The Great Influenza (63 page)

Constantly he tried to recruit people whose knowledge complemented his own. He wanted a biochemist, and, beginning in 1921, over and over he tried to lure Michael Heidelberger, a brilliant young biochemist, away from the laboratory of Nobel laureate Karl Landsteiner. Heidelberger recalled, 'Avery would come upstairs from his lab and show me a little vial of dirty looking dark grey stuff and say, 'See, my boy, the whole secret of bacterial specificity is in this little vial. When are you going to work on it?''

Inside the vial were dissolved capsules. Avery had isolated the material from the blood and urine of pneumonia patients. He believed that it held the secret to using the immune system to defeat pneumonia. If he could find that secret' Eventually Heidelberger did join Avery. So did others. And Avery settled into an unchanging routine. He lived on East Sixty-seventh Street and his laboratory was on Sixty-sixth and York. Every morning he walked in at the same time wearing what seemed the same gray jacket, took the elevator to his sixth-floor office, and traded the jacket for a light tan lab coat. Only if he was doing something unusual, if there was a special occasion, would he ever wear a white lab coat.

But there was nothing routine in this work. He conducted most experiments at the lab benches, actually wooden desks originally designed for an office. His equipment remained simple, almost primitive. Avery disliked gadgetry. When he experimented, remembered a colleague, he was 'intensely focused' His movements were limited, but of extreme precision and elegance; his whole being appeared to be identified with the sharply defined aspect of the reality that he was studying. Confusions seemed to vanish,' perhaps simply because everything seemed so organized around his person.'

Each experiment created its own world, with possibilities for joy and despair. He would leave cultures in an incubator overnight, and each morning he and his young colleagues would converge on the incubator not knowing what they would find. Quiet as he was, reserved as he was, he was always tense then, his expression simultaneously eager and fearful.

In 1923 he and Heidelberger turned the scientific world on its head by proving that the capsules did generate an immune response. The capsules were pure carbohydrate. Until then investigators had believed that only a protein or something containing proteins could stimulate the immune system to respond.

The finding only spurred Avery and his colleagues on. More than ever he concentrated on the capsule, forsaking practically everything else. He believed it to be the key to the specific reaction of the immune system, the key to making an effective therapy or vaccine, the key to killing the killer. And he believed that much of what he discovered about the pneumococcus would be applicable to all bacteria.

Then, in 1928, Fred Griffith in Britain published a striking and puzzling finding. Earlier Griffith had discovered that all known types of pneumococci could exist with or without capsules. Virulent pneumococci had capsules; pneumococci without capsules could be easily destroyed by the immune system. Now he found something much stranger. He killed virulent pneumococci, ones surrounded by capsules, and injected them into mice. Since the bacteria were dead, all the mice survived. He also injected living pneumococci that had no capsules, that were not virulent. Again the mice lived. Their immune systems devoured the unencapsulated pneumococci. But then he injected dead pneumococci surrounded by capsules and living pneumococci without capsules.

The mice
died.
Somehow the living pneumococci had acquired capsules. Somehow they had changed. And, when isolated from the mice, they continued to grow with the capsule - as if they had inherited it.

Griffith's report seemed to make meaningless years of Avery's work - and life. The immune system was based on specificity. Avery believed that the capsule was key to that specificity. But if the pneumococcus could change, that seemed to undermine everything Avery believed and thought he had proved. For months he dismissed Griffith's work as unsound. But Avery's despair seemed overwhelming. He left the laboratory for six months, suffering from Graves' disease, a disease likely related to stress. By the time he returned, Michael Dawson, a junior colleague he had asked to check Griffith's results, had confirmed them. Avery had to accept them.

* 

His work now turned in a different direction. He had to understand how one kind of pneumococcus was transformed into another. He was now almost sixty years old. Thomas Huxley said, 'A man of science past sixty does more harm than good.' But now, more than ever, Avery focused on his task.

