4
Joining the Fight Against Influenza
Of the 1918 influenza epidemic, Jonas Salk had just a vague memory of horse-drawn wagons filled with coffins. If he or any of his immediate family were stricken, as five thousand were every day in New York, none had died. His mother understood the threat. She could see quarantine signs in the neighbors’ windows, followed a few days later by a death cart; she could smell the uncollected garbage mixed with the stench of decaying flesh; she could read about the disturbing number of orphans, or worse yet, of entire families gone. She successfully shielded Jonas not only from the contagion but also from the terror pervading the Bronx.
Only later, in medical school, did Salk learn about the disease, its name derived from the Italian word influenza, as early astrologers blamed epidemics on the influence of heavenly bodies.1 Every few years, influenza spread throughout entire communities, but physicians considered it a temporary nuisance, not in the same league as smallpox or typhoid fever. So the initial US cases reported in the spring of 1918 didn’t alarm public health officials. What later became known as the first wave spread across the world in five months. It acquired the name “Spanish influenza,” as Spain was the first country to report a high number of victims, including King Alfonso XIII who, though gravely ill, survived. Most infections were mild, and by summer, the contagion seemed to have vanished. When it resurfaced in late August, it had changed its character and become vicious.
Johns Hopkins pathologist William Henry Welch and Rockefeller Institute microbiologist Rufus Cole had been sent by the surgeon general to investigate an outbreak at Camp Devens outside Boston.2 On September 7, 1918, a soldier had come to the infirmary complaining of headache and fever. He died so quickly medics diagnosed meningitis. The next day, a dozen recruits came in with the same symptoms, and before long medical officers suspected they were dealing with a highly virulent contagion. By the time Welch and Cole reached Camp Devens on September 23, more than twelve thousand recruits and officers had become ill. What they saw horrified them.
“It was cold and drizzling rain,” Cole recalled, “and there was a continuous line of men coming in from the various barracks [to the hospital], carrying their blankets, many of the men looking extremely ill, most of them cyanosed [blue] and coughing.”3 The course of the disease astonished them. Although it had all of the usual characteristics of influenza—rapid onset, headache, fever, muscle aches—it differed in two major respects. First, this influenza caused an inordinate number of pneumonias. Men were coughing up blood, drowning in their own secretions; a bluish-purple discoloration of the lips and face forecast imminent death. Second, it had a preference for young, healthy adults. Sixty-three died the day Welch and Cole arrived. “Owing to the rush and the great numbers of bodies coming into the morgue,” Cole reported, “they were placed on the floor without any order or system, and we had to step amongst them to get into the room where an autopsy was going on.”4 When the prosector opened the chest, they saw “blue, swollen lungs” with “wet, foamy surfaces”—quite different from bacterial pneumonia, which involved one or two lobes of the lung. This organism could destroy both lungs in a matter of hours. They had never seen anything like it. “This must be some new kind of infection or plague,” Welch told the team.5 Looking at the lung tissue under the microscope, however, they detected no microbe. Some elusive agent killed almost eight hundred at Camp Devens.
Barracks and troopships with their crowded quarters facilitated rapid dissemination of the disease within the armed forces. One sneeze could infect an entire platoon. Influenza soon spread to civilians. At San Francisco’s city hospital, three-quarters of the nurses fell ill; dental students served as doctors. In Providence, Rhode Island, as evangelist Billy Sunday exhorted a crowded assembly to “pray down the epidemic,” congregants collapsed around him.6 Steam shovels were used to dig mass graves in Philadelphia’s potter’s field. When a quarter of the citizens of Brockton, Massachusetts, lay ill, the local health commissioner said he felt like he was “fighting a ghost.”7 Transport of troops overseas hastened its dissemination. From Africa to Canada, no town seemed immune, no person safe. Influenza traversed the world with fury, killing 25 percent of the Samoan population, obliterating entire Eskimo villages, leaving streets throughout the Punjab Province littered with bodies. In six weeks’ time, the scourge devastated a city and moved on. President Wilson, one of the last afflicted, almost died. By the spring of 1919, it had dissipated, leaving twenty million dead. Between influenza and the war, a generation of young adults had been annihilated. And still no one had found the responsible microbe.
