Everything else about him was the opposite of Welch. Welch read widely, had curiosity about everything, traveled throughout Europe, China, and Japan, and seemed to embrace the universe. Welch often sought relaxation in elaborate dinners and almost daily retreated to his club. And Welch as a very young man was recognized as marked for great things.
Avery was none of those things. He was certainly not considered a brilliant young investigator. When Cole hired him, he was almost forty years old. By forty Welch was moving in the highest circles of science internationally. By forty those of Avery's contemporaries who would leave any significant scientific legacy had already made names for themselves. Yet Avery, like much younger investigators at Rockefeller, was essentially on probation and had made no particular mark. Indeed, he had made no mark - but not from want of ambition, nor from lack of work.
While Welch constantly socialized and traveled, Avery had almost no personal life. He fled from one. He almost never entertained and rarely went out to dinner. Although he was close to and felt responsible for his younger brother and an orphaned cousin, his life, his world, was his research. All else was extraneous. Once the editor of a scientific journal asked him to write a memorial piece about Nobel laureate Karl Landsteiner, with whom he had worked closely at Rockefeller. In it Avery said nothing whatsoever about Landsteiner's personal life. The editor asked him to insert some personal details. Avery refused, stating that personal information would help the reader understand nothing that mattered, neither Landsteiner's achievements nor his thought processes.
(Landsteiner likely would have approved Avery's treatment. When he was notified he'd won the Nobel Prize, he continued working in his laboratory all day, got home so late that his wife was asleep, and did not wake her to give her the news.)
The research mattered, Avery was saying, not the life. And the life of research, like that of any art, lay within. As Einstein once said, 'One of the strongest motives that lead persons to art or science is a flight from the everyday life' . With this negative motive goes a positive one. Man seeks to form for himself, in whatever manner is suitable for him, a simplified and lucid image of the world, and so to overcome the world of experience by striving to replace it to some extent by this image. This is what the painter does, and the poet, the speculative philosopher, the natural scientist, each in his own way. Into this image and its formation, he places the center of gravity of his emotional life, in order to attain the peace and serenity that he cannot find within the narrow confines of swirling personal experience.'
With the possible exception of his love for music, Avery seemed to have no existence outside the laboratory. For years he shared the same apartment with Alphonse Dochez, another bachelor scientist who worked closely with him at Rockefeller, and a shifting cast of more temporary scientist-roommates who left when they got married or changed jobs. Avery's roommates lived normal lives, going out, going away for a weekend. When they came home, there would be Avery, ready to begin a lengthy conversation that lasted deep into the night about an experimental problem or result.
But if Avery had little personal life, he did have ambition. His desire to make a mark after so long in the wilderness led him to publish two papers soon after he arrived at Rockefeller. In the first, based on only a few experiments, he and Dochez formulated 'a sweeping metabolic theory of virulence and immunity.' In the second, Avery again reached well beyond his experimental evidence for a conclusion.
Both were quickly proved wrong. Humiliated, he was determined never to suffer such embarrassment again. He became extraordinarily careful, extraordinarily cautious and conservative, in anything he published or even said outside his own laboratory. He did not stop speculating (privately) about the boldest and most far-reaching interpretations of an experiment, but from then on he published only the most rigorously tested and conservative conclusions. From then on, Avery would only (in public) inch his way forward. An inch at a time, he would ultimately cover an enormous and startling distance.
*
When one inches along progress comes slowly, but it can still be decisive. Cole and Avery worked together precisely the way Cole had hoped for when he organized the Rockefeller hospital. More importantly, the work produced results.
In the laboratory Avery and Dochez took the lead. They worked in simple laboratories with simple equipment. Each room had a single deep porcelain sink and several worktables, each with a gas outlet for a Bunsen burner and drawers underneath. The tabletop space was filled with racks of test tubes, simple mason jars, petri dishes, droppers for various dyes and chemicals, and tin cans holding pipettes and platinum loops. On the same tabletop investigators performed nearly all their work: inoculating, bleeding, and dissecting animals. Also on the tabletop was a cage for the occasional animal kept as a pet. In the middle of the room were incubators, vacuum pumps, and centrifuges.
