It was impossible to get a doctor, and perhaps more impossible to get a nurse. Reports came in that nurses were being held by force in the homes of patients too frightened and desperate to allow them to leave. Nurses were literally being kidnapped. It did not seem possible to put more pressure on the laboratory. Yet more pressure came.
*
The pressure pushed Park to abandon more than his ambitious plans. He had always been meticulous, had never compromised, had built much of his scientific reputation on exposing the flawed work of others, always moving forward carefully, basing his own experiments upon well-established premises and with as few assumptions as possible. 'On the basis of experimental facts,' he had always said, 'we are justified in' '
Now Park had no leisure for justification. If he was to have any impact on the course of the epidemic he would have to guess - and guess right. So those in his laboratory would, he reported, 'study closely only the more dominant types that were demonstrated by our procedure' . We recognized that our methods' did not take into account' heretofore undescribed organisms that might have an etiologic relationship to these infections.'
The laboratory had only two constants. One was an endless supply of samples, of swabbings, blood, sputum, and urine from live patients and organs from the dead. 'We had plenty of material, I am sorry to say,' Williams observed laconically.
And they had their routine. Only the need to keep to discipline saved the laboratory from utter chaos. There was nothing even faintly exciting about this work; it was pure tedium, and pure boredom. And yet every step involved contact with something that could kill, and every step involved passion. Technicians took sputum samples from patients in the hospital and immediately (they could not wait even an hour, or bacteria from the patient's mouth could penetrate into the sputum and contaminate it) began working with it. The steps began with 'washing': placing each small lump of balled mucus in a bottle of sterile water, removing it and repeating the process five times, then breaking up the mucus, washing it more, passing a platinum loop (a thin circle of platinum, like something one uses to blow bubbles) through it to transfer it to a test tube, taking another loop and repeating the step half a dozen times. Each step took time, time while people died, but they had no choice. They needed each step, needed to dilute the bacteria to prevent too many colonies from growing in the same medium. Then they took more time, more steps, isolating each of these growths.
Everything mattered. The most tedious tasks mattered. Washing glassware mattered. Contaminated glassware could ruin an experiment, waste time, cost lives. In the course of this work, 220,488 test tubes, bottles, and flasks would be sterilized. Everything mattered, and yet no one knew who would report to work each day, who would not (and who would suddenly be carried across the street to the hospital) and if someone failed to come into work it was nearly impossible to keep track of such simple jobs as removing growing cultures from incubators.
There were dozens of ways to grow bacteria but often only one way to grow a particular kind. Some grow only without oxygen, others only with it in plentiful supply. Some require alkaline media, others acid. Some are extremely delicate, others stable.
Every step, every attempt to grow the pathogen, meant effort, and effort meant time. Every hour incubating a culture meant time. They did not have time.
Four days after accepting the task from Pearce, Park wired, 'The only results so far that are of real importance have been obtained in two fatal cases, one a man coming from Brooklyn Navy Yard and one a doctor from the naval hospital in Boston. Both developed an acute septic pneumonia and died within a week of the onset of the first infection. In both cases the lungs showed a beginning pneumonia and in smears very abundant streptococci' . There were absolutely no influenza bacilli in either of the lungs.'
The failure to find the 'influenza bacillus' maddened Park. His best hope to produce a vaccine or serum would be to find a known pathogen, and the most likely suspect was the one Pfeiffer had named Bacillus influenzae. Pfeiffer had been and still was confident it caused the disease. Park would not hesitate to rule B. influenzae out if he did not find good evidence for it, but he had the utmost respect for Pfeiffer. Working in these desperate circumstances, he wanted to confirm rather than reject Pfeiffer's work. He wanted the answer to be Pfeiffer's bacillus. That would give them a chance, a chance to produce something that saved thousands of lives.