It wasn’t until 1931 that Richard Shope of the Rockefeller Institute provided the first evidence that a virus caused influenza, at least in animals, when he transmitted the disease from one pig to another.8 Two years later, during a London epidemic, three British researchers set out to prove a virus underlay the human disease. When one of them contracted influenza, they swabbed a filtrate from his throat washings into the noses of ferrets. The animals developed all the signs of influenza and made anti-influenza antibodies, protecting them against a second infection. Although it would be almost a decade until the invention of the electron microscope allowed scientists to actually see the viral structure, its identification as the responsible organism meant scientists could attempt to make a protective vaccine. Among the first to try was Thomas Francis, Jr.9
Francis was eighteen at the time of the 1918 pandemic, working at an Army Training Corps infirmary. If he didn’t see enough influenza there, he likely later heard Cole’s harrowing stories while at the Rockefeller Institute. Francis was born in 1900 in Gas City, Indiana, to Welsh immigrants. Shortly thereafter, the family moved to New Castle, Pennsylvania, where his father sought a better living working in the steel mills. There young Tommy enjoyed riding with the family doctor in his buggy to make house calls and looking at samples of blood and urine under the microscope. After graduating from Allegheny College in 1921, prompted by his surgeon brother-in-law, he studied medicine at Yale University. The chief of medicine recognized Francis’s potential and recommended he pursue research training at the hospital of the Rockefeller Institute. When Francis arrived on a Sunday in 1928, he found the gates locked. Undeterred, he threw his bag over the fence and scaled it.
Initially Francis conducted studies on pneumococci, bacteria that commonly cause pneumonia. But a chance occurrence shifted his attention to a different microorganism. On a train ride from New York to Princeton, New Jersey, he happened to sit with two leading scientists and listened to them talk about the new field of virology. By the time Francis reached Princeton, he had become intrigued by these smallest of microbes.
After ten years at Rockefeller, Francis became the chairman of the Department of Microbiology at New York University, where Salk, a medical student at the time, sought his mentorship. Not content with lab work alone, Francis delved into the new field of epidemiology, the study of disease transmission within populations. The breadth of it appealed to him, and, when offered the chairmanship of the University of Michigan’s new School of Public Health, he accepted. In Ann Arbor, Francis and his wife, Dorothy, frequently entertained scientists, who were impressed by their colleague’s knowledge of art, music, theater, and Michigan’s athletic teams. His refined speech, brush mustache, and tailored dress belied his origin. A short, somewhat pudgy, proper man, Francis had many devoted trainees. Although nurturing, he was tough—“fussy,”10 one junior colleague called him; “pitilessly critical,” another said.11 The dean of the School of Public Health described him as “a combination of articulateness, humor, wisdom, and sound criticism—yoked to friendliness.”12 What attracted Salk was the boldness and determination with which Francis attacked disease.13
Francis was the first American to isolate a human influenza virus. While at the Rockefeller Institute, he was investigating a Puerto Rican epidemic when he found the infecting agent to be a variant of the British strain. He called it PR8.14 Soon thereafter, he and his colleague Thomas Magill found another strain in a Philadelphia outbreak. So closely related were the viruses that animals infected with either of them produced antibodies that conferred immunity against infection with the other. Francis and Magill categorized them as Type A influenza viruses.15
Then in 1940, Francis made a startling and disquieting observation. At a convalescent home in Irvington, New York, children recovering from rheumatic fever fell ill with an infection resembling influenza. The antibodies in their blood, however, did not react with any of the Type A influenza strains. By infecting ferrets with throat washings from the children, Francis isolated an entirely new type of influenza virus, which he called Type B.16 Other virologists were incredulous; this finding meant that, unlike rabies or smallpox, not all influenza infections were caused by one virus. That explained why one episode of influenza did not confer lifetime immunity, as did a case of measles or mumps. Prevention through vaccination would be a more complex undertaking than they had thought.
