The Great Influenza: The Epic Story of the Deadliest Plague in History - John M. Barry (2004)

Part VII. THE RACE

Chapter 22

NATURE CHOSE to rage in 1918, and it chose the form of the influenza virus in which to do it. This meant that nature first crept upon the world in familiar, almost comic, form. It came in masquerade. Then it pulled down its mask and showed its fleshless bone.

Then, as the pathogen spread from cantonments to cities, as it spread within cities, as it moved from city to town to village to farmhouse, medical science began moving as well. It began its own race against the pathogen, moving more rapidly and with more purpose than it ever had.

Scientists did not presume to think that they would or could control this rage of nature. But they did not abandon their search for ways to control the damage of this rage. They still tried to save lives.

Worldwide their struggle, their race, commenced. In the United States that struggle would be fought by Welch, Gorgas, Cole, and their colleagues, as well as by the institutions they had built and the men and women they had trained. Neither these institutions nor these men and women had ever been tested like this. They had never imagined they would be tested like this. But any possibility of affecting the course of the disease lay in their hands.

To save lives they needed the answer to at least one of three questions. It was possible that even a single rough approximation of an answer would give them enough knowledge to intervene, to interrupt the disease at some critical juncture. But it was also possible they could learn detailed answers to all three questions and still remain helpless, utterly helpless.

First, they needed to understand the epidemiology of influenza, how it behaved and spread. Scientists had already learned to control cholera, typhoid, yellow fever, malaria, bubonic plague, and other diseases by understanding their epidemiology even before developing either a vaccine or cure.

Second, they needed to learn its pathology, what it did within the body, the precise course of the disease. That too might allow them to intervene in some way that saved lives.

Third, they needed to know what the pathogen was, what microorganism caused influenza. This could allow them to find a way to stimulate the immune system to prevent or cure the disease. It was also conceivable that even without knowing the precise cause, they could develop a serum or vaccine.

The easiest question to answer for influenza was its epidemiology. Although some respected investigators still believed in the miasma theory—they thought influenza spread too fast for person-to-person contact to account for it—most believed correctly it was an airborne pathogen. Breathing it in could cause the disease. They did not know the exact, precise details, that for example when the virus floats in the air it can infect someone else for anywhere from an hour to a day after it is exhaled (the lower the humidity, the longer the virus survives). But they did know that it was “a crowd disease,” spread most easily in crowds.

They also had an accurate estimate that someone with influenza “sheds” the virus—can infect others—usually from the third to the sixth day after he or she is infected.

They also believed, correctly, that people could catch influenza not only by inhaling it but by hand-to-mouth or -nose contact. They rightly thought, for instance, that a sick person could cover his mouth with his hand when he coughed, then several hours later shake hands, and the second person could then rub his chin in thought or touch his nose or stick a piece of candy in his mouth and infect himself. Similarly, someone sick could cough into a hand, touch a hard surface such as a doorknob, and spread it to someone else who turns the doorknob and later brings a hand to face. (In fact, the virus can remain infectious on a hard surface for up to two days.)

Knowledge of influenza’s epidemiology, then, was of little use. Only ruthless isolation and quarantine could affect its course. No scientist and no public health official had the political power to take such action. Some local authorities might take some action, but no national figure could. Even within the army Gorgas’s urgent and desperate calls to end the transfer of troops were ignored.

Scientists were also learning too well about the pathology of the disease and its natural course. They were learning chiefly that they could do almost nothing to intervene in serious cases, in the cases that progressed to viral pneumonia and ARDS; even administering oxygen seemed to have no effect.

They believed they could, however, possibly save lives if they could prevent or treat the slower moving pneumonias caused by what they were fairly quickly suspecting to be secondary invaders. Some preventive measures involved only giving proper guidance, such as to rest in bed after influenza infection, or giving good care, which was becoming more and more impossible as the numbers of the sick rose, as nurses and doctors themselves succumbed.

But if they could find the pathogen…They had tools, they could manipulate the immune system, they could prevent and cure some pneumonias—including the most common pneumonias. The conquest of bacterial pneumonias seemed tantalizingly within the reach of science, tantalizingly at the very edge of scientists’ reach—or just beyond it. If they could just find the pathogen…

All the energies of science rose to that challenge.

William Welch himself would not rise to it. From Camp Devens he had returned directly to Baltimore, neither stopping in New York City nor going on to report to the surgeon general’s office in Washington. Others could perform that duty, and on the phone he had said what he had to say.

In the meantime Welch wasn’t feeling very well. No doubt he tried to shrug off the discomfort. He had, after all, had an exceedingly difficult trip. Just before going to Devens he, Cole, and Vaughan had concluded their latest round of camp inspections and had just begun to relax for a few days in Asheville, North Carolina. He had even contemplated resigning his commission. Then they had been abruptly ordered to the surgeon general’s office on a Sunday, gone straight on to Devens, and there discovered this terrible disease.

