by Frank Ryan
Curiously it would not be Muller but another phage researcher, Salvador Luria, who would now give shape and direction to the young scientist's growing infatuation with the gene.
The Italian-born Luria was another European scientist—a microbiologist, like Avery—who found refuge in America from the European war zone. By now he had entered into a working collaboration with Max Delbrück, who was professor of biology at the California Institute of Technology. In 1943, Luria and Delbrück designed and conducted an experiment that demonstrated that genetic inheritance in bacteria followed precise evolutionary principles. This experiment became one of the foundation stones of modern Darwinism. That same year, Delbrück befriended another microbiologist called Alfred Hershey, who would subsequently write the key DNA paper with Martha Chase. In a letter to Luria, Delbrück summarized Hershey as follows: “Drinks whiskey but not tea. Likes living in a sailboat…Likes independence.” The three scientists joined forces to become the nucleus of a cooperating and mutually supportive network of scientists that would become known as the “phage group.” Delbrück would subsequently explain that they would be a group only in the sense that they communicated freely on a regular basis and that they told one another what they were thinking and doing. In this way, a loose creative movement grew around the two European expatriate scientists, all working toward the common ambition of figuring out how genes worked.
Luria, Delbrück, and Hershey now posed some interesting questions. How does the phage virus actually get into the bacterium? How, once inside, does it multiply? Does it multiply like a bacterium, growing and budding off daughter viruses? Or does it multiply by an entirely different mechanism? Is this multiplication some complex physical or chemical process that could be understood in terms of known physical and chemical principles? Through making use of the phage reproductive system, they hoped to solve the mystery of the gene. To begin with, it all seemed simple in principle, but as experiment followed experiment and year followed year, they found themselves no closer to the answer.
Up to 1940 or so, people like Delbrück and Luria had assumed that viruses were simple. They had little to go on since the majority of viruses were so minuscule they could not be seen with any clarity through the ordinary light microscope. They would even talk about them as if they were akin to protein molecules. Luria would come to define phage viruses, in a misleading oversimplification, as extensions of the bacterial genome. But with the invention of the electron microscope by the German company Siemens, even the smallest viruses, including bacteriophages, would soon become visible for the first time. And when they did become visible, they proved to be more complex than the two scientists had initially conceived.
Many phages had a head that was cylindrical in shape, with a narrow sheath below it, as tall as the head, and a base plate with six spikes with fibers attached. Now that they could visualize phages in the process of infecting their host bacteria, something struck Delbrück and Luria as exceedingly odd. The viruses didn't actually pass through the bacterial cell wall. What they appeared to do was to squat down against the wall and inject their hereditary material into the cell. In 1951, a phage researcher called Roger Herriott would write to Hershey, “I've been thinking that the virus may behave like a little hypodermic needle full of transforming principles.” This became the background to Hershey and Chase's experiment in which they confirmed that that was precisely what happened. The virus behaved exactly like a hypodermic syringe; the tail and its elongated fibrils would attach to the bacterial wall, and the phage would then inject its viral DNA in through the bacterial wall to take over the bacterium's own genetic machinery, the viral genome compelling the bacterial genome to construct what was necessary for the generation of daughter viruses. In effect, the infected bacterium became a factory for the production of daughter viruses.
It would be this discovery, together with many associated extrapolations to microbiology and genetics, that would lead to all three scientists—Delbrück, Luria, and Hershey—sharing the Nobel Prize in 1969.
Meanwhile, back in 1947, it was the dynamic energy and infectious charm of Luria, and the innovative genius of Delbrück, that proved most influential to the youthful Watson after his arrival at Indiana University. Still fascinated by the mystery of the gene, it was his hope that the mystery might be solved without his bothering to learn any of the complex physics or chemistry.
