The Great Influenza

by John M. Barry

  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 The generation who had transformed American medicine had withdrawn from the race.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 s
cientist 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.'

  CHAPTER TWENTY-THREE

  LABORATORIES EVERYWHERE had turned to influenza. Pasteur's protegé Emile Roux, one of those who had raced German competitors for a diphtheria antitoxin, directed the work at the Pasteur Institute. In Britain virtually everyone in Almroth Wright's laboratory worked on it, including Alexander Fleming, whose later discovery of penicillin he first applied to research on Pfeiffer's so-called influenza bacillus. In Germany, in Italy, even in revolution-torn Russia, desperate investigators searched for an answer.

  But by the fall of 1918 these laboratories could function only on a far-reduced scale. Research had been cut back and focused on war, on poison gas or defending against it, on preventing infection of wounds, on ways to prevent diseases that incapacitated troops such as 'trench fever,' an infection related to typhus that was not serious in itself but had taken more troops out of the line any other disease. Laboratory animals had become unavailable; armies consumed them for testing poison gas and similar purposes. The war had also sucked into itself technicians and young researchers.

  Laboratories in both Europe and the United States were affected, but Europeans suffered far more, with their work limited by shortages not only of people but of everything from coal for heat to money for petri dishes. At least those resources Americans had. And if the United States still lagged behind Europe in the number of investigators, it no longer lagged in the quality of investigators. The Rockefeller Institute had already become arguably the best research institute in the world; out of a mere handful of scientists working there then, one man had already won the Nobel Prize and two would win it. In the most relevant area of work, in pneumonia, the Rockefeller Institute had a clear lead over the rest of the world. And Rockefeller scientists were hardly the only Americans doing world-class work.

  For Welch, Michigan's Victor Vaughan, Harvard's Charles Eliot, Penn's William Pepper, and the handful of colleagues who had pushed so hard for change had succeeded. They had transformed American medical science. If that transformation had only just occurred, if it had only recently risen to the level of Europe, it also had the vitality that comes from recent conversion. And the nation at large was not so exhausted as Europe. It was not exhausted at all.

  As influenza stretched its fingers across the country and began to crush out lives in its grip, virtually every serious medical scientist (and many simple physicians who considered themselves of scientific bent) began looking for a cure. They were determined to prove that science could indeed perform miracles.

  Most of them, simply, were not good enough to address the problem with any hope of success. They tried anyway. Their attempt was heroic. It required not just scientific ability but physical courage. They moved among the dead and dying, reached swabs into mouths and nasal passages of the desperately ill, steeped themselves in blood in the autopsy room, dug deep into bodies, and struggled to grow from swabbings, blood, and tissue the pathogen that was killing more humans than any other in history.

  A few of these investigators, possibly as few as a few dozen, were smart enough, creative enough, knowledgeable enough, skilled enough, and commanded enough resources that they were not on a fool's errand. They could confront this disease with at least the hope of success.

  In Boston, Rosenau and Keegan continued to study the disease in the laboratory. The bulk of the army's pneumonia commission had been ordered to Camp Pike, Arkansas, where, even as Welch arrived at Devens, they began investigating 'a new bronchopneumonia.' The Rockefeller team whom Welch had
brought to Devens headed back to New York, where they added Martha Wollstein, a respected bacteriologist also associated with the Rockefeller Institute, to the effort; she had studied the influenza bacillus since 1905. In Chicago at the Memorial Institute for Infectious Diseases, Ludwig Hektoen dove into the work. And at the Mayo Clinic, E. C. Rosenow did the same. The only civilian government research institution, the Public Health Service's Hygienic Laboratory and its director George McCoy joined in.

  But of all those working on it in the United States, perhaps the most important were Oswald Avery at Rockefeller, William Park and Anna Williams at the New York City Department of Public Health, and Paul Lewis in Philadelphia.

  Each of them brought a different style to the problem, a different method of doing science. For Park and Williams, the work would come as close to routine as something could be in the midst of such extreme crisis; their efforts would have no impact on their own lives in any personal sense, although they would help direct research on influenza down the path that ultimately yielded the right answer. For Avery the work would confirm him in a direction that he would follow for decades, decades first of enormous frustration but then of momentous discovery - in fact a discovery that opened the door to an entire universe even now just beginning to be explored. For Lewis, although he could not have known it, his work on influenza would mark a turning point in his own life, one that would lead to a great tragedy, for science, for his family, and for himself.

  *

  It was not a good time to confront a major new threat in the Bureau of Laboratories of the New York City Department of Public Health, the bureau Park ran and in which Williams worked. For they had a special problem: New York City politics.

  On January 1, 1918, Tammany Hall reclaimed control of the city. Patronage came first. Hermann Biggs, the pioneer who had built the department, had left a year earlier to become state health commissoner; Biggs had been untouchable because he had treated a top Tammany leader who had protected the entire department during prior Tammany administrations. His successor was not untouchable. Mayor John Hylan replaced him two weeks after taking control. But most jobs in the Department of Health were not patronage positions, so to create vacancies Tammany began to smear the best municipal health department in the world. Soon Hylan demanded the firing of division chiefs and the removal of highly respected physicians on the advisory board.