So he had every reason to be tired and out of sorts. Likely he told himself something akin to that. The rattling of the train would have disturbed him, exacerbating the first signs of a headache. Large a man as he was, he had difficulty getting comfortable on a train anyway.

But as the train moved south he felt worse and worse, perhaps suffering a sudden violent headache and an unproductive cough, cough in which nothing came up, and certainly with a fever. He would have looked at himself clinically, objectively, and made a correct diagnosis. He had influenza.

No record exists of his precise clinical course. All of Baltimore, all of the East Coast, was erupting in flames. The virus struck the Hopkins itself so hard that the university closed its hospital to all but its own staff and students. Three Hopkins medical students, three Hopkins nurses, and three Hopkins doctors would die.

Welch did not go to the hospital. Almost seventy years old, forty years older than those who were dying in the greatest numbers, having just left the horror at Devens and knowing the enormous strain on and therefore the likely poor care even at the Hopkins facility, he later said, “I could not have dreamed of going to a hospital at that time.”

Instead, he went to bed immediately in his own rooms, and stayed there. He knew better than to push himself now: pushing oneself after infection with this disease could easily open the path for a secondary invader to kill. After ten days in bed at home, when he felt well enough to travel at all, to recuperate more he withdrew entirely to his beloved Hotel Dennis in Atlantic City, the odd tacky place that was his haven.

In the midst of the chaos that was everywhere, he returned to this familiar place that gave him comfort. What had he always liked about it? Perhaps the life that roared through it. Quiet resorts bored him: he described Mohonk, a mountain resort ninety miles above New York City, as “a kind of twin-lakes-resort with Miss Dares sitting in rockers on the broad piazza,…where it seems as if nine o’clock will never come so that one could go decently to bed…[C]olored neckties are not allowed.” But Atlantic City! and “the most terrifying, miraculous, blood-curdling affair called the Flip-flap railroad…just built on a long pier out over the ocean…[Y]ou go down from a height of about 75 feet…with the head down and the feet up, so that you would drop out of the car, if it was not for the tremendous speed. As you go round the circle the effect is indescribable…. Crowds stand around and say they would not try it for $1000.”

Yes, the life that roared through Atlantic City—the young men and women and their frolicking, the sensuality of sweat and surf and salt, the vibrancy and thrust of flesh about the ocean and boardwalk, all that—made one feel as if one were not merely observing but partaking. But now Atlantic City was quiet. It was October, off-season, the resorts quiet. And here, as everywhere, was influenza. Here, as everywhere, there was a shortage of doctors, a shortage of nurses, a shortage of hospitals, a shortage of coffins, its schools closed, its places of public amusement closed, its Flip-flap railroad closed.

He stayed in bed for several more weeks, recuperating. The disease, he told his nephew, “seems to have localized itself in my intestinal, rather than the respiratory tract, which is probably fortunate.” He also insisted that his nephew, later a U.S. senator, make certain if any symptoms of influenza appeared at all in his family that the victim stay in bed “until the temperature has been normal for three days.”

He had planned to attend a meeting on the disease at the Rockefeller Institute, but almost two weeks after arriving in Atlantic City, a month after first becoming ill, he canceled; he had not recovered enough to attend. He would play no further role in medical science for the course of the epidemic. He would not participate in the search for a solution. He had of course done no laboratory work in years, but he had often proved an extraordinarily useful conduit, knowing everyone and everything, a cross-pollinator recognizing how the work of one investigator might complement the work of another, and directly or indirectly putting the two in touch. Now he would not play even that role.

Coincidentally, both Flexner and Gorgas arrived in Europe on unrelated business just as influenza erupted in America. The generation who had transformed American medicine had withdrawn from the race. If anything was to be done in the nature of a scientific breakthrough, their spiritual descendants would do the doing.

Welch had left Massachusetts with Burt Wolbach performing more autopsies, Milton Rosenau already beginning experiments on human volunteers, and Oswald Avery beginning bacteriological investigations. Other outstanding scientists had also already engaged this problem—William Park and Anna Williams in New York, Paul Lewis in Philadelphia, Preston Kyes in Chicago, and others. If the country was lucky, very lucky indeed, one of them might find something soon enough to help.

For all the urgency, investigators could not allow themselves to be panicked into a disorderly approach. Disorder would lead nowhere. They began with what they knew and with what they could do.

They could kill pathogens outside the body. An assortment of chemicals could disinfect a room, or clothes, and they knew precisely the amount of chemicals needed and the duration of exposure necessary to fumigate a room. They knew how to disinfect instruments and materials. They knew how to grow bacteria, and how to stain bacteria to make them visible under microscopes. They knew that what Ehrlich called “magic bullets” existed that could kill infectious pathogens, and they even had started down the right pathways to find them.

