The Great Influenza: The Epic Story of the Deadliest Plague in History - John M. Barry (2004)
Part VII. THE RACE
WHEN WELCH had first seen autopsies of victims at Devens he had walked out of the morgue and made three calls: to a Harvard pathologist, asking him to conduct further autopsies; to Gorgas’s office, warning of the coming of an epidemic; and to Oswald Avery at the Rockefeller Institute, asking him to get on the next train from New York. He hoped Avery could identify the pathogen killing the men at Devens.
Avery immediately left his own lab, walked the few blocks home for a change of clothes, then went to Pennsylvania Station, that magnificent and uplifting building. For the length of his train ride through the Connecticut countryside, through the teeming train stations of New Haven, Providence, and Boston, up to Devens, he began to prepare, reviewing the best approaches to this problem.
Welch had told him of his concern that, despite clinical symptoms that looked like influenza, this might be a new disease. Avery’s first step would still be to look for the presence of B. influenzae, everyone’s chief suspect as the cause of influenza. Avery knew a fair amount about Pfeiffer’s bacillus, including that it was exceptionally difficult to grow and that its chemistry made it difficult to stain and hence see in a smear under the microscope. The chemistry and metabolism of the bacteria interested him. He wondered how to make it grow better, how to make it easier to find, how to make it easier to identify. For he always did everything, down to washing the glassware, with precision and discipline.
Late that afternoon Avery arrived at the camp and immediately began laboratory tests. He was all but impervious to the chaos about him, impervious to the bodies of young men lying naked or in bloody sheets he had to step over—as Welch, Cole, Vaughan, Russell, and the others of that party had—to reach the autopsy room.
From the first he encountered difficulties, getting puzzling results from the Gram test. In this test, bacteria are stained with crystal violet, treated with iodine, washed with alcohol, and then stained again with a contrasting dye. Bacteria retaining the violet color are called “Grampositive.” Those that do not are “Gram-negative.” The result of the Gram test is comparable to a witness identifying an assailant as white or black; the answer simply eliminates some possible suspects.
Unlike other investigators, Avery found no Gram-negative bacteria. B. influenzae is Gram-negative. The test eliminated B. influenzae as even a possibility. It eliminated all Gram-negative bacteria as possibilities. He repeated the experiment; again he found no Gram-negative bacteria, none at all.
Avery soon solved this particular puzzle. He discovered that all the liquid in the laboratory bottles labeled “alcohol” was actually water. Soldiers had apparently drunk the alcohol and replaced it with water. When he got alcohol, the test results came in as expected. He found Gram-negative bacteria.
Now he began his hunt in earnest. He began it with dead bodies, those of the men who had died most recently, some of whom so recently that their bodies remained warm to the touch. He felt the soggy sponginess of the still-warm lungs and respiratory tract with his gloved hands, seeking out areas of the most obvious infection from which to cut tissue samples, dipping into pockets of pus, seeking the organism responsible for the killing. Perhaps he was a little afraid, this tiny man surrounded by dead young soldiers, but he had courage and he was not hunting rabbits. He had no interest in hunting rabbits.
Smears across slides turned up several possible pathogens, all of them potential killers. He needed to know which one did the killing.
He stayed at Devens long enough to grow cultures of bacteria. Like Park and Lewis, Avery had initial difficulty but began to find Pfeiffer’s bacillus. He discovered it in twenty-two of thirty dead soldiers and gave Welch his results. Meanwhile Burt Wolbach, the Harvard pathologist whom Welch had also asked to help at Devens, made a stronger statement: “Every case showed the influenza bacillus, in many instances pure cultures from one or more lobes…. Mixed cultures, usually pneumococcus, where bronchial dilation was marked…. Pure cultures of influenza bacillus in the more recent stages and therefore usually in the upper lobes.” In an article in Science, another respected investigator also wrote, “The causative agent is believed to be the bacillus of Pfeiffer.”
On September 27, Welch, Cole, and Victor Vaughan wired the surgeon general from Devens, “It is established that the influenza at Camp Devens is caused by the bacillus of Pfeiffer.”
