by Frank Ryan
One day, in early 1934, the same year that Avery suffered the onset of his thyrotoxicosis, Dubos told Avery that he was about to be married. The lady in question was a Frenchwoman living in New York named Marie Louise Bonnet. Avery immediately rejoiced at the news. They were conversing in the laboratory on the sixth floor of the Rockefeller hospital building. During the subsequent animated conversation, Avery climbed out of his chair, walked to the window and looked out, as if lost for a moment in deep reflection. Returning to his chair, he mentioned that he had contemplated marriage years before, but that circumstances had not proved favorable to his plans. It seems likely that the lady in question was a nurse that Avery had met during the course he had taught to student nurses at the Hoagland Laboratory. Avery would have been about 32 years old at the time. For a moment or two the older man's eyes were full of longing.
“One of the great joys of life,” he remarked to Dubos, “is to go home to someone who would rather see you than anybody else.”
Fate would prove cruel to both men. Marie Louise Bonnet subsequently died from tuberculosis at a time when Dubos was pioneering the very antibiotics that would eventually help to cure the same illness. The marriage was childless, and the effects of his wife's death on Dubos were devastating. He resigned, forthwith, from his antibiotic research, which were later taken up by his former teacher, Selman Waksman at Rutgers Agricultural College, now Rutgers University, and which led to the discovery of a series of important antibiotics, including streptomycin. This breakthrough resulted in Waksman being awarded the Nobel Prize in Physiology or Medicine in 1952.
Much of what Dubos witnessed of Avery spoke of an intense focus and purity of purpose in science and his work. But, increasingly, his devotion to his research appeared to be accompanied by insularity bordering on reclusiveness.
Scientists who have labored long and hard at a difficult but eventually rewarding line of research are usually happy to talk about it—if not to the media or ordinary social channels, certainly to colleagues. They travel to scientific symposia. They take part in conferences. They enjoy the camaraderie that comes from sharing the same interests. In the words of Frank Portugal, “wide-ranging discussions with peers both individually and at meetings are part and parcel of the scientific process. It is an important component of how collaborations are formed and scientific advances are made and respected.” Most scientists are only too glad to accept the, often rare, honors and distinction their work brings their way. Not so Oswald Avery.
In 1944, Avery was proposed for an honorary degree at Cambridge University, a recognition most scientists would cherish. The following year he was awarded the Copley Medal by the Royal Society of London. Avery's roots were English—in the late nineteenth century his family had emigrated to Canada from the city of Norwich—but he refused to visit England even on such prestigious occasions, putting forward the excuse that his state of health did not permit it except by traveling first class. In Dubos's opinion, this was disingenuous, since the respective foundations would have funded the flights. That he might have felt nervous, claustrophobic, on the lengthy flight is possible. Recalling those dark moods in which Avery might mumble to himself about the damaging inflictions of resentment, it seemed more than likely to Dubos that he might have been unable to suppress lingering anger at the hurtful controversy provoked years ago by his polysaccharide typing of pneumococci. Whatever his reasons, Avery refused both honors.
An incident highlighted just how strong was Avery's aversion to such formal acknowledgment of his work. Sir Henry Dale, who was President of the Royal Society in England, took it upon himself to bring the Copley Medal to the Rockefeller Institute, there to confer it on the shy and retiring Avery in person. Dale was accompanied by a Dr. Todd, who knew Avery personally. The two highly respected English visitors arrived at the Institute in New York unannounced and went directly to Avery's department in the main hospital building. But when they saw Avery working in his lab, through the ever-open door, they retreated without intruding on his presence.
Dr. Todd would later recount how Sir Henry Dale said simply: “Now I understand everything.”
Bizarre as this behavior would appear, it was in keeping with Avery's increasingly reclusive personality: a man who avoided any of the normal personal contacts outside of immediate family and work colleagues. Genius can be strange. Yet such idiosyncratic behavior apart, it was this son of an evangelical Baptist preacher who first discovered that DNA was the molecule of heredity. And putting such personal matters aside, the question remains: Why was such a fundamental discovery not recognized by the awarding of the Nobel Prize?
In his letters to his brother, Avery retained a modest outlook. Could it be that a combination of Avery's innate conservatism, his tendency to over-caution, and his downplaying of the implications of his discovery in the paper of 1944 might have contributed to his being overlooked? In Dubos's words, the paper…“did not make it obvious that the findings opened the door to a new era of biology.” Dubos wondered if the Nobel Committee, unaccustomed to such restraint and self-criticism “bordering on the neurotic,” might have decided to wait a while for both confirmation of the discovery and to see what the broader implications might be. To put it another way, Dubos questioned if the paper might have been a failure not in its own merits, as a scientific communication, but from the public relations point of view.
This lack of recognition is made all the more puzzling by the fact that, if the importance of the 1944 paper was not universally recognized when it was published, it became more and more obvious with the passage of time. The Hershey and Chase paper was published in 1952. And although he was retired by the time Crick and Watson published their famous discovery of the three-dimensional chemical structure of DNA in 1953, Avery was still alive. He wouldn't die until two years later in 1955.