Yet in the midst of crisis, with death everywhere, none of that knowledge was useful. Fumigation and disinfecting required too much labor to work on a mass scale, and finding a magic bullet required discovering more unknowns than was then possible. Investigators quickly recognized they would get no help from materia medica.

Medicine had, however, if not entirely mastered at least knew how to use one tool: the immune system itself.

Investigators understood the basic principles of the immune system. They knew how to manipulate those principles to prevent and cure some diseases. They knew how to grow and weaken or strengthen bacteria in the laboratory, and how to stimulate an immune response in an animal. They knew how to make vaccines, and they knew how to make antiserum.

They also understood the specificity of the immune system. Vaccines and antisera work only against the specific etiological agent, the specific pathogen or toxin causing the disease. Few investigators cared how elegant their experiments were as friends, families, and colleagues fell ill. But to have the best hope of protecting with a vaccine or curing with a serum, investigators needed to isolate the pathogen. They needed to answer a first question, the most important question—indeed, at this point the only question. What caused the disease?

Richard Pfeiffer believed he had found the answer to that question a quarter century earlier. One of Koch’s most brilliant disciples, scientific director of the Institute for Infectious Disease in Berlin, and a general in the German army, he was sixty years old in 1918 and by then had become somewhat imperious. Over his career he had addressed some of the great questions of medicine, and he had made enormous contributions. By any standard he was a giant.

During and after the 1889–90 influenza pandemic—with the exception of 1918–19, the most severe influenza pandemic in the last three centuries—he had searched for the cause. Carefully, painstakingly, he had isolated tiny, slender, rod-shaped bacteria with rounded ends, although they sometimes appeared in somewhat different forms, from people suffering from influenza. He often found the bacteria the sole organism present, and he found it in “astonishing numbers.”

This bacteria clearly had the ability to kill, although in animals the disease produced did not quite resemble human influenza. Thus, the evidence against it did not fulfill “Koch’s postulates.” But human pathogens often either do not sicken animals or cause different symptoms in them, and many pathogens are accepted as the cause of a disease without fully satisfying Koch’s postulates.

Pfeiffer was confident that he had found the cause of influenza. He even named the bacteria Bacillus influenzae. (Today this bacteria is called Hemophilus influenzae.)

Among scientists the bacteria quickly became known as “Pfeiffer’s bacillus,” and, given his deserved reputation, few doubted the validity of his discovery.

Certainty creates strength. Certainty gives one something upon which to lean. Uncertainty creates weakness. Uncertainty makes one tentative if not fearful, and tentative steps, even when in the right direction, may not overcome significant obstacles.

To be a scientist requires not only intelligence and curiosity, but passion, patience, creativity, self-sufficiency, and courage. It is not the courage to venture into the unknown. It is the courage to accept—indeed, embrace—uncertainty. For as Claude Bernard, the great French physiologist of the nineteenth century, said, “Science teaches us to doubt.”

A scientist must accept the fact that all his or her work, even beliefs, may break apart upon the sharp edge of a single laboratory finding. And just as Einstein refused to accept his own theory until his predictions were tested, one must seek out such findings. Ultimately a scientist has nothing to believe in but the process of inquiry. To move forcefully and aggressively even while uncertain requires a confidence and strength deeper than physical courage.

All real scientists exist on the frontier. Even the least ambitious among them deal with the unknown, if only one step beyond the known. The best among them move deep into a wilderness region where they know almost nothing, where the very tools and techniques needed to clear the wilderness, to bring order to it, do not exist. There they probe in a disciplined way. There a single step can take them through the looking glass into a world that seems entirely different, and if they are at least partly correct their probing acts like a crystal to precipitate an order out of chaos, to create form, structure, and direction. A single step can also take one off a cliff.

In the wilderness the scientist must create…everything. It is grunt work, tedious work that begins with figuring out what tools one needs and then making them. A shovel can dig up dirt but cannot penetrate rock. Would a pick then be best, or would dynamite be better—or would dynamite be too indiscriminately destructive? If the rock is impenetrable, if dynamite would destroy what one is looking for, is there another way of getting information about what the rock holds? There is a stream passing over the rock. Would analyzing the water after it passes over the rock reveal anything useful? How would one analyze it?

Ultimately, if the researcher succeeds, a flood of colleagues will pave roads over the path laid, and those roads will be orderly and straight, taking an investigator in minutes to a place the pioneer spent months or years looking for. And the perfect tool will be available for purchase, just as laboratory mice can now be ordered from supply houses.

