influenza A viruses that cause pandemics–carry not one but two major antigens on their surface. H is the metaphorical crowbar that allows the virus to break into a cell, while neuraminidase (N), the second major antigen, is the glass cutter that allows it to exit again.

  Flu’s genetic material consists of single-stranded RNA, as opposed to double-stranded DNA in humans, and this RNA is packaged into eight segments (for ease, we’ll call them genes). Two of these genes are translated into the surface proteins H and N, while the other six–the so-called internal genes–encode proteins that modulate functions such as the virus’s ability to replicate or to fend off the host’s immune response. When the flu virus reproduces itself, these genes have to be copied, but because RNA is less chemically stable than DNA, the copying mechanism is sloppy, and errors creep in. This sloppiness is the key to flu’s notorious lability–that capacity it has to generate endless new variations on itself–because errors at the genetic level translate into structural changes in the proteins they encode, and even tiny ones can have a big effect. Every year, for example, about 2 per cent of the units–called amino acids–that make up flu’s surface proteins are replaced. That’s enough to alter the shape of the H antigen such that an antibody that once bound to it can no longer do so very well. The virus ‘escapes’ the host’s immunity, partially, and causes a new, seasonal outbreak. It is the reason why flu vaccines have to be updated each year.

  That slow accumulation of errors is known as drift, but flu can also reinvent itself in a more radical way. This happens when two different flu viruses meet in a single host, swap genes and produce a new one–a virus with a novel H-N combination, for example. This kind of change, called shift–or more memorably, ‘viral sex’–tends to trigger a pandemic, because a radically different virus demands a radically different immune response, and that takes time to mobilise. If the two ‘parent’ viruses come from two different hosts–a human and a bird, say–their encounter may result in an antigen that is novel to humans being introduced into an otherwise human-adapted virus. Every flu pandemic of the twentieth century was triggered by the emergence of a new H in influenza A: H1 in 1918, H2 in 1957 and H3 in 1968.

  Once the human immune system has been mobilised against the new virus, it enters a more stable equilibrium with its host. The pandemic passes, but the virus continues to circulate in a benign, seasonal form, provoking occasional outbreaks as it evolves through drift. That equilibrium is maintained until another novel virus emerges. But an old H can also cause a new pandemic, if it emerges in a population that has become immunologically naive again–that is, in a generation that has never been exposed to it. In other words, it can be recycled over roughly the human lifespan. There is some evidence that H3, which caused the ‘Hong Kong’ flu pandemic of 1968, also caused the Russian flu of the 1890s, wh
ile H1 caused the Spanish flu of 1918 and the so-called ‘swine flu’ (actually a human flu) of 2009. A novel N may also be capable of triggering a pandemic (this is currently a subject of debate), and there are, to date, eighteen known varieties of H and eleven known varieties of N. Nowadays, therefore, influenza A viruses are classified by subtype according to which versions of these two antigens they carry. A given subtype can be further divided into strains, depending on the make-up of its internal genes. The subtype that caused the Spanish flu was H1N1–all the ones, a ghostly echo of ‘disease eleven’, as French Army doctors dubbed it, on the far side of a gulf of knowledge.

  14

  Beware the barnyard

  Extinct until 2005, the H1N1 strain that caused the Spanish flu is, today, alive and well (if we can call a virus alive) and imprisoned in a high-security containment facility in Atlanta, Georgia. It was brought back to life for the purposes of scientific study, though not everybody was persuaded of the wisdom of that move. Fellow scientists accused those responsible of having revived ‘perhaps the most effective bioweapons agent now known’. Since the method for its reconstruction was available on the Internet, they argued, ‘its production by rogue scientists is now a real possibility’.1

  The researchers who reanimated the virus (two groups, to date) countered that doing so would help them answer critical questions about what happened in 1918, and so prevent a similar disaster from happening again. The virus remains safely tucked away in its level-four biohazard laboratory, nobody has unleashed it on the world, and it has indeed shed light on the 1918 pandemic–so that, for now, the cost-benefit analysis seems to be in favour of those who revived it.2

  By the 1990s, there were still many outstanding questions about the Spanish flu. Of all the flu pandemics in living memory, and even some that we know about only through historical texts, it was the odd one out. It was the most deadly. Although the vast majority of its victims experienced something not much worse than seasonal flu, it killed a much higher proportion of them–at least 2.5 per cent, compared to less than 0.1 per cent for other flu pandemics (making it at least twenty-five times as lethal). It was vicious in its own right, and it was also more likely to be complicated by pneumonia, which was usually the ultimate cause of death. Its mortality ‘curve’ was W-shaped, not U-shaped as is typical of flu, with adults aged between twenty and forty being particularly vulnerable, as well as the very young and the very old. It seemed to strike in three waves, but the first two waves presented so differently–the first being confused with seasonal flu, the second with pneumonic plague–that many people doubted they were caused by the same organism (the third wave, which was intermediate in virulence between the other two, aroused less curiosity). Whereas previous flu pandemics had tended to take three years to circle the globe, this one raced around it in two at the outside. And finally, it wasn’t clear where it had come from. Origins in France, China and the US would all be proposed.