More recently, the Nobel authorities have allowed open access to their earlier thinking, and this has confirmed much of what Dubos had concluded. As part of the system for deciding who should get Nobel Prizes, the Nobel Committee receives proposals from leading experts around the world. In the words of Portugal, who reviewed their considerations and archives, “It seems that key biological chemists were not convinced by Avery's claim that DNA was the basis of heredity.” Not a single geneticist nominated Avery for the Nobel Prize. In part this may have reflected a difficulty in extrapolating his discovery in a single type of bacterium to genetics more widely, but even those colleagues who did nominate him for the Nobel Prize tended to overlook his work on DNA in favor of his immunological typing of the pneumococcal capsule. Portugal also wondered if Avery's own idiosyncratic behavior, including his reluctance to meet with and exchange findings with colleagues, and in particular geneticists, at scientific meetings had unintentionally confounded the acceptance of his groundbreaking discovery.
We are left with a lingering sense of regret that Avery was not accorded the recognition he deserved. He was 67 years old when his iconoclastic paper was published. It was, in the words of the eminent biochemist Erwin Chargaff, the rare instance of an old man making a major scientific discovery. “He was a quiet man: and it would have honored the world more, had it honored him more.”
But there is a greater acknowledgment of discovery than the awarding of a prize, no matter how respected and prestigious. In the words of Freeland Judson, “Avery opened up a new space in biologists’ minds.” By space he meant he had unraveled a major truth, revealing new unknowns and raising important new questions. Avery himself had, with quintessential modesty, touched upon those important new questions in his letter to his brother:
If we are right, and of course that is not yet proven, then it means that nucleic acids are not merely structurally important but functionally active substances in determining the biochemical activities and specific characteristics of cells—and that by means of a known chemical substance it is possible to induce predictable and hereditary changes in cells. This is something that has long been the dream of geneticists�
�Sounds like a virus—may be a gene. But with mechanisms I am not now concerned—one step at a time—and the first is, what is the chemical nature of the transforming principle? Someone else can work out the rest…
You look at science (or at least talk of it) as some sort of demoralising invention of man, something apart from real life, and which must be cautiously guarded and kept separate from everyday existence. But science and everyday life cannot and should not be separated.
ROSALIND FRANKLIN
The discovery of the “transforming substance” by Avery, MacLeod, and McCarty, confirmed by Hershey and Chase's elegant experiment with the bacteriophage, proved that DNA was the molecule of heredity. But both groups were working with microbes, bacteria, and viruses, which were known to be much simpler in their hereditary nature than, say, animals and plants. This left huge unknowns that needed to be explored. Was DNA the key to the heredity of all of life, or was it just relevant to bacteria and viruses? By the early 1950s, work in many different laboratories had confirmed that DNA was a major ingredient in the nuclei of animals and plants. This supported the idea that DNA was the coding molecule of life. But if so, how did it really work? How, for example, did a single chemical molecule code for the complex heredity of a living organism?
Biologists, doctors, molecular biochemists, and geneticists were now asking themselves the same, or similar, questions. Critical to any such understanding was the precise molecular structure of DNA. If, for example, we were to regard the role of DNA as akin to a stored genetic memory, how did that molecular structure enable the quality of such a phenomenally complex memory? How was that genetic memory transferred from parents to offspring? How did the same stored memory explain embryological development, where a single cell arising from the genomic union of a paternal sperm and maternal ovum gives rise to the developing human embryo and future adult human being?
There was another profoundly important question.
Darwinian evolution lay at the heart of biology. To put it simply, Darwin's idea of natural selection implied that nature selected from a range of variations in the heredity of different individuals within a species. The way in which it worked was exceedingly simple, if brutal. Those individuals, and by inference their variant heredities, who carried a small advantage for survival and thus a better chance of giving rise to offspring, would therefore be more likely to contribute to the species gene pool. In reality, natural selection worked more through a process of attrition. Those less advantaged individuals who did not carry the advantage for survival, were more likely to perish in the struggle for existence, and thus they were less likely to contribute to the species gene pool.
This is what Darwinian evolutionary biologists refer to as “relative fitness.” It is the measure of the individual's contribution to the species gene pool. Certainly it has nothing to do with racist notions of superiority and inferiority attached to “survival of the fittest”—a term introduced not by Darwin but by the social philosopher Herbert Spencer. But if we take a pause and think about it, such variant heredity, essential for natural selection to work, must also come about through mechanisms involving this wonder molecule, DNA, which must lie not only at the heart of heredity but also at the absolute dead center of evolution. All of these questions needed to be answered by the scientists now struggling to understand the structure and, assuming structure was function, the properties of this remarkable chemical, DNA.