B. influenzae was a particularly difficult bacteria to isolate. It is tiny, even by the standards of bacteria, and usually occurs singly or in pairs rather than in large groups. It requires particular factors, including blood, in culture medium for it to grow. It grows only within a very narrow range of temperatures, and its colonies are minute, transparent, and without structure. (Most bacteria form distinctive colonies with a particular shape and color, distinctive enough that they can sometimes be identified just by looking at the colony in the same way that some ants can be identified by the form of their anthill.) B. influenzae grows only on the surface of the medium, since it depends heavily upon oxygen. It is also difficult to stain, hence difficult to see under the microscope. It is an easy target to miss unless one is specifically looking for it and unless one uses excellent technique.
While others in the lab searched for other organisms, Park asked Anna Williams to concentrate on finding Pfeiffer's. Anna Williams found it. She found it constantly. Ultimately, once she perfected her technique, she would find it in 80 percent of all samples from the Willard Parker Hospital, in every single sample from the Marine Hospital, in 98 percent of the samples from the Home for Children.
As much as he wanted Williams to be right, he would not let his desire corrupt his science. He went a step further, to 'the most delicate test of identity' agglutination.'
'Agglutination' refers to a phenomenon in which antibodies in a test tube bind to the antigen of the bacterium and form clumps, often large enough to be visible to the naked eye.
Since the binding of antibodies to an antigen is specific, since the antibodies to the influenza bacillus will bind to only that bacteria and to no other, it is a precise confirmation of identity. The agglutination tests proved without doubt that Williams had found Pfeiffer's influenza bacillus.
Less than a week after first reporting his failure to find it, Park wired Pearce that B. influenzae 'would seem to be the starting point of the disease.' But he was well aware that his methods had been less than thorough, adding, 'There is of course the possibility that some unknown filterable virus may be the starting point.'
*
The report had consequences. Park's laboratory began the struggle to produce an antiserum and vaccine to Pfeiffer's bacillus. Soon they were culturing liters and liters of the bacteria, transporting it north, and injecting it into the horses on the Health Department's 175-acre farm sixty-five miles north of the city.
But the only way to know for certain that B. influenzae caused the disease was to follow Koch's postulates: isolate the pathogen, use it to recreate the disease in an experimental animal, and then re-isolate the pathogen from the animal. The bacillus did kill laboratory rats. But their symptoms did not resemble influenza.
The results, suggestive as they were, did not fully satisfy Koch's postulates. In this case the necessary experimental animal was man.
Human experiments had begun. In Boston, Rosenau and Keegan were already trying to give the disease to volunteers from a navy brig.
None of the volunteer subjects had yet gotten sick. One of the doctors conducting the study did. In fact he died of influenza. In a scientific sense, however, his death demonstrated nothing.
CHAPTER TWENTY-FOUR
WHILE PARK TRIED to produce an antiserum or vaccine against the disease in New York, Philadelphia was already approaching collapse. Its experience would soon be echoed in many cities around the country.
There Paul Lewis was searching for the answer as well. Few, including Park, were more likely to find it. The son of a physician, Lewis grew up in Milwaukee, went to the
University of Wisconsin, and finished his medical training at Penn in 1904. Even before leaving medical school he knew he intended to spend his life in the laboratory, and he quickly acquired both a pedigree and a well-deserved reputation. He started as a junior investigator working on pneumonia under Welch, Osler, Biggs, and several others who comprised the Rockefeller Institute's Board of Scientific Advisers. Lewis impressed them all. Most impressed was Theobald Smith, one of the world's leading bacteriologists, for whom Lewis then worked in Boston. Later Smith recommended Lewis to Simon Flexner, saying that Harvard lacked the resources to allow Lewis to develop fully and that '[h]is heart lies in research.'
From Smith there could come no higher compliment. Lewis deserved it. He seemed born for the laboratory. At least that was the only place where he was happy; he loved not only the work itself but the laboratory environment, loved disappearing into the laboratory and into thought. 'Love' was not too strong a word; his passions lay in the lab. At Rockefeller, Lewis had started off pursuing his own ideas but when a polio epidemic erupted Flexner asked him to work with him on it. He agreed. It was a perfect match. Their polio work was a model combination of speed and good science. They not only proved that polio was a viral disease, still considered a landmark finding in virology, but they developed a vaccine that protected monkeys from polio 100 percent of the time. It would take nearly half a century to develop a polio vaccine for humans. In the course of this research Lewis became one of the leading experts in the world on viruses.