  The only thing that most people agreed upon was that it probably had its origins in birds. Wild waterbirds had been considered the natural reservoir of influenza A since the 1970s, when an American veterinarian named Richard Slemons isolated the virus from a wild duck.3 His discovery motivated others to conduct surveys of wild bird populations, and thanks to their efforts we know that waterbirds harbour a vast diversity of flu–not in their lungs as in humans, but in their digestive tracts, and generally without suffering any ill effects. They shed the virus into the water in their droppings, from where other birds pick it up, and different strains meeting in the same bird may swap genes to produce a novel one. Ducks make particularly good flu incubators. When, soon after Slemons’ discovery, French virologist Claude Hannoun surveyed five species of migratory duck in the Somme estuary, he found that they harboured around a hundred different flu strains between them. Often, an individual bird harboured more than one strain, and some were hybrids that didn’t match any known subtypes. Hannoun had caught flu, in other words, in flagrante delicto–in the act of evolving.4

  In the 1990s, however, nobody suspected that a bird flu virus could infect a human or cause a pandemic. The receptors on a cell lining a human lung are shaped differently from those on a cell lining a duck’s intestine, and the prevailing idea was that, for the virus to jump to humans, an intermediate host was required, in which it could adapt from one receptor type to another. That intermediate host was thought to be pigs. The cells lining a pig’s respiratory tract carry receptors to which both bird and human flu viruses can bind, meaning that pigs provide an ideal crucible for the mixing of a novel strain that infects people.

  Following this line of thought, John Oxford, the man who proposed a French origin for the Spanish flu, pointed out that Étaples was only fifty kilometres from the Somme estuary–a major stopping point on the route taken by waterbirds migrating from the Arctic to Africa–and that the camp had its own piggery. Camp caterers brought in live poultry that they had purchased in surrounding villages, and some of these domesticated birds may have been infected, having mingled with wild birds passing through the bay. (By way of comparison, Haskell County, the putative Kansas origin of the pandemic, is 200 kilometres from the nearest significant wetlands, Cheyenne Bottoms in Barton County, while the closest wetlands to Taiyuan, the capital of Shansi, are 500 kilometres away and beyond the provincial borders.) It was only the death in 1997 of a little boy in Hong Kong, from a flu subtype that was known in birds but had not previously been detected in humans–H5N1–that raised the frightening possibility that a flu virus could be transmitted directly from birds to humans. At that point the question had to be asked: could this also have happened in 1918?

  By the 1990s, gene sequencing had become a powerful tool, and scientists had begun to hope that it might help them solve the puzzle of the Spanish flu. A gene consists of thousands of units called bases. If they could determine the sequence of those units across all eight genes of the Spanish flu virus, and compare it to those of other flu viruses, perhaps they would discover why that pandemic was so unusual. Unfortunately, by the 1990s, the Spanish flu was a distant memory, so the first challenge was to obtain a sample of the virus. That meant finding infected lung tissue that had been preserved for nearly eighty years, and it wasn’t just the tissue that had to have survived, but the records that went with it. The race was on: pathologists began scouring the planet for the elusive microbe.

  The first glimmer of success came in 1996, when biologist Ann Reid and pathologist Jeffery Taubenberger discovered it hiding in almost plain sight, at the US Armed Forces Institute of Pathology (AFIP) in Washington DC where they worked. It was in a scrap of lung that had been stored there ever since an army pathologist had removed it from Roscoe Vaughan, a twenty-one-year-old private who had died at a military camp in South Carolina, in September 1918. The tissue had been treated with formaldehyde to preserve it, and embedded in paraffin wax. The formaldehyde had damaged the virus’s RNA, so the scientists were only able to sequence fragments of it (they later obtained a second flu-containing sample from AFIP), but they published these first partial sequences in 1997, and a doctor in San Francisco named Johan Hultin happened to read their paper.

  Hultin, who was in his seventies by then, had a long-standing interest in the Spanish flu. In 1951, as an eager young medical student, he had set out to find the virus himself. He knew that there were places in Alaska where people had died in large numbers, and been buried in mass graves, and he thought that if the permafrost had preserved them, he might be able to extract the virus from their remains. He organised an expedition to the village of Brevig Mission on the Seward Peninsula (about 800 kilometres north of Dillingham), which lost 85 per cent of its population in five days in 1918, and having obtained permission from the village council, excavated the grave where the victims had been buried. He found lung tissue and brought it back with him, intending to analyse it in the lab. But it was 1951. Though scientists knew viruses existed, though they had seen them under electron microscopes and grown them
in eggs, they couldn’t extract the fragile organisms from decades-old tissue that had–despite the misleading term ‘permafrost’–been through cycles of potentially damaging freezing and melting. Hultin shelved the project and moved on to other things.

  Nearly five decades later, he barely skipped a beat. Back he went, alone, to the same mass grave. This time, he discovered the remains of a woman who had been overweight in life, so that the fat around her torso had protected her lungs from the worst ravages of decomposition. He packaged up her lung tissue, posted it to Taubenberger, replaced two large crosses that had marked the grave in 1951 and since rotted away, and got back on the plane to San Francisco. Taubenberger succeeded in extracting viral RNA from the tissue–though this too had been damaged, in this case by the freezing-melting cycle–and to sequence further fragments. In 2005, after nine years of painstakingly ‘stitching’ the partial sequences together, he and Reid published the first complete sequence of the Spanish flu virus (Taubenberger’s group has since repeated that feat in a couple of weeks, using a new, high-powered sequencing technique). Further partial sequences were obtained from samples stored in hospital archives in London.

  The first thing Reid and Taubenberger noticed about the sequence was how very like known sequences of bird flu it was. The virus had kept much of its bird flu-like structure, which might explain why it was so virulent: it was a very alien invader that took the human immune system by storm in 1918, yet one that could still recognise–that is, bind to–human cells. It was, in other words, a formidable vehicle of disease. Reconstructing it was a natural next step, though they deliberated long and hard about it. With virologist Terrence Tumpey and others at the Centers for Disease Control and Prevention (CDC) in Atlanta, they ‘fed’ the viral sequence to human kidney cells growing in a dish, forcing them to manufacture the virus just as a virus forces a host cell to do in the normal process of infection. Then they infected mice with it, and saw just how formidable it really was.