But it was not so established, at least not to Avery. Although he respected Wolbach, not to mention Park, Williams, and Lewis, all of whom were reaching the same conclusion at about the same time, he based conclusions only upon his own findings. And his findings did not convince him yet. In seven of the autopsies he found no sign of any bacterial invasion whatsoever, despite the devastation of the lungs. Also, although he found potentially lethal bacteria without any sign of Pfeiffer’s in only a single instance, in roughly half the cases he was finding both Pfeiffer’s and other organisms, including the pneumococcus, hemolytic streptococcus, and staphylococcus aureus, which although a lethal organism rarely caused pneumonia.
He could interpret these findings several ways. They might mean that Pfeiffer’s B. influenzae did not cause the disease. But that was only one possible conclusion. Pfeiffer’s might well be the cause of the disease, and, after it infected the victim, other bacteria took advantage of a weakened immune system to follow its lead. This would not be unusual. Finding several pathogens might even actually strengthen the case for Pfeiffer’s. Pfeiffer’s grew poorly in laboratory cultures whenever other bacteria, especially the pneumococcus or hemolytic streptococcus, were also present. So its existence at all in cultures with these other organisms might indicate that B. influenzae had been present in enormous numbers in the victim.
Methodically he ran through all this in his mind. By early October, he was back at Rockefeller hearing reports from dozens of other investigators around the country and the world that they too were finding the influenza bacillus. But there were also reports of failures to find B. influenzae. It would be easy to dismiss the failures to find it as failures of technique; Pfeiffer’s was after all one of the most difficult organisms to grow. Still, Avery’s own findings alone left too many unanswered questions for him to reach a conclusion, crisis or not. Unlike Park, Williams, and Lewis, Avery was not ready to reach even a tentative conclusion. Yes, Pfeiffer’s might cause influenza. Oh yes it might. But he was not convinced. From Avery came no reports of finding influenza’s cause, no phone calls or telegrams that he was sending cultures with which to infect horses and produce serum or vaccine.
He was pushing himself harder than he ever had at Devens—and he always pushed hard. He ate in the laboratory, ran dozens of experiments simultaneously, barely slept, bounced ideas by telephone off Rosenau and others. He bore into his experiments like a drill, breaking them apart and examining every fractured crack in the data for a clue. But if he pushed himself to work, he would not push himself toward a conclusion.
He was not convinced.
Oswald Avery was different. Pressure troubled him less than having to force the direction of his work, and that he could not pursue the trail wherever it led, could not move at his own pace, could not take the time to think. Make-do solutions were foreign to his nature. He worked on the vertical. He dove deeply into a thing, to the deepest depths, following down the narrowest pathways and into the tiniest openings, leaving no loose ends. In every way his life was vertical, focused, narrow, controlled.
He prepared…everything, wanting to control every effect. Even the drafts of his rare talks show marks denoting what words to emphasize, where to change the tone of his voice, where to use nuance. Even in casual conversation it sometimes seemed each word, indeed each hesitation, was carefully prepared, weighed, and perhaps staged. His personal office, adjacent to his laboratory, reflected focus as well. René Dubos, a prominent scientist, called it “small and bare, as empty as possible, without the photographs, mementos, pictures, unused books, and other friendly items that usually adorn and clutter a work place. The austerity symbolized how much he had given up all aspects of his life for the sake of utter concentration on a few chosen goals.”
For in digging deep, Avery did not wish to be disturbed. He was not rude or unkind or ungenerous. Far from it. Young investigators who worked under him uniformly became his most loyal admirers. But he burrowed in, deeper and deeper into the world of his own making, a world—however narrow—that he could define and over which exert some control.
But narrow did not mean small. There was nothing small about his thinking. He used information like a springboard, a jumping-off point that allowed his mind to roam freely, indeed to race freely—even carelessly—to speculate. Colin MacLeod, like Dubos a brilliant Avery protégé, said that whenever an experiment yielded unexpected information Avery’s “imagination was now fired…. He would explore theoretical implications exhaustively.”
Dubos put it another way. He believed Avery uncomfortable in and possibly incapable of handling the chaos of social interaction. But he believed Avery comfortable with and capable of confronting the chaos of nature. Avery could do so because of his “uncanny sense of what was truly important” and “imaginative vision of reality…. He had the creative impulse to compose those facts into meaningful and elegant structures…. His scientific compositions had, indeed, much in common with artistic creations which do not imitate actuality but transcend it and illuminate reality.”
