Prof. Dr. James Dewey Watson > Research Profile
by Luisa Bonolis
James Dewey Watson
Nobel Prize in Physiology or Medicine 1962 together with Francis Crick and Maurice Wilkins
"for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material".
From ornithology to molecular biology
James Dewey Watson was born in Chicago, Illinois, where he grew up and received his early education. He was such a child prodigy that in 1942 he appeared on the radio program The Quiz Kids. In 1943, after only two years of high school, he received a scholarship to the University of Chicago's experimental four-year college, where he cultivated his interest in ornithology, stemming from his boyhood interest in bird watching. By 1947, when he received a B.S. in zoology, he had turned to genetics. He enrolled at the University of Indiana, attracted by the geneticist Hermann Muller who was especially known for his work on the physiological and genetic effects of radiation (X-ray mutagenesis), that he had discovered in 1926, and for which he had just been awarded the Nobel Prize in Physiology or Medicine.
At Indiana, Watson was deeply influenced by the brilliant Italian-born bacteriologist Salvador Luria, who was doing bacteriophage research. Bacteriophages are bacteria-infecting viruses that at the time were used as experimental model organisms by the so-called Phage Group, an informal network of biologists established by Luria and his close friend Max Delbrück, two extraordinary scientists who had emigrated from continental Europe in the 1930s. Delbrück had been formed by Niels Bohr, one of the most influential physicists of his times, who had made Copenhagen one of the capital cities of science between the wars. Delbrück had been one of the first theoretical physicists who had discovered how his background in physical sciences could be productively applied to biological problems. His ideas about the physical properties of the gene had led Erwin Schrödinger to write What is Life?, a book that in turn deeply influenced other physicists - notably Francis Crick and Maurice Wilkins - to cross over to biology. With his enthusiasm, Delbrück brought many biologists into phage research in the early 1940s and instilled the characteristic math- and physics-oriented approach to biology, also encouraging research under standardised experimental conditions in different laboratories, helping to unify the field of bacterial genetics. In 1950, Watson completed his dissertation on the effects of X rays on bacteriophage multiplication under Luria. The group was strongly committed to the problem of unravelling the mystery of phage reproduction, so after his Ph.D in zoology Delbrück suggested that it would be good for Watson to learn DNA chemistry, because DNA might have something to do with genetics. He was sent to learn nucleic acid chemistry in Copenhagen with a National Research Council grant. There, with Ole Maaløe, Watson tried to establish the identity of the substances that gave genetic continuity to successive generations of phage particles conducting research on the biochemistry of deoxyribonucleic acid (DNA) in the bacteriophage.
The nucleic acids were first discovered in the nucleus of the human cell by the Swiss researcher Friedrich Miescher in 1869. In 1929, the biochemist Phoebus Levene, the discoverer of ribose and deoxyribose sugars, had identified the components that make up a DNA molecule: four nitrogen-containing bases (adenine, thymine, guanine, and cytosine), a 5-carbon sugar (deoxyribose) and phosphate. He showed that the components of DNA were linked in the order phosphate-sugar-base, a unit that he called a nucleotide. He suggested that the DNA molecule consisted of a string of nucleotide units linked together through the phosphate groups, the latter forming the backbone of the molecule. In 1937, William Astbury at Leeds started pioneer X-ray diffraction studies of DNA fibres and found evidence of considerable regularity. In 1947, he had deduced that nucleotides must be stacked along the fibre axis 'like a pile of pennies' each 3.4 angstrom thick. In the mid- 1940s, Oswald Avery, Colin MacLeod, and Maclyn McCarthy had presented evidence that DNA might be the hereditary material, but that conclusion was not widely accepted. Analysis showed that chromosomes contained both nucleic acid and proteins. Proteins were well known as versatile molecules that played many exciting roles, but virtually nothing was known about the functional roles of the nucleic acids, so they were seen as materials with a purely structural function while most scientists thought that genes were proteins. Most biologists thought that proteins were the strongest candidates for the material of heredity: their 20 amino acids led to a complexity of molecular structure that nucleic acids with a mere four nucleotides could not match. Mainly for this reason, before 1950 many people received conclusions about DNA being the fabric of genes with some scepticism.
In the late fall of 1950, Watson had attended in Copenhagen a lecture given by Lawrence Bragg discussing Linus Pauling's recent proposal regarding the existence of what he called the “alpha helix,” a secondary structure of protein molecules, whose three-dimensional helical structure he had derived relying on a combination of model building and of the simple laws of structural chemistry, like bond angles and other parameters of the atoms. Pauling, one of the founders of quantum chemistry, was already considered one of the most influential chemists of his time.
Watson was so struck by Bragg's talk, that he turned to his colleague Gunther Stent and said: “That's what we've got to do, Gunther! Get the 3-D structure of DNA, instead of farting around with phage DNA metabolism!” At the moment, Stent thought, “Jim had gone off his rocker. What did he think an ornithologist could do about working, out the 3-D structure of DNA, when a physical chemist like me wouldn't dare to wrestle with that problem?”
