The Flu of Flus

“The 1918 influenza epidemic is one of history’s great conundrums,” Gina Kolata writes in introducing the fascinating medical and scientific stories gathered together in her new book. As the subtitle explains, they are about the flu of 1918, and about recent efforts “to resurrect the virus’s genetic code,” which she believes may soon provide

a key clue in a medical mystery story that is as astonishing as the 1918 influenza itself. It involves science and politics, at their most confused, and at their finest. It involves a virus that is one of the worst killers ever known. And it involves researchers who became obsessed with tracking the virus down. Like all good mystery stories, it also has elements of serendipity and surprise.

It is a story that begged to be told, both for the sheer drama of the tale and for its implications. The resolution of the mystery could help scientists save humanity if that terrible virus or another like it stalks the earth again.

Allowing for a bit of enthusiastic exaggeration, the book delivers everything she promises. Artfully (indeed archly) constructed as a detective story, it tells how heroes and heroines of science, working in obscurity and on their own, encountered not wicked but pompous, misguided, or perhaps merely jealous scientific colleagues, and prevailed in the end. Or perhaps not, since the sequence of only one of the 1918 flu virus’s eight genes had been discovered when she finished her book. Nor had her heroes yet found any distinctive difference between it and other flu viruses that would explain its unusual lethal effects and permit the manufacture of a vaccine that would be fully effective in preventing its recurrence.

The book begins with a sketch of what happened in 1918: how an epidemic that took the medical establishment completely aback first came to public attention in Spain, largely because that country was neutral in World War I and allowed news of the infection to get out, whereas elsewhere military censors kept initial outbreaks secret. But in fact the “Spanish flu” seems to have broken out at almost the same time in many different parts of the world. The United States, Central and South America, remote Eskimo villages in Alaska, as well as Europe and Asia were all affected, and it was in Asia that by far the heaviest loss of life occurred. Expert, but always unreliable, estimates of flu deaths in India alone rise as high as 20 million, and for the world as a whole anywhere between 40 and 100 million are believed to have died.

In the United States, Kolata declares, 28 percent of the entire population fell ill and 2.5 percent of those infected died. But accurate figures for American deaths from the flu of 1918 do not exist, partly because pneumonia often followed the flu and was often listed as cause of death, and partly because at the height of the epidemic in locality after locality record keeping in general and medical administration in particular briefly broke down. But there is no doubt that far more people died from the flu than from combat in World War I; and, according to Kolata, General Erich von Ludendorff subsequently blamed the flu for the failure of the German offensive in July 1918, which “nearly won the war for Germany.”

At the time, viruses were as yet undetected, and for a while many American doctors jumped to the conclusion that a recently identified organism named Pfeiffer’s bacillus, which often appeared in the lungs of flu casualties, was responsible for the flu. When the epidemic was still in its early stages, this mistaken assumption allowed the Philadelphia Inquirer to announce that the medical profession now had “absolute knowledge on which to base its campaign against this disease.” But frantic efforts to vaccinate against the flu, using preparations made from Pfeiffer’s bacillus, as well as other prophylactic gestures, all proved futile.

As a result, the infection simply ran its natural course, almost unaffected by medical intervention. And as private family recollections still attest, when local infection peaked doctors and nurses succumbed in such numbers that most professional medical services ground to a halt. (I myself was thirteen months old when the flu paralyzed Chicago. My parents and I came down with the flu at the same time, and while severely ill my mother gave birth prematurely to a sister whose first months of life were precarious as a result of how she came into the world. It was an experience so searing that my parents almost never spoke of it afterward.)

When the epidemic faded away, medical men, popular memory, and professional historians agreed with my parents and tried to forget the whole thing. No one had much to be proud of. Suffering was over, and even though deaths of innumerable young men and women in the prime of life were privately mourned there was nothing useful to do or say about it. So, like other inexplicable infectious disasters of the more distant past, the flu of 1918 disappeared from the world and from public memory.

Kolata is puzzled by this reaction, failing to realize that in 1918 anyone over thirty-five years of age remembered a time when sudden death from infectious disease, especially in infancy, was an entirely normal human experience. The germ theory had been decisively established only after 1884, when Robert Koch announced his discovery of the cholera bacillus. But many doctors resisted the idea at first, and decades passed before sanitary engineering made the water supplies of American cities more or less germ-free. This, together with other forms of medical prophylaxis against germs, had begun to diminish deaths from infections significantly by 1918, so that, before the flu came, medical authorities of the American army were, in Kolata’s words, “flush with the success of the public health effort that seemed to have made disease in the military almost a thing of the past.” But unexpected death from infection was still a vivid memory for most adults. For them the flu was remarkable only for the number of persons it affected. Once it was over, the wish to forget the epidemic was wholly normal and natural.