Flexner pronounced Lewis 'one of the best men in the country,' a very gifted fellow.' That may have been an understatement. Richard Shope worked closely with him in the 1920s, knew many of the world's best scientists (including Flexner, Welch, Park, Williams, and many Nobel laureates) and himself became a member of the National Academy of Sciences. He called Lewis the smartest man he ever knew. Joseph Aronson, a prize-winning University of Pennsylvania scientist who had also done research at the Pasteur Institute, named his son after Lewis and, like Shope, said Lewis was the brightest man he had ever met.
When the war began, Pearce, the National Research Council official, told Lewis what he told only four or five other scientists in the country: to expect to be asked 'for special service in connection with epidemic disease.'
Lewis was ready. He received a navy commission and told Flexner he had 'no onerous routine duties.' His laboratory abilities were far more important. He was still cooperating with Cole and Avery on the development of pneumonia serum, and he was also, as he told Flexner, experimenting with dyes 'as regards their capacity to inhibit the growth' of the bacteria that cause tuberculosis. The idea that dyes might kill bacteria was not original with him, but he was doing world-class work in the area and his instincts were right about its importance. Twenty years later a Nobel Prize would go to Gerhard Domagk for turning a dye into the first antibiotic, the first of the sulfa drugs.
But now the city did not need laboratory breakthroughs that deepened understanding. It needed instant successes. Lewis had reached his conclusions about polio with tremendous speed (roughly a year) and they had been both sound and pioneering conclusions. But now he had only weeks, even days. Now he was watching bodies literally pile up in the hospital morgue at the Navy Yard, in the morgues of civilian hospitals, in undertaking establishments, in homes.
He remembered Flexner's work on meningitis during an epidemic of that disease. Flexner had solved that problem and the success had made the reputation of the Rockefeller Institute. Knowing that Flexner had succeeded then made a solution to this seem possible. Perhaps Lewis could do the same.
He considered whether a filter-passing organism caused influenza. But to look for a virus Lewis would have to look in darkness. That was science, the best of science (at least to look into the gloaming was) but he was not now engaged only in science. Not right now. He was trying to save lives now.
He had to look where there was light.
First, light shone on a kind of blunt-force use of the immune system. Even if they could not find the pathogen, even if they could not follow normal procedures and infect horses with the pathogen and then prepare the blood from horses, there was one animal that was suffering from the disease that was scorching its way across the earth. That animal was man.
Most people who contracted the disease survived. Even most people who contracted pneumonia survived. It was quite possible that their blood and their serum held antibodies that would cure or prevent disease in others. Lewis and Flexner had had some success using this approach with polio in 1910. In Boston, Dr. W. R. Redden at the navy hospital also remembered, as he reported, 'the experimental evidence presented by Flexner and Lewis with convalescent serum from poliomyelitis.' Now Redden and a colleague drew blood from those who had survived an influenza attack, extracted the serum, and injected it into thirty-six pneumonia patients in a row, beginning October 1. This was not a scientific experiment with controls, and in a scientific sense the results proved nothing. But by the time they reported the results in the October 19 JAMA, thirty patients had recovered, five were still undergoing treatment, and only one had died.
Experiments began in Philadelphia using both the whole blood and serum of survivors of influenza as well. These too were not scientific experiments; they were desperate attempts to save lives. If there was any sign this procedure worked, the science could follow later.
Lewis let others conduct that blunt-force work. It took no truly special skills, and others could do it as well as he. He spent his time on four things. He did not do these things sequentially. He did them simultaneously, moving down different paths (setting up experiments to test each hypothesis) at the same time.