When the United States entered the war in December 1941, military leaders feared another pandemic would wipe out their troops. As the director of the Commission on Influenza, Francis was charged with investigating suspected cases, providing assistance in the event of an outbreak, and developing an influenza vaccine—a formidable task. He needed to anticipate which viral strain would emerge in any given year, make a vaccine against that particular strain, substantiate its safety, prove it prevented influenza, oversee the manufacture of large quantities of vaccine, and decide when and how to inoculate the troops.
At that time, only three vaccines had been constituted against viral diseases.17 Smallpox had plagued the world until 1796, when English physician Edward Jenner performed a daring experiment. For years he had heard that milkmaids infected with cowpox—akin to but far less virulent than smallpox—seemed immune. When dairymaid Sarah Nelms developed fresh cowpox on her hands and arms, Jenner inoculated eight-year-old James Phipps, his gardener’s son, with pus from her lesions. The boy developed fever and a pustule at the inoculation site. Then six weeks later, Jenner did the unthinkable—he injected the boy with pus from a smallpox lesion. The boy remained well, resistant to infection with the deadly microbe. Jenner called this substance a “vaccine” after the Latin word for cowpox—vaccinia.
In the late 1800s, Louis Pasteur concocted a rabies vaccine from the saliva of a rabid dog. He knew that following a bite the rabies virus spread from the wound along nerves to the brain, taking several weeks to reach its target. At that point, the victim developed severe pain, violent jerking movements, high fever, and impaired swallowing, causing hydrophobia (fear of drinking) and foaming at the mouth. Coma followed, then death. Pasteur had been cultivating the virus in rabbit spinal cord when nine-year-old Joseph Meister, mauled by a rabid dog, was brought to his laboratory. Pasteur inoculated the boy with a small amount of the live, weakened rabies virus daily for two weeks. Instead of dying in agony, Meister survived.
Unlike bacteria, which could be cultivated in what is known as broth, media that contained essential nutrients, virus could only be grown in living cells, requiring large numbers of laboratory animals in a cumbersome, prolonged undertaking. Finally, in 1931, when pathologist Ernest Goodpasture developed a technique for growing viruses in chick embryos, he provided a major tool for viral vaccine preparation. Six years later, South African microbiologist Max Theiler announced a successful vaccine against the yellow fever virus.
Francis had already made some headway on an influenza vaccine when the war broke out. In 1935, he and Magill had made a crude vaccine and began testing human volunteers for antibody response following inoculation. The method was tedious, as they had to measure how well serum from the subject’s blood protected mice from infection after exposure to influenza. Then in 1941, Rockefeller virologist George Hirst made an observation that revolutionized the field.18 While he was harvesting some influenza-infected chicken embryos, he accidentally spilled a drop of blood on one, and the red blood cells clumped, a process known as hemagglutination. It appeared the virus had caused red blood cells to stick together. Hirst found that if he added serum from immunized mice, their antibodies blocked the clumping. By measuring the amount of clumping, he could determine antibody levels rapidly and accurately.
Now Francis could proceed at a faster pace.19 Although he had demonstrated the presence of influenza antibodies in volunteers, that didn’t prove they had protection against the disease. This required a field trial—vaccinating a large number of individuals and comparing their rate of infection to that of a control group who did not get the vaccine. A proper field trial required a stable population of subjects, a team of experienced personnel, and a pharmaceutical company capable of manufacturing large quantities of vaccine. The task seemed almost insurmountable, especially since Francis was busy traveling to suspected sites of outbreaks around the world. In addition to that, he faced the constant pressure of time: the 1918 pandemic had erupted shortly after the troops had been mobilized. His University of Michigan team included just a couple of laboratory investigators, by no means enough manpower to complete the monumental undertaking. Then, in April of 1942, Jonas Salk arrived.
Salk made a wise choice in attaching himself to this highly respected physician-scientist. Francis would provide him with many of the elements necessary for success—laboratory space, an opportunity to participate in the country’s largest vaccine trials, credibility in the cliquish field of virology, a steadying hand for his overeagerness, wisdom for his naiveté, and a stepping stone for his academic career. Salk didn’t consider these when he moved to Ann Arbor shortly after the United States entered the war. He joined Francis to help prevent a disease that could decimate their troops and change the course of history.