The really unusual fact is that in the second half of the twentieth century, public experience of disease altered so radically that in retrospect the epidemic of 1918 began to seem as horrendous as Kolata makes it out to be. Beginning with DDT, atabrin, sulfa drugs, and penicillin, all of which first became widely available during World War II, new chemical compounds and organized, large-scale inoculations made infections preventable or curable as never before. Additional successes came thick and fast. More and more powerful antibiotics were discovered one after another; and in 1955 a vaccine against poliomyelitis brought the last widespread, publicly dreaded infection under control. The World Health Organization even managed to eliminate smallpox—the most lethal viral disease afflicting humankind—from the entire world in 1976. Optimistic medical men and a grateful public jumped to the conclusion that infectious diseases had been permanently conquered, or at least reduced to triviality.

Flu remained an exception. Global but comparatively mild epidemics of flu recurred, decade after decade, most notably in 1946, 1957, 1968, and (abortively) 1976 and 1997. It was against this background that in 1976 a pioneering historian, Alfred W. Crosby, resurrected the story of the flu of 1918 in his book Epidemic and Peace: 1918.^* In 1995, a handful of medical outsiders, emboldened by recent advances in molecular biology and partly inspired by Crosby’s book, decided to try to decipher the genetic code of the 1918 flu virus in the hope of becoming able to forestall any recurrence of such a lethal form of the familiar infection. The story of that extraordinary undertaking, together with accounts of the bureaucratic fiasco of an official effort to prevent an expected epidemic of “swine flu” in 1976 and a drastic but successful effort to stop a new, lethal form of flu in Hong Kong in 1997, make up the rest of the book.

But first Kolata devotes a hasty chapter to comparing the flu of 1918 with a few well-known earlier epidemics—the plague of Athens in 429 BC, the Black Death in the fourteenth century, and the spread of cholera and TB in the nineteenth century. This is the weakest part of the book. As a science reporter for The New York Times she knows a lot about recent and contemporary medical affairs but did not take time to learn much about the deeper past, and so makes mistakes. For example, despite the well-known fact that pious Europeans established numerous leprosariums and other hospitals in the thirteenth century, she says that “Europe had been relatively free of disease for three centuries” before the Black Death appeared in 1347. She also dates the first recorded flu epidemic, in China, to 1888, instead of 1558-1569, when detailed descriptions of symptoms clearly indicate that flu ravaged England (provoking, by one count, an amazingly high 20 percent mortality there) as well as breaking out in the Americas and in Japan (and very probably elsewhere).

Kolata then turns to episodes from the post-1918 scientific effort to decipher what caused influenza and why it was so infectious. As a skilled journalist and storyteller, Kolata concentrates on aspects of these studies that are relevant for the stories that are to follow. Accordingly, she has little to say about the mainstream of flu research and prevention, referring only in passing to the initial identification of the virus in 1933, and devotes only three brisk sentences to the fact that American health officials inaugurated annual immunization campaigns against flu in 1944, and helped to set up a worldwide watch for new forms of the flu virus in 1947. The central accomplishment of recent research on flu appears only briefly near the end of the book, where she devotes a page and a half to explaining how flu viruses are now believed to mutate by circulating among birds, pigs, and human beings, most notably in southern China, where all three hosts live intimately together and where recent flu epidemics all appear to have first emerged.

As a result, anyone wishing to discover how experts learned to decipher the secret of flu’s ever-renewed infectiousness will not find much help in this book. That was not Kolata’s intention. Instead, she has tales to tell of scientific adventure and misadventure, and her skillful presentation of the work of particular scientists and their derring-do makes her book delightful to read. Successive chapters move back and forth between her chosen characters, beginning with a stirring chapter about how Johan V. Hultin, a Swedish-born graduate student at Iowa, organized an expedition to Alaska in 1951 and discovered a grave where Eskimo victims of the 1918 flu epidemic had been buried in permafrost. He was hoping to recover intact viruses from the frozen bodies and succeeded in securing some still-frozen lung tissue. But using the best techniques available at the time, he was unable to isolate or replicate the 1918 flu virus from his samples and had to give up the quest. He then became a medical pathologist in California, without ever forgetting or quite giving up on the idea behind his youthful adventure.

Kolata’s focus then shifts to the swine flu scare of 1976 and what she calls the “litigation nightmare” that ensued. As always, she concentrates on personalities, starting with the army private at Fort Dix, New Jersey, who died of flu and pneumonia in February 1976. Fear that Private David Lewis’s death might presage a return to the 1918 epidemic became acute a week later when analysis of swabbings from his throat yielded a “swine flu virus” that was “closely related to, if not identical to, the virus that…was thought to have caused the 1918 influenza pandemic.”