As Watson himself later recalled, he “was becoming frustrated with phage experiments and wanted to learn more about the actual structure of the [DNA] molecule, which geneticists talked about so passionately,” A further occasion proved instrumental in redirecting his research line. In the spring of 1951, while attending a symposium in Naples, Italy, Watson met Maurice Wilkins, who had been working since 1946 as Assistant Director of the Biophysics Research Unit at King's College in London. Working with his graduate student Raymond Gosling, Wilkins had succeeded in obtaining X-ray diffraction photographs containing dozens of well-defined spots on a clear background. This clearly showed for the first time that DNA was truly crystalline, and that one “could be very hopeful that its structure could be derived from X-ray patterns...” In his Nobel lecture, Wilkins immediately remarked that, on the other hand, they knew that, “genes had to be complicated and therefore DNA had to be complicated.” However, when Wilkins set up to work with DNA, there were already many different indications of simplicity and regularity in its structure. In the electron microscope, DNA was seen as a uniform unbranched thread of diameter about 20 Angstrom. Thus the conclusion that a chemical substance was invested with a deeply significant biological activity coincided with a considerable growth of many-sided knowledge of the nature of the substance. But nobody had the slightest idea of what the molecule might look like. Working closely with Gosling, Wilkins obtained detailed X-ray diffraction data of unprecedented quality of what we now know as the A-form of DNA, presenting 100 diffraction spots. As soon as good diffraction patterns were obtained, the mathematician Alex Stokes at King's worked out the theory of diffraction by a helix. Wilkins presented his photographs in Naples, at the Conference on large molecules attended by James Watson.
Excited by Wilkins' photographs, Watson was stimulated to investigate the structural chemistry of the nucleic acids. His contacts with the phage group had made him aware of DNA and the unsolved problem of how genetic information is transmitted from an organism to its offspring, but there was little awareness in the community at large that the problem could be attacked at the molecular level. Illuminated by Wilkins' slides, he became a convert to X-ray crystallography, strongly convinced by the revelatory derivation of the alpha helix motif in proteins by Linus Pauling. What attracted Watson was that the alpha helix had not been found only studying X ray pictures. Watson became convinced that he could use the same method to solve the structure of DNA if only he could have access to X-ray crystallographic data. He definitely decided to turn from the biochemical approach to the possibility of a structural attack on DNA. Changing disciplines in the middle of a fellowship was not an easy affair, but Watson was so resolute, that he travelled to Cambridge in early September to meet with Max Perutz and Lawrence Bragg to request a place for one year in the Molecular Biology Unit at Cavendish Laboratory, a world centre for the investigation of the three-dimensional structure of proteins through the techniques of X-ray diffraction. He had been recommended by Luria to John Kendrew, who was working on the structure of myoglobin, a small protein acting as a temporary storehouse for the oxygen brought by the haemoglobin in the blood.
An American biologist at the Cavendish Laboratory
Watson returned to Cambridge at the beginning of the semester in early October. It was then that he met Francis Crick, a physicist who had switched to biology. Watson was only 23 years old, and already on a postdoctoral fellowship, whereas Crick was 35 and had yet to complete his doctorate. Crick had studied physics at University College in London and after graduating in 1937 with a B.S, he conducted research on the viscosity of water at high temperatures. His work was interrupted in 1939 by the outbreak of World War II. After the war, like many young scientists of his generation, Crick was struck by Schrödinger's vision, conveying in an exciting way the concept of a highly complex molecular structure that controlled living processes. At the time Crick was already 30, considering a career in particle physics, but he was so stimulated by the idea that fundamental biological problems could be thought about using the concepts of physics and chemistry, that he began to think of making a completely fresh start as a biologist. After working for a couple of years on experimental cytology at Strangeways Research Laboratory at Cambridge, Crick was faced with a decision about future employment. He remembered how, on his first visit to Cambridge, it had been suggested to him to visit Max Perutz at the Cavendish Laboratory. When Rutherford died in 1937, Lawrence Bragg was appointed as his successor and the Cavendish had become a world-leading centre for X-ray crystallography. While still a young student, Bragg, together with his father Henry, had pioneered the application of X-ray diffraction, discovered in 1912 by Max von Laue, to the analysis of crystals. In 1915, when he was only 25 years old, Lawrence Bragg shared with his father the Nobel Prize in Physics for their discoveries related to X-Ray diffraction. The Braggs led the field of X-ray crystallography for several decades, encouraging a new generation of researchers, including John Desmond Bernal and William Astbury, both pioneers of molecular biology. After the war, Lawrence Bragg promoted the establishment of specific laboratories for research into the molecular structure of biological systems. He organised the research effort, found support for the project of protein analysis, and assembled a team to tackle these new problems. Perutz was named director of the Unit for Molecular Biology established in 1947 by the Medical Research Council in the Cavendish Laboratory attracted more and more researchers who felt that the new field of molecular biology had great promise. Among Bragg's students were Dorothy Crowfoot Hodgkin, Rosalind Franklin, who would play a major part in the discovery of the structure of DNA, Aaron Klug, who later developed crystallographic electron complexes and was awarded the Nobel Prize for Chemistry in 1982; and of course Max Perutz. Stimulated by Bernal's visionary faith in the power of X-ray diffraction, in the late 1930s Perutz began investigating haemoglobin, the carrier of oxygen from the respiratory organs to the rest of the body. But this was only the beginning of a long and ambitious research path. It took Perutz more than 20 years of hard work to solve the structure of haemoglobin. When Crick joined Perutz's unit in 1949, its members included John Kendrew, who was working on the structure of myoglobin, a small, bright red protein contained within muscle cells, which acts as a temporary storehouse for the oxygen brought by the haemoglobin in the blood.
