The Great Influenza (23 page)

In the diseases scientists could defeat, the antigen (the molecules on the surfaces of invading organisms that stimulated the immune system to respond, the target the immune response aimed at) did not change. In diphtheria the dangerous part was not even the bacteria itself but a toxin the bacteria produced.

The toxin was not alive, did not evolve, and had a fixed form, and the production of antitoxin had become routine. Horses were injected with gradually increasing doses of virulent bacteria. The bacteria made the toxin. In turn, the horse's immune system generated antibodies that bound to and neutralized the toxin. The horse was then bled, solids removed from the blood until only the serum remained, and this was then purified into the antitoxin that had become so common and lifesaving.

An identical process produced tetanus antitoxin, Flexner's serum against meningitis, and several other sera or antitoxins. Scientists were vaccinating the horse against a disease, then extracting the horse antibodies and injecting them into people. This borrowing of immune-system defenses from an outside source is called 'passive immunity.'

When vaccines are used to stimulate people's own immune systems directly, so that they develop their own defenses against bacteria or viruses, it is called 'active immunity.'

But in all the diseases treated successfully so far, the antigens, the target the immune system aimed at, remained constant. The target stayed still; it did not move. And so the target was easy to hit.

The pneumococcus was different. The discovery of 'typical' and 'atypical' pneumococci had opened a door, and investigators were now finding many types of the bacteria. Different types had different antigens. Sometimes also the same type was virulent, sometimes not, but why one killed and another caused mild or no disease was not yet a question anyone was designing experiments to answer. That lay out there for the future, a sort of undertow pulling at the data. The focus was far more immediate: finding a curative serum, a preventative vaccine, or both.

By 1912 Cole at Rockefeller had developed a serum that had measurable if not dramatic curative power against a single type of pneumococcus. He happened to read a paper by Avery on an entirely different subject - secondary infections in victims of tuberculosis. Although narrow and hardly a classic, the paper still made a deep impression on Cole. It was solid, thorough, tight, and yet was deeply analytical, showing an awareness of the potential implications of the conclusions and possible new directions for research. It also demonstrated Avery's knowledge of chemistry and ability to carry out a fully scientific laboratory investigation of illness in patients. Cole wrote Avery a note offering him a job at the institute. Avery did not reply. Cole sent a second note. Still he received no reply. Finally Cole visited Avery and raised the salary offer. Later he realized Avery rarely read his mail. It was typical of Avery; his focus was always on his experiments. Now he accepted. Soon after the Great War started, but before America's entry into it, Avery also began working on pneumonia.

Pneumonia was Cole's passion. For Avery it would become an obsession.

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Oswald Avery was a short thin fragile man, a tiny man really who weighed at most 110 pounds. With his large head and intense eyes, he looked like someone who would have been laughed at as an 'egghead,' if that word had been in use then, and bullied in a schoolyard as a boy. If that was the case, it appeared to have left no scars; he seemed friendly, cheerful, even outgoing.

Born in Montreal, he grew up in New York City the son of a Baptist minister who preached at a church in the city. He had a good many talents. At Colgate University he tied for first prize in an oratory contest with classmate Harry Emerson Fosdick, who became among the most prominent preachers of the early twentieth century (Fosdick's brother Raymond ultimately headed the Rockefeller Foundation; John Rockefeller Sr. built Riverside Church for Harry). Avery also played cornet well enough to have performed in concert with the National Conservatory of Music (a concert conducted by Antonin Dvorjak) and he often drew ink caricatures and painted landscapes.

Yet for all his outward friendliness and sociability, Avery spoke himself of what he called 'the true inwardness of research.'

René Dubos, an Avery protegé, recalled, 'To a few of us who saw him in every day life, however, there was often revealed another aspect of his personality,' a more haunting quality,' a melancholy figure whistling gently to himself the lonely tune of the shepherd song in
Tristan and Isolde.
An acute need for privacy, even if it had to be bought at the cost of loneliness, conditioned much of Avery's behavior.'

If the phone rang Avery would talk animatedly, as if happy to hear from the caller, but when he hung up, Dubos recalled, 'It was as if a mask dropped, his smile replaced with a tired and almost tortured expression, the telephone pushed away on the desk as a symbol of protest against the encroaching world.'

Like Welch, he never married, nor was he known to have had an emotional or intimate relationship with anyone of either sex. Like Welch, he could be charming and the center of attention; he did comic impersonations so well that one colleague called him 'a natural born comedian.' Yet he resented any kind of intrusion upon himself, resented even attempts by others to entertain him.

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.

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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.
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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 potential, 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.