In fact, the first step toward answering these questions had already been taken back in 1943, in what might appear unlikely circumstances. It was taken not by a biochemist, biologist, or geneticist, but by an Austrian physicist. The spark was lit when, at 4:30 p.m. on Friday, February 5, Erwin Schrödinger stepped up to the podium in Dublin to deliver a lecture that is now seen as a landmark moment in the history of biology. Schrödinger had been awarded the Nobel Prize in 1933 for work in quantum physics that expanded our understanding of wave mechanics—but I won't confuse myself or my readers by entering further into the physics. The simple facts were that Schrödinger had exiled himself from his native Austria in protest at human rights abuses and had been given sanctuary in neutral Ireland by its president, Eamon de Valera. In Dublin, Schrödinger had helped found the Institute for Advanced Studies. As part of his duties in support of the Institute, he had agreed to give a series of three lectures in which he developed a central theme: “What Is Life?”
Such was Schrödinger's fame that the lecture theater, which had a seating capacity for 400, could not accommodate all who wished to attend the lectures—this despite the fact that they had been warned in advance that the subject matter was a difficult one and that the lecture was not going to be pitched at an easy or popular level, even though Schrödinger had promised to eschew mathematics. De Valera himself was present in the audience, as were his cabinet ministers and a reporter for Time magazine. One wonders what these politicians and journalists made of Schrödinger's focus on “how the events in space and time which take place within the spatial boundary of a living organism can be accounted for by physics and chemistry.”
Schrödinger subsequently extrapolated the three lectures into a book of less than a hundred pages with the same title: What Is Life? This was published the following year. In what is now a very famous book, Schrödinger popularized a quantum mechanics interpretation of the gene that had been proposed earlier by another distinguished physicist, the previously mentioned Max Delbrück.
In the opening pages of the first chapter, Schrödinger posed the question: “How can the events which take place within a living organism be accounted for by physics and chemistry?” Admitting that at the time of writing, the prevailing knowledge within the disciplines of physics and chemistry was inadequate to explain this, he nevertheless hazarded the opinion that “the most essential part of a living cell—the chromosome fiber—may suitably be called an aperiodic crystal.” The italicization is Schrödinger's to emphasize, as he further explained, that the physics up to this time had only concerned itself with periodic crystals, the kind of repetitive atomic structures seen, for example, in very obvious crystalline compounds such as gemstones.
What did he mean by an “aperiodic crystal”?
He explained this with a metaphor. If we examined the images within the pattern of a wallpaper, we could see how the pattern was repeated, over and over. This was the equivalent of a periodic crystal. But if we examined the complex elaboration of a Raphael tapestry, we saw a pattern of images that did not repeat themselves, yet the pattern was coherent and meaningful.
Schrödinger intuited further.
It was the chromosomes, or more likely an axial fiber much finer than what was visible under the microscope, that contained what he termed “some kind of code-script” that determined the blueprint of the individual's development from fertilized egg to birth—and further determined the functioning of what we would now term the genome throughout the lifetime of the individual.
That intuition would provide the drive for a naïve but highly inquisitive young American, called James Dewey Watson, to join forces with a slightly older but equally inquisitive Englishman, Francis Crick, and form what is now seen as one of the most famous partnerships in scientific history. Both men would take their inspiration from Schrödinger to search for the aperiodic crystal that coded for DNA.
Watson was an exceptionally bright child who lived at home with his family in Chicago while attending the local university. He enrolled when aged just 15, and he graduated, aged 19, in 1947 with a bachelor's degree that included a year studying zoology. His teacher of embryology would remember him as a student who showed little interest in lectures and made no notes whatsoever, so it was all the more puzzling when he graduated top of his class. Watson would subsequently admit to a habitual laziness. Though vaguely interested in birds, he had deliberately avoided any courses that involved chemistry or physics of “even medium difficulty.” This self-indulgent student left Chicago with only a rudimentary knowledge of genetics or biochemistry
. As part of his education, he had attended lectures by the geneticist Sewall Wright, who had devised a mathematical system of studying population genetics. Wright's course included a discussion of Avery's work, but Watson would subsequently confess that he took little notice. He would also confess that the inspiration for his subsequent interest in the “mystery of the gene” was Schrödinger's book, What Is Life?
Inspired by this book, Watson landed a research fellowship at Indiana University, at Bloomington. He was delighted by the move because Nobel Laureate Hermann Joseph Muller was the local professor of zoology. As early as 1921, Muller had observed that the genes of the fruit fly underwent mutations—as did the genes of the bacteriophages—the viruses that had inspired Hershey and Chase. Watson was intrigued by the fact that phage viruses could be manipulated in test tubes. Their reproductive cycles were extremely brief—an important consideration for an impatient young scientist. There were simple test systems that could be employed to follow their life cycles, and numbers, in a way that would open up new angles from which to attack the gene problem. All you had to do was carefully design an experiment aimed at probing some particular aspect of the gene problem, and the whole shebang could be completed in a matter of days. This intimate, if brutal, interplay between phage viruses and their host bacteria allowed scientists to figure the complex chemistry of genes, genetics, and chromosomes.