What to do? Wait and see whether an epidemic really developed before launching emergency efforts to manufacture and administer appropriate vaccines? Or rush into the breech and anticipate potential disaster by initiating heroic measures at once? Deliberations by experts swiftly climbed up the bureaucratic hierarchy, until forty-seven days after Private Lewis’s death, and before any sign of an epidemic had appeared, President Ford accepted medical advice and announced that he would ask Congress to appropriate $135 million “for production of sufficient vaccine to inoculate every man, woman, and child in the United States.” Congress acted promptly and the effort went ahead swiftly, but only after the federal government assumed liability for lawsuits that might result from unexpected side effects of vaccination.

The first swine flu shots were administered on October 1, 1976, and by mid-December 40 million Americans had been immunized. This was by far the largest mass vaccination ever undertaken. Only a few other countries, like the Netherlands, followed the US example: other countries either stock-piled flu vaccines against possible need or did nothing. But as it turned out, no sign of the expected flu epidemic ever appeared in the United States or anywhere else. Instead, an epidemic of lawsuits began after a doctor in Minnesota “called his local health officials to report that he had immunized one of his patients against swine flu and the man had developed a nerve disorder called Guillain-Barré syndrome.”

The American public health establishment reacted as before by mobilizing its full resources to find out whether other cases of this rare disease were associated with inoculation against the flu; and sure enough doctors across the country began reporting more and more patients who developed the syndrome after getting flu shots. Substantial doubt remains about whether these reports were not generated by the inquiry itself. The Guillain-Barré syndrome is an ill-defined and rare affliction and, when asked about it, many doctors probably found it convenient to use the strange and unfamiliar term to describe muscular weakness and a cluster of other ailments that were difficult to diagnose.

Nevertheless, as Kolata says, “It looked like not only was there no danger from swine flu but the vaccine itself might be injuring people.” On December 16, 1976, the vaccination campaign was called off; and “by May 1980, 3,917 claims had been filed, seeking more than $3.5 billion in damages” from the government. It took years to untangle the mess—mostly by out-of-court settlements.

Ever since, public health officials and flu experts in the United States have been haunted by the way their good intentions, professional ambitions, and all-out bureaucratic mobilization went so miserably astray in 1976. Soon thereafter, earlier victories over infectious diseases also began to show unexpected limitations. On the one hand, exposure to antibiotics accelerated ordinary processes of natural selection among all kinds of infectious organisms to produce resistant strains of old diseases with disturbing rapidity. On top of that, a few newly discovered infections, of which the most important was AIDS (named and identified in 1981-1982), proved extremely recalcitrant to older methods of chemical cure. It thus became apparent that scientific medicine had not permanently conquered infectious diseases after all, and at a time when the American public, having become swiftly accustomed to medical miracles, began to demand efficacious health care as a right. This creates the current ironic situation whereby their extraordinary past successes have created expectations that American doctors are unable to fulfill, i.e., that they will keep us all alive and well, at least for a (very elastic) foreseeable future.

The appearance of more formidable infections also imparted new vivacity to the longstanding fear that a lethal epidemic, like that of 1918, might break out again in the US. And, of course, among all the infections known to the medical profession, flu was by far the most likely candidate for such a doomsday role. Ever since 1947, year after year, flu monitoring stations around the world had identified slightly modified and therefore freshly infectious flu viruses. It became routine for medical laboratories to tailor their flu vaccines accordingly and, as we all know, public health agencies began to carry out annual campaigns to persuade members of the public to immunize themselves against the latest form of the disease by having a flu shot each fall, before the newest form of the infection could spread very far.

But what if a really lethal mutation of the flu virus escaped this defense net? What if there were insufficient time to manufacture enough vaccine against it? Breakdown of medical services, such as had occurred in locality after locality in 1918, would surely ensue, since doctors and nurses are the most exposed. Another and perhaps far larger death toll could be counted on. Kolata, for example, writes that “if such a plague came today, killing a similar fraction of the US population, 1.5 million Americans would die.”

The obvious way to head off such an outcome would be to stockpile vaccines against unusually lethal forms of flu. And to make recurrence of the epidemic of 1918 impossible, all that would be needed is enough time to manufacture inoculations from a sample of the virus that had caused it. That was why Hultin had tried in vain to recover the virus from Alaskan permafrost in 1951, and it was why in 1995 a young doctor named Jeffery Taubenberger hit on the idea of using a delicate new technique, known as polymerase chain reaction (PCR), to reconstitute genes from small tissue samples, and thus discover the exact architecture of the flu virus of 1918.

As it happened, Kolata writes, Taubenberger was

sitting on a molecular treasure trove. He could get preserved tissue from people who had died long ago—an entire warehouse of tissue. It was part of the Armed Forces Institute of Pathology, where he worked, and it had been established by President Lincoln himself…. Over the years the armed forces’ specimen collection swelled until it contained millions of scraps of tissue…. It was a veritable Library of Congress of the dead.