Not all scientific investigators can deal comfortably with uncertainty, and those who can may not be creative enough to understand and design the experiments that will illuminate a subject—to know both where and how to look. Others may lack the confidence to persist. Experiments do not simply work. Regardless of design and preparation, experiments—especially at the beginning, when one proceeds by intelligent guesswork—rarely yield the results desired. An investigator must make them work. The less known, the more one has to manipulate and even force experiments to yield an answer.

Which raises another question: How does one know when one knows? In turn this leads to more practical questions: How does one know when to continue to push an experiment? And how does one know when to abandon a clue as a false trail?

No one interested in any truth will torture the data itself, ever. But a scientist can—and should—torture an experiment to get data, to get a result, especially when investigating a new area. A scientist can—and should—seek any way to answer a question: if using mice and guinea pigs and rabbits does not provide a satisfactory answer, then trying dogs, pigs, cats, monkeys. And if one experiment shows a hint of a result, the slightest bump on a flat line of information, then a scientist designs the next experiment to focus on that bump, to create conditions more likely to get more bumps until they become either consistent and meaningful or demonstrate that the initial bump was mere random variation without meaning.

There are limits to such manipulation. Even under torture, nature will not lie, will not yield a consistent, reproducible result, unless it is true. But if tortured enough, nature will mislead; it will confess to something that is true only under special conditions—the conditions the investigator created in the laboratory. Its truth is then artificial, an experimental artifact.

One key to science is that work be reproducible. Someone in another laboratory doing the same experiment will get the same result. The result then is reliable enough that someone else can build upon it. The most damning condemnation is to dismiss a finding as “not reproducible.” That can call into question not only ability but on occasion ethics.

If a reproducible finding comes from torturing nature, however, it is not useful. To be useful a result must not only be reproducible, it must be…perhaps one should call it expandable. One must be able to enlarge it, explore it, learn more from it, use it as a foundation to build structures upon.

These things become easy to discern in hindsight. But how does one know when to persist, when to continue to try to make an experiment work, when to make adjustments—and when finally to abandon a line of thought as mistaken or incapable of solution with present techniques?

How does one know when to do either?

The question is one of judgment. For the distinguishing element in science is not intelligence but judgment. Or perhaps it is simply luck. George Sternberg did not pursue his discovery of the pneumococcus, and he did not pursue his discovery that white blood cells devoured bacteria. He did not because doing so would have deflected him from his unsuccessful pursuit of yellow fever. Given his abilities, had he focused on either of those other discoveries, his name would be well known instead of forgotten in the history of science.

Judgment is so difficult because a negative result does not mean that a hypothesis is wrong. Nor do ten negative results, nor do one hundred negative results. Ehrlich believed that magic bullets existed; chemical compounds could cure disease. His reasoning led him to try certain compounds against a certain infection. Ultimately he tried more than nine hundred chemical compounds. Each experiment began with hope. Each was performed meticulously. Each failed. Finally he found the compound that did work. The result was not only the first drug that could cure an infection; it confirmed a line of reasoning that led to thousands of investigators’ following the same path.

How does one know when one knows? When one is on the edge one cannot know. One can only test.

Thomas Huxley advised, “Surely there is a time to submit to guidance and a time to take one’s own way at all hazards.”

Thomas Rivers was one of the young men from the Hopkins on the army’s pneumonia commission. He would later—only a few years later—define the differences between viruses and bacteria, become one of the world’s leading virologists, and succeed Cole as head of the Rockefeller Institute Hospital. He gave an example of the difficulty of knowing when one knows when he spoke of two Rockefeller colleagues, Albert Sabin and Peter Olitsky. As Rivers recalled, they “proved polio virus would grow only in nervous tissue. Elegant work, absolutely convincing. Everyone believed it.”

Everyone believed it, that is, except John Enders. The virus Sabin and Olitsky were working with had been used in the laboratory so long that it had mutated. That particular virus would grow only in nervous tissue. Enders won a Nobel Prize for growing polio virus in other tissue, work that led directly to a polio vaccine. Sabin’s career was hardly ruined by his error; he went on to develop the best polio vaccine. Olitsky did well, too. But had Enders pursued his intuition and been wrong, much of his own career would have been utterly wasted.

Richard Pfeiffer insisted he had discovered the cause, the etiological agent, of influenza. His confidence was so great he had even named it Bacillus influenzae. He had tremendous stature, half a rung below Pasteur, Koch, and Ehrlich. Surely his reputation stood higher than that of any American investigator before the war. Who would challenge him?

His reputation gave his finding tremendous weight. Around the world, many scientists believed it. Indeed, some accepted it as an axiom: without the bacteria there could be no influenza. “No influenza bacilli have been found in cases here,” wrote one European investigator. Therefore the disease was, he concluded, “not influenza.”