First they replicated earlier experiments, partly to familiarize themselves with techniques. They exposed rabbits and mice to gradually increasing dosages of pneumococci. Soon the animals developed antibodies to the bacteria. They drew blood from them, allowed solids to settle out, siphoned off the serum, added chemicals to precipitate remaining solids, then purified the serum by passing it through several filters. Others had done the equivalent. They succeeded in curing mice with the serum. Others had done that, too. But the mice were not people.
In a way, they weren't really mice either. Scientists had to keep as many factors constant as possible, limit variables, to make it easier to understand precisely what caused an experimental result. So mice were inbred until all mice in a given strain had virtually identical genes, except for sex differences. (Male mice were and are generally not used in experiments because they sometimes attack each other; the death or injury of a single mouse for any reason can distort experimental results and ruin weeks of work.) These mice were fully alive but also model systems, with as much of the complexity, diversity, and spontaneity of life eliminated as possible; they were bred to be as close to a test tube as a living thing can be.*
But if scientists were curing mice, no one anywhere had made any progress in curing people. Experiment after experiment had failed. Elsewhere other investigators trying similar approaches quit, convinced by their failures that their theories were wrong or that their techniques were not good enough to yield results - or they simply grew impatient and moved on to easier problems.
Avery did not move on. He saw snatches of evidence suggesting he was right. He persisted, experimenting repeatedly, trying to learn from each failure. He and Dochez grew hundreds of cultures of pneumococci, changing the strains, learning more and more about its metabolism, changing the composition of the media in which the bacteria grew. (Soon Avery became one of the best in the world at figuring out what medium would most effectively grow different bacteria.) His background in both chemistry and immunology began paying off, and they used every piece of information as a wedge, pounding it into the problem, cracking or prying open other secrets, improving techniques, and, finally, gradually inching past the work that others had done.
They and others identified three fairly uniform and common strains of pneumococci, which they called simply Type I, Type II, and Type III. Other pneumococci were designated as Type IV, a catchall for dozens of other strains (ninety have been identified) that appeared less often. The first three types gave them a far more specific target for an antiserum, which they made. When they exposed different cultures of pneumococci to the serum they discovered that the antibodies in the serum would bind only to its matching culture and not to any other. The binding was even visible in a test tube without a microscope; the bacteria and antibodies clumped together. The process was called 'agglutination' and was a test for specificity.
But many things that work in vitro, in the narrow universe of a test tube, fail in vivo, in the nearly infinite complexity of life. Now they went through the cycle of testing in rabbits and mice again, testing different strains of the bacteria in animals for killing pot
ential, testing how well they generated antibodies, how well the antibodies bound to them. They tried injecting massive dosages of killed bacteria, thinking it might spark a large immune response, then using the serum generated by that technique. They tried mixing small doses of living bacteria and massive doses of dead ones. They tried live bacteria. In mice they ultimately achieved spectacular cure rates.
At the same time, Avery's understanding of the bacteria deepened. It deepened enough that he forced scientists to change their thinking about the immune system.
One of the most puzzling aspects of pneumococci was that some were virulent and lethal, some were not. Avery thought he had a clue to the answer to this question. He and Dochez focused on the fact that some pneumococci (but only some) were surrounded by a capsule made of polysaccharides, a sugar, like the hard shell of sugar surrounding the soft insides of M&M candy. Avery's very first paper on the pneumococcus, in 1917, dealt with these 'specific soluble substances.' He would pursue this subject for more than a quarter of a century. As he tried to unravel this puzzle, he began calling the pneumococcus, this killing bacterium, the 'sugar-coated microbe.' His pursuit would yield a momentous discovery and a deep understanding of life itself.