It is instructive to discover, from conversations between Luria and Watson, that there was no ignorance at Bloomington about Avery's discovery of DNA. Luria had visited Avery in 1943, prior to the publication of the key paper, when he had the opportunity of discussing Avery's findings in detail. He would recall Avery to Watson as an utterly non-pompous scientist, precise in his language, with a tendency as he spoke to close his eyes and rub his bald head—“every bit of a chemist, even though he was an MD.” Watson would take his cue from Luria, writing, in The Double Helix, how Avery had shown that hereditary traits could be transmitted from one bacterial cell to another by purified DNA molecules. Given the fact that DNA was known to occur in the chromosomes of every type of living cell, “Avery's experiments strongly suggested that…all genes were composed of DNA.”
In the autumn of 1947, Watson, still just 19, took Luria's course in bacteriology and Muller's in X-ray-induced gene mutation. Faced with the choice of entering into research with Muller on Drosophila or with Luria on microbes, he plumped for Luria, despite the fact that the Italian scientist had a reputation among the graduate students for having a short fuse with dimwits. Watson would subsequently adopt his patron's example. Delbrück was a heroic figure to Watson because he had inspired Schrödinger's ideas in the inspirational book. Watson was delighted when Luria introduced him to Delbrück when the eminent German physicist paid a visit to Bloomington.
Luria set Watson a PhD dissertation on the pathological effects on phage of exposure to X-rays. The work proved so mundane that Watson would barely mention it in his biography. But his obsession with the gene was undimmed. By the summer of 1949, his thesis nearing completion, he had the itch to travel to Europe. Luria arranged a Merck Fellowship from the National Research Council—three thousand dollars for the first year, potentially renewable. In May the following year, with his PhD under his belt, he sailed for Denmark, where he had been assigned to study nucleotides with a biochemist named Herman Kalckar. Kalckar was a gifted scientist but his interest was neither the gene nor the bacteriophage. A disenchanted Watson switched his attentions to another Dane, and a member of the phage group, Ole Maaløe, who was working on the transfer of radioactively-tagged DNA from phages to their viral offspring.
Out of the blue, Kalckar accepted a short-term project in the Zoological Station in Naples. He suggested that Watson might tag along. Though he had little interest in marine biology, Watson was delighted to acquiesce. He hoped to warm himself in the Italian sun. But he was disappointed to find Naples chilly, with no heater in his room on the sixth floor of a nineteenth-century house. “Most of my time I spent walking the streets or reading journal articles…I daydreamed about discovering the secret of the gene, but not once did I have the faintest trace of a respectable idea.”
Here, by happenstance, he attended a lecture in the Zoological Station given by an English scientist named Maurice Wilkins. The lecture could hardly have excited him in prospect, knowing that most of it would be about the biochemistry of proteins. “Why should I get excited learning boring chemical facts as long as the chemists never provided anything incisive about the nucleic acids?”
But he took the risk and attended anyway.
Tall, bespectacled, asthenic, and somewhat diffident in manner, you might have expected Wilkins's presentation to bore the restless and impatient Watson. But it did not. To begin with, it was delivered in a language that Watson readily understood. And for all of his diffident manner, Wilkins kept to the point. Then suddenly, close to the end of the lecture, a projected slide jarred Watson to full attention. On the screen was a photograph th
at showed something Wilkins called an X-ray diffraction pattern of DNA that had been taken in the King's College laboratory in London. Watson would subsequently admit that he knew nothing about X-ray crystallography. He hadn't understood a word of what he had read about it in the scientific journals, and he thought that much of what the “wild crystallographers” were claiming was very likely baloney.
But now here was Wilkins mentioning in passing that this was the clearest picture of DNA that he and his colleagues had yet obtained from their X-ray studies. In the same audience was the Leeds-based English physicist, William Astbury, who had pioneered X-ray diffraction studies of biological molecules and who had produced the first X-ray pictures of DNA. Astbury would subsequently confirm that no one had ever shown such a sharp, discrete set of reflections from the DNA molecule as Wilkins then projected onto the screen. “There was nothing like it in the literature.” In explaining the picture, Wilkins suggested that DNA might be thought of as a crystalline substance.