Years after the pandemic, Avery’s colleague and friend Alphonse Dochez received the Kober Medal, an award Avery himself had received earlier. In a tribute, Avery described Dochez’s work ethic. He could have been describing his own: “[R]esults…are not random products of chance observations. They are the fruit of years of wise reflection, objective thinking, and thoughtful experimentation. I have never seen his laboratory desk piled high with Petri dishes and bristling with test tubes like a forest wherein the trail ends and the searcher becomes lost in dense thickets of confused thought…. I have never known him to engage in purposeless rivalries or competitive research. But often have I seen him sit calmly, lost in thought, while all around him others with great show of activity were flitting about like particles in Brownian motion; then, I have watched him rouse himself, smilingly saunter to his desk, assemble a few pipettes, borrow a few tubes of media, perhaps a jar of ice, and then do a simple experiment which answered the question.”
But now, in the midst of a killing epidemic, everything and everyone around him—including even the pressure from Welch—shouldered thought aside, shouldered perspective and preparation aside, substituting for it what Avery so disdained: Brownian motion—the random movement of particles in a fluid. Others hated influenza for the death it caused. Avery hated it for that, too, but for a more personal assault as well, an assault upon his integrity. He would not yield to it.
When Avery experimented, a colleague said, “His attitude had many similarities with the hunter in search of his prey. For the hunter, all the components—the rocks, the vegetation, the sky—are fraught with information and meanings that enable him to become part of the intimate world of his prey.” Avery had a hunter’s patience. He could lie in wait, for an hour, a day, a week, a month, a season. If the prey mattered enough, he could wait through an entire season and then another and then another. But he did not simply wait; he wasted not a single hour, he plotted, he observed, he learned. He learned his prey’s escape routes and closed them off; he found better and better vantage points; he bracketed the field through which the prey passed and kept tightening that field until, eventually, the prey had to pass through a noose. And he could lay traps: studying pneumococci by scratching it into the skin, for example, where the immune system could easily control the infection, but which still gave him the opportunity to experiment with the bacteria outside a test tube. He advised, “Whenever you fall, pick up something.” And he often said, “Disappointment is my daily bread. I thrive on it.”
He would not be rushed. There was pressure on him, pressure on everyone. But he would not be rushed. At Rockefeller he was hardly the only one devoting all his energies to influenza. Martha Wollstein, who had years before collaborated with Flexner on an unsuccessful effort to develop a serum for Pfeiffer’s, was searching for antibodies in the blood of recovered patients. Dochez was making an intensive study of throats. Many others were working on the disease. But they had made little progress. Rufus Cole reported to Gorgas’s office in mid-October, “We have been compelled to take care of the cases of influenza arising in the Hospital and Institute and these patients have occupied all of our space.” Because of the time treating the patients took, he added, “I do not think we can add very much, so far, to the knowledge concerning the disease.”
Everywhere the pressure was intense. Eugene Opie, another Hopkins product who was now a lieutenant colonel on the army’s pneumonia commission, had been at Camp Pike in Arkansas when the epidemic broke out. He had gone there because, during the measles epidemic, Pike had had the highest rate of pneumonia of any cantonment in the country. Now of course his orders were to work entirely on influenza. Frederick Russell, speaking for Gorgas, demanded “daily…a statement of your findings, as you interpret them.” Every day he was to report. If he found anything that gave the faintest hint of progress, Gorgas wanted to know it—instantly—so it could be shared. Opie would find no shortage of experimental material. Camp Pike held sixty thousand troops. At the crest of the epidemic thirteen thousand of them would be hospitalized simultaneously.
Investigators struggled to find something—anything—that could help, that could contain the explosion. Though no one had found anything certain, in Philadelphia following Lewis’s methods, in New York following Park’s, in Chicago following those developed at the Mayo Clinic, laboratories were producing enough vaccines and serum for hundreds of thousands and perhaps millions of people, while from Boston a huge and much-publicized shipment of vaccine was rushed across the country to San Francisco. On October 3, Gorgas’s office in Washington offered all headquarters personnel the antipneumococcal vaccine that Cole and Avery had such hopes for, the one vaccine that had been tested—and with such success—that spring at Camp Upton.