In 1931, Dawson, then at Columbia University but still working closely with Avery, and an assistant succeeded in changing (in a test tube) a pneumococcus that lacked a capsule into one that had a capsule. The next year people in Avery's own laboratory managed to use a cell-free extract from dead encapsulated pneumococci to do the same thing, to make bacteria without capsules change into ones with capsules.

One after another the young scientists in his laboratory moved on. Avery kept on. By the late 1930s he was working with Colin MacLeod and Maclyn McCarty, and they now turned all their energies to understanding how this happened. If Avery had demanded precision before, now he demanded virtual perfection, irrefutability. They grew huge amounts of virulent Type III pneumococci, and spent not just hours or days but months and years breaking the bacteria down, looking at each constituent part, trying to understand. The work was of the utmost tedium, and it was work that yielded failure after failure after failure after failure.

Avery's name was appearing on fewer and fewer papers. Much of that was because he put his name on papers of people in his laboratory only if he had physically performed an experiment included in the research the paper detailed, no matter how much he had contributed conceptually to the work, or how often he had talked over ideas with the investigator. This was highly generous of Avery; usually a laboratory chief puts his or her name on virtually every paper anyone in his laboratory writes. Dubos recalled that he worked under Avery for fourteen years, that Avery influenced nearly all his work but only four times did Avery's name appear on his papers. Another young investigator said, 'I had always felt so deeply that I was an associate of Avery that' with great astonishment I realized for the first time that we had never published a joint paper.')

But Avery was also publishing less because he had little to report. The work was extraordinarily difficult, pushing the limits of the technically possible.
Disappointment is my daily bread,
he had said.
I thrive on it
. But he did not thrive. Often he thought of abandoning the work, abandoning all of it. Yet every day he continued to fill nearly every waking hour with thinking about it. Between 1934 and 1941 he published nothing.
Nothing
. For a scientist to go through such a dry period is more than depressing. It is a refutation of one's abilities, of one's life. But in the midst of that dry spell, Avery told a young researcher there were two types of investigators: most 'go around picking up surface nuggets, and whenever they can spot a surface nugget of gold they pick it up and add it to their collection' . [The other type] is not really interested in the surface nugget. He is much more interested in digging a deep hole in one place, hoping to hit a vein. And of course if he strikes a vein of gold he makes a tremendous advance.'

By 1940 he had gone deep enough to believe he would find something, something of value. Between 1941 and 1944, he again published nothing. But now it was different. Now what he was working on excited him as nothing else had. He was gaining confidence that he would reach his destination. Heidelberger recalled, 'Avery would come and talk about his work on the transforming substance' . There was something that told him that this transforming substance was something really fundamental to biology,' to the understanding of life itself.'

Avery loved an Arab saying: 'The dogs bark, the caravan moves on.' He had nothing to publish because his work was being done chiefly by subtraction. But it was moving on. He had isolated whatever transformed the pneumococcus. Now he was analyzing that substance by eliminating one possibility after another.

First, he eliminated proteins. Enzymes that deactivated proteins had no effect on the substance. Then he eliminated lipids (fatty acids). Other enzymes that destroyed lipids had no effect on the ability of this substance to transform pneumococci. He eliminated carbohydrates. What he had left was rich in nucleic acids, but an enzyme isolated by Dubos that destroys ribonucleic acid had no effect on the transforming substance either. Each of these steps had taken months, or years. But he could see it now.

In 1943 he nominally retired and became an emeritus member of the institute. His retirement changed nothing. He worked exactly as he always had, experimenting, pushing, tightening. That year he wrote his younger brother, a physician, about extraordinary findings and in April informed the institute's Board of Scientific Directors. His findings would revolutionize all biology, and his evidence seemed beyond solid. Other scientists who had found what he had found would have published already. Still he would not publish. One of his junior colleagues asked, 'Fess, what more do you want?'