Watson was electrified to hear Schrödinger's prophecy confirmed. He sat in a daze of wonderment as Wilkins went on to explain that if and when we understood the structure of DNA, then we might be in a better position to understand how genes worked. Watson was now asking himself some pertinent questions. Who was this interesting English scientist, Wilkins? And how could he get to join his team at King's College in London?
Maurice Hugh Frederick Wilkins was not, in fact, English, as Watson initially surmised. He was born in Pongaroa, New Zealand, where his father, Edgar Henry, was a practicing doctor. The family were Anglo-Irish in origins, hailing from Dublin, where Maurice's paternal grandfather had been headmaster of the high school and his maternal grandfather chief of police. On leaving New Zealand, the family first returned to Ireland, then headed for London, where Dr. Wilkins was later to do his pioneering work in public health.
Maurice had had a natural scientific curiosity even as a boy, and it was this curiosity that led to his studying physics as part of his BA at Cambridge University, after which he worked for his PhD under John Turton Randall (later knighted), a physicist who played a leading role in the development of radar during the war.
As a postgraduate, Wilkins moved to the University of Birmingham, following the posting of his Cambridge tutor, Randall, where the two scientists continued their collaboration on radar. But then, out of the blue, Wilkins found himself dispatched to the United States to work on the Manhattan Project. His purpose was to figure out how to purify suitable isotopes of uranium from impure sources, to make them suitable for the atomic bomb. In February 1944, Wilkins crossed the dangerous waters of the Atlantic on the Queen Elizabeth, heading for the University of Berkeley, California. Here he made a modest contribution to the development of the atomic bomb. However, the subsequent destruction of Hiroshima and Nagasaki by the very weapons that he had worked on left Wilkins somewhat unsettled in conscience.
After the war, Wilkins returned to England where he ended up as assistant director of the new Biophysics Unit at King's College London, funded by the Medical Research Council, and where his former boss, Randall, was now the Wheatstone Professor of Physics. The new departmental remit was to apply the experimental methods of physics to important biological problems. This would result in Wilkins developing a relationship with Watson and Crick and joining the search for the molecular code of DNA. It would also involve him in a somewhat infamous strained working relationship with the X-ray crystallographer Rosalind Franklin.
Given this developing history, we might pause a moment or two to consider Wilkins's personality and its relevance to the coming storm. From what one can gather from his belatedly published biography, and the memory of those who knew him and worked with him, Wilkins was a quiet, highly moral man, somewhat Quaker-like in social attitudes. As a boy, he enjoyed a close emotional relationship with his elder sister, Eithne, who taught him to dance. But this intimacy was torn apart when Eithne developed a bacterial infection that turned into a septicemia, the blood-borne infection provoking septic arthritis in multiple joints. This would have been a shockingly painful and disabling condition, which, prior to antibiotics, might have proved fatal. She spent months in a hospital bed with her limbs dangling from hoists, her joints lanced open to drain the pus. The unfortunate Eithne survived, but the intimacy with her younger brother ended. The trauma of this experience may well have affected his self-confidence, particularly in his relationships with women.
While an undergraduate at Cambridge, he fell in love with a woman called Margaret Ramsey, but he “was incapable of making a suitable advance to her.” After he told her of his love, there was a short silence after which she walked from the room. During his stay in Berkeley, Wilkins was attracted to an artist named Ruth who had shared lodgings with him. She conceived a child, and they subsequently married, but when, as the war was ending, he informed Ruth that he intended to return to the UK, she refused to accompany him. “Ruth told me one day that she had made an appointment for me with a lawyer and when I arrived at his office I was shocked to hear that Ruth wanted to end our marriage.” Shortly after the divorce, Ruth gave birth to a son. Wilkins went to see her, and their baby, in the hospital ward, before returning to the UK alone.