Even in the midst of this death, this pressure, Avery would not be rushed. More and more reports came in that investigators around the world could not find the influenza bacillus. This in itself proved nothing. It was almost a test of a bacteriologist’s skill to grow Pfeiffer’s in the laboratory. At Camp Dodge in Iowa, for example, bacteriologists found Pfeiffer’s B. influenzae in only 9.6 percent of the autopsied cases. An official army report blamed them: “The low incidence was undoubtedly due to poor technique in handling cultures…. [B]acteriologic methods…of this camp…were not to be depended upon.” The laboratory chief at Camp Grant, whom Welch himself had pronounced “excellent” just three months before the epidemic struck, found Pfeiffer’s bacillus in only six of 198 autopsies. Even so, his own report said, “We are inclined to take the stand that this study does not prove the lack of association between the Pfeiffer’s bacillus and the epidemic owing to the irregular technique followed.”
Perhaps that was the case, perhaps technical errors prevented those at Dodge and Grant and elsewhere from identifying the bacillus. Or perhaps Pfeiffer’s was not present to be identified.
In his usual methodical way Avery took the step most likely to settle the question. There was no drama to this step. He poured his energies into perfecting the tool, to find ways to make it easier to grow B. influenzae. If he succeeded, then everyone could learn whether the inability to find the bacillus was because of incompetence or the absence of the bacteria.
He filled his laboratory with petri dishes, prepared the culture media in dozens of different ways, isolated the different factors, and observed in which dishes the bacteria seemed to grow best. Then he pushed each element that seemed to encourage growth. A hypothesis lay behind each individual experiment. He had learned, for example, that the pneumococcus inhibited the growth of Pfeiffer’s. So he wanted to prevent any pneumococci from growing. He already knew as much about the chemistry and metabolism of the pneumococcus as did any person living. He added a chemical, sodium oleate, to the medium to block pneumococcal growth. It worked. In cultures with sodium oleate the pneumococcus did not grow, and Pfeiffer’s grew better.
Over a period of weeks he made significant progress. Pfeiffer’s also required blood in the culture medium to grow, which was not so unusual. But blood serum inactivated the sodium oleate. So he centrifuged out only red blood cells and used them. And his experiments suggested that blood added to the culture at roughly body temperature inhibited growth. Avery found that heated blood, adding blood to media at nearly 200 degrees Fahrenheit, allowed the B. influenzae to flourish.
He promptly published the recipe for his preparation, which became known as “chocolate agar,” in the Journal of the American Medical Association, writing, “It is possible that technical difficulties in the isolation and growth of this microorganism may be in part responsible for the discordant results obtained in different laboratories…. The use of this medium has led to an increase in positive findings of B. influenzae in actual cases of the disease and in convalescents.”
With this information any reasonably competent scientist could grow and identify the bacteria. At least now they would know that if Pfeiffer’s was not found it was because it was not there.
Avery himself still would not be rushed, would not discuss a conclusion he was not yet ready to support. But based on Avery’s work Cole told Russell, “I feel less and less inclined to ascribe the primary infection to the influenza bacilli—although that possiblity cannot be excluded until the real cause of the infection is demonstrated…. I am very hopeful that the anti-pneumococcus vaccination can be pushed rapidly. While the anti-influenzal vaccination”—by this he meant vaccine against B. influenzae—“seems to me still doubtful we have very good evidence that the anti-pneumococcus vaccination is going to prove to be of a great help.” He added, “It seems to me the influenza epidemic gives an opportunity for developing this in a way that could not have otherwise been done.”
There was nothing easy about making either the antipneumococcus serum, which in tests had just cured twenty-eight of twenty-nine patients suffering infection with Type I pneumococcus, or the vaccine. It took two months to prepare the vaccine properly, two months of a difficult process: making 300-liter batches of broth—and the pneumococci themselves dissolved too often in ordinary broth, which meant adding chemicals that later had to be removed—concentrating it, precipitating some of it out with alcohol, separating out the additives, standardizing it. Avery and other Rockefeller investigators did make one important advance in production: by adjusting the amount of glucose in the media they increased the yield tenfold. But they could still move only twenty-five liters a day through centrifuges. It mocked the need.
In the meanwhile the killing continued.