And of course it contained numerous samples taken from the lungs of soldiers who had died of the flu in 1918.

Taubenberger knew nothing of the flu when he first had the idea of using the PCR technique to reconstitute dead viruses from preserved tissue samples, but after considering and rejecting other possibilities, “Suddenly the idea hit. ‘We were sitting around and somebody thought of the 1918 flu,’ Taubenberger recalled.” With the help of “Amy Krafft, a young microbiologist, who had just joined the group,” and a talented lab technician named Ann Reid, Taubenberger set to work. After more than a year of repeated failures, in 1996 the team was able to reconstitute segments of the 1918 flu virus derived from the lungs of a soldier named Roscoe Vaughan, who had died at Camp Jackson in South Carolina in 1918.

But when they wrote a paper describing their feats and submitted it to the editors of Nature, it was rejected out of hand. Taubenberger, Krafft, and Reid were unknown outsiders, and editors of scientific journals habitually reject what seem to be crackpot submissions from unknowns. Reconstitution of the genes of a flu virus after almost eighty years surely sounded like a crackpot claim, and when the authors submitted the article to Science, another prestigious journal, a second, equally brisk, rejection followed.

“It gave the flu community a shock to think that a non-flu person was working on this flu project,” Taubenberger speculates. “In the flu community, people may not have heard of us.” Only after some senior scientists intervened on Taubenberger’s behalf was his paper sent out for review. Then, he said, the reviewers were enthusiastic about the paper and it was accepted for publication.

When the article duly appeared in Science in March 1997, it had the effect of “catapulting the unprepossessing researcher, who had spent his life in obscurity, into a media spotlight.” Thus unknown medical outsiders, operating with minimal funding and modest staff, emerged victorious—or did they?

There is more suspense to come, for Kolata then interrupts her main story to devote a chapter to how medical authorities in Rotterdam and Atlanta collaborated with their counterparts in Hong Kong to identify and suppress a novel and unusually lethal form of flu that had suddenly appeared in that city late in 1997. Since the Hong Kong flu derived from birds, they checked its spread to humans by ordering all the chickens in the territory killed, and prohibiting import of live chickens from the Chinese interior. The scheme worked, and the strange type of flu disappeared after killing only a handful of people in Hong Kong. Here, then, is a counterexample of how top-level expertise within the scientific “flu community” used bureaucratic intervention to head off what, in Kolata’s words, “might have been a deadly pandemic.”

In her penultimate chapter Kolata returns to Taubenberger and the colleagues and rivals who crowded onto the scene soon after his initial paper was published. Chief among colleagues, of course, was the venturesome Swede, Johan Hultin, who, when he read of Taubenberger’s success, wrote him a letter offering to recover frozen lung tissue from Alaska to back up and confirm results from the lungs of Private Vaughan. Taubenberger was glad to have Hultin’s help and surprised when the retired pathologist told him he could be off to find the diseased tissue within a week.

Hultin’s single-handed operation, assisted only by four young men from the Eskimo village who helped him dig the frozen ground, cost a total of $3,200. This contrasted with a rival, half-million-dollar expedition seeking frozen tissue from miners buried in Spitsbergen, a remote island in northern Norway. It had been organized by another enthusiastic outsider, a young Canadian named Kirsty Duncan. After years of preparation, Duncan succeeded in stirring up press attention for her enterprise and enlisted help from top British flu specialists.

Results were also in striking contrast. Hultin succeeded, as he had in 1951, by working quietly and unobtrusively, and only after getting agreement from the local community, whereas Duncan’s expedition failed to find intact tissue from the graves they opened. Moreover, reconstituted gene fragments from Hultin’s find in Alaska turned out to match the patterns Taubenberger had found before, thus confirming that his reconstituted gene fragments derived from identical 1918 originals, whereas the Spitsbergen expedition had not published any results when Kolata last interviewed Kirsty Duncan, eliciting the bitter remark “I’ve been lied to by many, many people, from government agencies to individual scientists. It’s been the most unpleasant experience of my life.”

Yet Kolata presents Duncan in a sympathetic—perhaps better, pathetic—light as a young woman obsessed with her self-appointed mission, using her physical charms to get necessary help only to be overwhelmed by resulting entanglements with bureaucrats and journalists. Kolata’s great achievement, in fact, is to present Duncan, Hultin, Reid, and Taubenberger, as well as some of the lesser characters of her account, as live human beings whose distinct personalities helped to shape their scientific aspirations and accomplishments. The strange minuet of their careers, as portrayed in her book, perhaps smacks more of fiction than of sober history, but so far as I can tell it is accurate to fact. She presents, therefore, a case of life imitating art, or rather of life presented so artfully as to command admiration and wonder from anyone who reads about it.