But he had been burned so long ago in that very first work at Rockefeller, when he had published a sweeping theory encompassing bacterial metabolism, virulence, and immunity. He had been wrong, and he never forgot the humiliation. He did more work. Then, finally, in November 1943 he, MacLeod, and McCarty submitted a paper titled 'Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types. Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumoccus Type III' to the
Journal of Experimental Medicine,
the journal founded by Welch. In February 1944 the journal published the paper.

DNA, deoxyribonucleic acid, had been isolated in the late 1860s by a Swiss investigator. No one knew its function. Geneticists ignored it. The molecule seemed far too simple to have anything to do with genes or heredity. Geneticists believed that proteins, which are far more complex molecules, carried the genetic code. Avery, MacLeod, and McCarty wrote, 'The inducing substance has been likened to a gene, and the capsular antigen which is produced in response to it has been regarded as a gene product.'

Avery had found that the substance that transformed a pneumococcus from one without a capsule to one with a capsule was DNA. Once the pneumococcus changed, its progeny inherited the change. He had demonstrated that DNA carried genetic information, that genes lay within DNA.

His experiments were exquisite, elegant, and irrefutable. A Rockefeller colleague conducted confirming experiments on Pfeiffer's
B. influenzae
.

Among historians of science, there has been some controversy over how much immediate impact Avery's paper had, largely because one geneticist, Gunther Stent, wrote that it 'had little influence on thought about the mechanisms of heredity for the next eight years.' And Avery's conclusions were not immediately accepted as true by the broad scientific community.

But they were accepted as true by the scientists who mattered.

* 

Prior to Avery's discovery (and proof) that DNA carried the genetic code, he was being seriously considered for the Nobel Prize for his lifetime of contributions to knowledge of immunochemistry. But then came his revolutionary paper. Instead of guaranteeing him the prize, the Nobel Committee found it too revolutionary, too startling. A prize would endorse his findings and the committee would take no such risk, not until others confirmed them. The official history of the organization that gives the prize states, 'Those results were obviously of fundamental importance, but the Nobel Committee found it desirable to wait until more became known' .'

Others were determined to make more known.

James Watson, with Francis Crick the codiscoverer of the structure of DNA, wrote in his classic
The Double Helix
that 'there was general acceptance that genes were special types of protein molecules' until 'Avery showed that hereditary traits could be transmitted from one bacterial cell to another by purified DNA molecules' . A very's experiments strongly suggested that future experiments would show that all genes were composed of DNA' . A very's experiment made [DNA] smell like the essential genetic material' . Of course there were scientists who thought the evidence favoring DNA was inconclusive and preferred to believe that genes were protein molecules. Francis, however, did not worry about these skeptics. Many were cantankerous fools who always backed the wrong horses,' not only narrow-minded and dull, but also just stupid.'

Watson and Crick were not the only investigators seeking the great prize, the greatest prize, the key to heredity and possibly to life, who immediately grasped the significance of Avery's work. Erwin Chargaff, a chemist whose findings were crucial to Watson and Crick's understanding enough about the DNA molecule to determine its structure, said, 'Avery gave us the the first text of a new language, or rather he showed us where to look for it. I resolved to search for this text.'

Max Delbruck, who was trying to use viruses to understand heredity, said, 'He was very attentive to what we were doing and we were very attentive to what he was doing' . [I]t was obvious that he had something interesting there.'

Salvador Luria, who worked with Delbruck (Watson was a graduate student under him) similarly rejected Stent's contention that Avery's findings were ignored. Luria recalled having lunch with Avery at the Rockefeller Institute and discussing the implications of his work with him: 'I think it is complete nonsense to say that we were not aware.'

Peter Medawar observed, 'The dark ages of DNA came to an end in 1944 with' Avery. Medawar called the work 'the most interesting and portentous biological experiment of the 20th century.'

Macfarlane Burnet was, like Avery, studying infectious diseases, not genes, but in 1943 he visited Avery's laboratory and left astounded. Avery, he said, was doing 'nothing less than the isolation of a pure gene in the form of desoxyribonucleic acid.'