Meanwhile, with the rest of the Western world already at war, Cole, Avery, Dochez, and their colleagues were ready to test their immune serum in people.
CHAPTER THIRTEEN
EVEN WHEN COLE first tried the new serum on patients it showed promise. He and Avery immediately devoted themselves to refining their procedures in the laboratory, in the methods of infecting horses and producing serum, in the way they administered it. Finally they began a careful series of trials with a finished product. They found that giving large dosages of serum (half a liter) intravenously cut the death rate of Type I pneumonias by more than half, from 23 percent to 10 percent.
It was not a cure. Pneumonias caused by other types of pneumococci did not yield so easily. And, as Avery and Cole stated, 'Protection in man is inferior to protection in mice.'
But of all pneumonias, those caused by Type I pneumococci were the single most common. Cutting the death rate by more than half in the single most common pneumonia was progress, real progress, enough progress that in 1917 the institute published a ninety-page monograph by Cole, Avery, Dochez, and Henry Chickering, another young Rockefeller scientist, entitled 'Acute Lobar Pneumonia Prevention and Serum Treatment.'
It was a landmark work, for the first time explaining step-by-step a way to prepare and use a serum that could cure pneumonia. And it very much anticipated outbreaks of the disease in army cantonments, noting, 'Pneumonia bids fair in the present war to lead all diseases as a cause of death.'
In October 1917, Gorgas told army hospital commanders that, 'in view of the probability that pneumonia will be one of the most important diseases amongst the troops,' they must send even more doctors to the Rockefeller Institute to learn how to prepare and administer this serum. Avery, still a private, was already diverting time from his research to teach bacteriology to officers who would be working in cantonments. Now he and his colleagues also taught this serum therapy. His students, rather than call him 'Private,' addressed him respectfully as 'Professor' - a nickname already occasionally given him. His colleagues shortened it to 'Fess,' which stuck with him for the rest of his life.
Simultaneously Cole, Avery, and Dochez were developing a vaccine to prevent pneumonia caused by Types I, II, and III pneumococci. After proving it worked in animals, they and six other Rockefeller researchers turned themselves into guinea pigs, testing its safety in humans by giving each other massive doses. All of them had negative reactions to the vaccine itself; three had severe reactions. They decided that the vaccine was too dangerous to administer in those dosages but planned another experiment with lower doses administered once a week for four weeks, which gave recipients time to gradually build up immunity.
This vaccine came too late for any large-scale impact on the measles epidemic, but at Camp Gordon outside Atlanta, a vaccine against the strain of pneumococcus causing most of the pneumonias there was tested on one hundred men with measles, with fifty men vaccinated and fifty used as controls. Only two of those vaccinated developed this pneumonia, compared to fourteen unvaccinated men.
Meanwhile, Cole wrote Colonel Frederick Russell, who during his own scientific career in the army had significantly improved typhoid vaccine, about 'the progress we have already made in the matter of prophylactic vaccination against pneumonia.' But, Cole added, 'The manufacture of large amounts of vaccine will be a big matter, much more difficult than the manufacture of typhoid vaccine' . I have been getting an organization together so that the large amounts of media necessary could be prepared, and so the vaccine could be made on a large scale.'
Cole's organization was ready for a large test in March 1918, just as influenza was first surfacing among soldiers in Kansas. The vaccine was given to twelve thousand troops at Camp Upton on Long Island (that used up all the vaccine available) while nineteen thousand troops served as controls, receiving no vaccine. Over the next three months, not a single vaccinated soldier developed pneumonia caused by any of the types of pneumococci vaccinated against. The controls suffered 101 cases. This result was not absolutely conclusive. But it was more than suggestive. And it was a far better result than was being achieved anywhere else in the world. The Pasteur Institute was also testing a pneumonia vaccine, but without success.