First, he tried to develop an influenza vaccine using the same methods he had used against polio. This was a more sophisticated version of the blunt-force approach of transfusing the blood or serum of influenza survivors. For he at least suspected a virus might cause influenza.
Second, he stayed in the laboratory following a shimmer of light. As Park had reasoned, so Lewis reasoned. Research could find bacteria. Pfeiffer had already pointed an accusing finger at one bacillus. Lewis and everyone in his laboratories were working hours and days without relief, taking only a few hours off for sleep, running procedure after procedure - agglutination, filtration, transferring culture growths, injecting laboratory animals. His team too searched for bacteria. They took more swabs from the throats and noses of the first victims, exposed the medium to it, and waited. They worked intensively, twenty-four hours a day in shifts, and then they waited, frustrated by the time it took bacteria to grow in the cultures, frustrated by the number of cultures that became contaminated, frustrated by everything that interfered with their progress.
In the first fifteen cases, Lewis found no B. influenzae. Ironically, the disease had exploded so quickly, spreading to hospital staff, that Lewis had little except sputum samples to work with: 'The hospitals were so depleted [of staff]' I have had no autopsy material' except from four 'badly decomposed' bodies, almost certainly too long dead to be of any use.
Then, like Park and Williams, Lewis adjusted his techniques and did begin to find the bacillus regularly. He gave this information to Krusen, the health commissioner. The Inquirer and other newspapers, desperate to say something positive, declared that he had found the cause of influenza and 'armed the medical profession with absolute knowledge on which to base their campaign against the disease.'
Lewis had no such absolute knowledge, nor did he believe he had it. True, he had isolated B. influenzae. But he had also isolated a pneumococcus and a hemolytic streptococcus. Some instinct pointed him another direction. He began third and fourth lines of inquiry. The third involved shifting his dye experiments from trying to kill tuberculosis bacteria to trying to kill pneumococci.
But death surrounded him, enveloped him. He turned his attention back to helping produce the only thing that might work now. After the emergency, if anything seemed to work he could always return to the laborat
ory and do careful, deliberate experimentation to understand it and prove its effectiveness.
So he chose as his targets the bacteria he and others had found. From the first instant he had seen the dying sailors, he had known he would have to begin work on it now. For even if he had guessed right, even if what he was doing could succeed, it would take time to succeed. So, in his laboratory and in other laboratories around the city, the investigators no longer investigated. They simply tried to produce. There was no certainty that anything they produced would work. There was only hope.
He started by preparing medium using beef peptone broth with blood added, and then growing cultures of the pathogens they had isolated from cases B. influenzae, Types I and II of the pneumococcus, and hemolytic streptococcus. He personally prepared small batches of vaccine including these organisms and gave it to sixty people. Of those sixty, only three people developed pneumonia and none died. A control group had ten pneumonias and three deaths.
This seemed more than just promising. It was not proof. Many factors could explain the results, including random chance. But he could not wait for explanations.
His laboratory had no ability to produce the immense quantities of vaccine needed. It required an industrial operation. They needed vats to grow these things in, not petri dishes or laboratory flasks. They needed vats like those in a brewery.
He handed off this task to others in the city, including those who ran the municipal laboratory. It would take time to grow enough for tens of thousands of people.
The whole process, even in its most accelerated state, would take at least three weeks. And it would take time once they made the vaccine to administer it to thousands and thousands of people in a series of injections of increasing doses spaced several days apart. In all that time, the disease would be killing.
Meanwhile, Lewis began work on still a fifth line of inquiry, making a serum that could cure the disease. This work was trickier. They could make a vaccine with a shotgun approach, combining several organisms and protecting against all of them. (Today vaccines against diphtheria, pertussis, whooping cough, and tetanus are combined in a single shot; a single shot protecting against measles, mumps, and rubella is routinely given to children; and today's flu shots contain vaccines against both the influenza virus and pneumococci) and the pneumococcal vaccine is a descendant of the work done at Rockefeller Institute in 1917.)
The Great Influenza Page 31