Wilkins would admit to difficulty overcoming an innate shyness, and he would require periodic psychotherapy in his time working at King's, but he subsequently found a wife, Patricia, who appreciated the sensitive soul behind the diffident exterior, and he enjoyed a happy marriage and the joys of rearing a family of four children. There was also a fruitful outcome of his unsettled conscience following his work on the Manhattan Project. Before leaving Berkeley, one of his working colleagues came to his rescue…“Seeing I wanted to find some new direction, he lent me a new book with the rather ambitious title, What Is Life?”
Francis likes to talk…He doesn't stop unless he gets tired or he thinks the idea's no good. And since we hoped to solve the structure by talking our way through it, Francis was the ideal person to do it.
JAMES WATSON
It is somewhat ironic that Maurice Wilkins only arrived in Naples by happenstance, since he was substituting for Randall, who had agreed to present the talk but had been unable to attend. It seems unlikely, had Randall himself presented the lecture, that he would have included the DNA slide, or that he would have spoken of what it portrayed with such clear reference to Schrödinger's book. This lecture, which so excited Watson, was on the physico-chemical structure of big biological molecules, mostly proteins, made up of thousands of atoms. The key photograph had been taken by Wilkins, working together with a graduate student called Raymond Gosling, while using a technique called X-ray diffraction. One of the things this technique was particularly good at was finding the sort of repetitive molecular themes you found in crystals, hence the other term for it: X-ray crystallography.
“Suddenly,” as Watson would later recall, “I was excited about chemistry.”
Up to this moment, Watson had had no idea that genes could crystallize. To crystallize, substances must have a regular atomic structure—a lattice-like structure of atoms at the ultramicroscopic level. The youthful Watson appears to have been a wonderfully free spirit journeying from one interesting encounter to another. Impulsive, impatient, egregiously direct, yet all the while on the hunt for new adventure.
“Immediately I began to wonder whether it would be possible for me to join Wilkins in working on DNA.” But Watson never got to work with Wilkins. Instead, happenstance headed him in the direction of another X-ray crystallographer called Max Perutz, who was working at the Cavendish Laboratory at Cambridge University.
The Cavendish Laboratory is a world-famous department of physics. First established in the late nineteenth century to celebrate the work of British chemist and physicist Henry Cavendish, one of its founders and the first Cavendish Professor of Physics was James Clerk Maxwell, famous for his development of electromagnetic theory. The fifth Cavendish Professor and the director of the laboratory at the time of Wat
son's arrival was William Lawrence Bragg, who was the successor, as director, to Lord Ernest Rutherford, another Nobel Prize–winner and the first physicist to split the atom. Bragg was an Australian-born physicist who, jointly with his father, had been awarded the Nobel Prize in Physics in 1915 for establishing the use of X-rays in analyzing the physico-chemical structures of crystals. X-ray beams are bent when they pass through the orderly atomic lattice of crystals. What is projected onto the photographic plate is not the picture of the atoms within the structure but the refracted pathways of the X-rays after they have collided with the atoms. This is called “diffraction” and is similar to how light is bent when it passes through water. In a structure with haphazard positioning of atoms in space, the X-rays will be scattered randomly and form no pattern. But in a structure that contains atoms in a repetitive atomic lattice—such as a crystal—the X-rays are deflected in a recognizable pattern of blobs on the X-ray plate. From this diffraction pattern, the atomic structure of the structure can be deduced.
The two Braggs—father and son working as a team at the University of Leeds—had constructed the first X-ray spectrometer, allowing scientists to study the atomic structure of crystals. At the age of 22, Bragg Junior, now a Fellow of Trinity at Cambridge, had produced a mathematical system, Bragg's Law, that enabled physicists to calculate the positions of the atoms within a crystal from the X-ray diffraction pictures. At the time of Watson's arrival into the laboratory, Bragg's main focus of study was the structure of proteins. It was this potential for the X-ray diffraction of proteins that had attracted Max Perutz to the Cavendish Laboratory.