If Avery and Cole could develop a serum or vaccine with real effectiveness against the captain of death' If they could do that, it would be the greatest triumph medical science had yet known.
*
Both the prospect of finally being able to defeat pneumonia and its appearance in the army camps only intensified Gorgas's determination to find a way to limit its killing. He asked Welch to create and chair a special board on the disease. Gorgas wanted the board run, literally, out of his own office; Welch's desk was in Gorgas's personal office.
Welch demurred and called Flexner. Both men agreed that the best man in the country, and probably in the world, to chair the board was Rufus Cole. The next day Flexner and Cole got on a train to Washington to meet Gorgas and Welch at the Cosmos Club. There they picked the members of the pneumonia board, a board to be supported by all the knowledge and resources of Gorgas, Welch, Flexner, and the institutions they represented.
They chose well. Each person selected would later be elected to membership in the National Academy of Sciences, arguably the most exclusive scientific organization in the world.
Avery would of course lead the actual laboratory investigations and stay in New York. Most of the others would work in the field. Lieutenant Thomas Rivers, a Hopkins graduate and Welch protegé, would become one of the world's leading virologists and succeed Cole as head of the Rockefeller Institute Hospital. Lieutenant Francis Blake, another Rockefeller researcher, would become dean of the Yale Medical School. Captain Eugene Opie, regarded as one of the most brilliant of Welch's pathology students, was already dean of the Washington University Medical School when he joined the army. Collaborating with them, although not actual board members, were future Nobel laureates Karl Landsteiner at Rockefeller and George Whipple at the Hopkins. Years later another Rockefeller scientist recalled, 'It was really a privilege to be on the pneumonia team.'
On a routine basis (if such urgency could be routine) Cole traveled to Washington to discuss the latest findings with Welch and senior army medical officers in Gorgas's office. Cole, Welch, Victor Vaughan, and Russell had also been conducting a series of the most rigorous inspection tours of cantonments, checking on everything from the quality of the camp's surgeons, bacteriologists, and epidemiologists right down to the way camp kitchens washed dishes. Any recommendations they made were immediately ordered to be carried out. But they did not simply dictate; many of the camp hospitals and laboratories were run by men they respected, and they listened to ideas as well.
Late that spring, Cole reported to the American Medica
l Association one of his conclusions about measles: that it 'seems to render the respiratory mucous membrane especially susceptible to secondary infection.' He also believed that these secondary infections, like measles itself, 'occur chiefly in epidemic form' . Every new case of the infection adds not only to the extent but also to the intensity of the epidemic.'
On June 4, 1918, Cole, Welch, and several other members of the pneumonia board appeared in Gorgas's office once more, this time with Hermann Biggs, New York State health commissoner; Milton Rosenau, a prominent Harvard scientist who was then a navy lieutenant commander; and L. Emmett Holt, one of those instrumental in the founding of the Rockefeller Institute. This time the discussion was wide-ranging, focusing on how to minimize the possibility of something worse than the measles epidemic. They were all worried about Gorgas's nightmare.
They were not particularly worried about influenza, although they were tracking outbreaks of the disease. For the moment those outbreaks were mild, not nearly as dangerous as the measles epidemic had been. They well knew that when influenza kills, it kills through pneumonia, but Gorgas had already asked the Rockefeller Institute to gear up its production and study of pneumonia serum and vaccine, and both the institute and the Army Medical School had launched major efforts to do so.
Then the conversation turned from the laboratory to epidemiological issues. The inspection tours of the camps had convinced Welch, Cole, Vaughan, and Russell that cross-infections had caused many of the measles-related pneumonia deaths. To prevent such a problem from recurring, Cole suggested creating contagious-disease wards with specially trained staffs, something the best civilian hospitals had. Welch pointed out that the British had isolation hospitals with entirely separate organizations and rigid discipline. Another possible solution to cross-infection involved using cubicles in hospitals - creating a warren of partitions around hospital beds.
The Great Influenza Page 18