Perutz was struck by Crick and thought that he, as a physicist, might be very useful for the project of using methods of X-ray analysis to determine the structure of proteins and allied molecules. But several months after his arrival at the Cavendish, Crick had not yet succeeded in finding a suitable protein of his own to work out its structure, as both Bragg and Perutz expected. He had thoroughly studied the methods of interpretation of X-ray data being used by Bragg, Perutz and Kendrew in their attempts to find the structure of haemoglobin and other proteins and was still lacking a definite problem for his dissertation, when Bragg asked him to work on the determination of the kind of diffraction pattern that a helical molecule would produce. British researchers thought that alpha-keratin (a very common protein, the stuff of hair, fingernails and animal horn) and other proteins might have a molecular structure like a spiral. In October 1950, Bragg, Kendrew, and Perutz had published a systematic paper enumerating the potential conformation of protein helices, proposing in particular a specific model for alpha-keratin. Soon after, between February and March 1951, Pauling had published with his collaborators a series of articles in the Proceedings of the National Academy of Sciences, in which he deduced the two main structural features of proteins: the alpha-helix and beta-sheet, now known to form the backbones of tens of thousands of proteins. Actually Pauling had succeeded in building a helical mental model of alpha helix already in 1948. He had conceived it while ill in bed, using a sheet of paper on which he had drawn a polypeptide chain that he folded to construct a helical model. But something was wrong: it was not possible to correlate the model with the X-ray diffraction pattern of alpha-keratin. The discrepancy could not be removed by minor adjustments and thus he refrained from publish his findings at the time. He did it only after three years, following the British scientists' article, because they were proposing potential helical structures for alpha-keratin that were all unacceptable in Pauling's view. As he later clarified: “I knew that if they could come up with all of the wrong helices, they would soon come up with the one right one, so I felt the need to publish it.” Bragg was completely upset by the fiasco. He and his colleagues had missed this important achievement, lacking the necessary chemical insight that provided the clue to the actual structure of the alpha helix. But the confirmation of the structure had come from Max Perutz, who realised that Pauling and Corey's alpha helix was actually like a spiral staircase in which the amino acid residues formed the steps and the height of each step was 1.5 angstrom. It was for him a thrilling experience when he immediately observed in keratin the characteristic X-ray reflection of this regular repeating pattern confirming the existence of this fundamental structure.
Helices had thus become a hot topic at Cavendish. In fall 1951, in conjunction with the crystallographers Vladimir Vand and William Cochran, Crick succeeded in formulating a theory predicting several major features of the diffraction pattern yielded by helical, long-chain molecules, packed tightly together and lined up in the direction of the fibre. Crick was also able for the first time to interpret the early diffraction pattern obtained by Astbury in terms of Pauling's helices. In October 1952, independently of Pauling, he also published a paper related to the structure of keratin alpha helix that contained a brilliant explanation accounting for a specific spot in the X-ray pattern. Helical molecules had fully taken hold of Crick's mind by the end on 1951, and he began to give original and significant contributions, deriving of the kind of diffraction pattern produced by a helical molecule and applying it to protein fibre structures. He also become a convert to the crystallographer's use of model building to help solve the structure of fibrous proteins and synthetic polypeptides. He considered this approach as a form of experimental science. It was the great lesson that Pauling, by his example of the alpha helix, had taught Crick.
First attack to the structure of DNA
At that time, in the fall of 1951, Watson arrived at Cambridge University's world famous Cavendish Laboratory. Watson immediately discovered the fun of talking to Francis Crick: “Finding someone in Max's lab who knew that DNA was more important than proteins was real luck.” They began to talk several hours each day and a main topic, particularly important to understand, were the exact arguments that had led to Linus Pauling’s discovery of the alpha helix. Crick, too, was deeply impressed by Pauling's achievement. The powerful method of combining the process of creative and conjectural model building with attention to correct empirical data on the directions, degrees of freedom, and lengths of the bonds between atoms in the molecule, might lead to the creation of molecular structures, narrowing down the different possibilities coming from raw data.
Within a few days after Watson's arrival, they knew what to do: imitate Linus Pauling and beat him at his own game. And so the stage was set for the most famous partnership in biology. From their first conversations, they assumed that the DNA molecule contained a very large number of nucleotides, linearly linked together in a regular way. They could see that the solution to DNA might be more tricky than that of the alpha helix, where a single polypeptide (a collection of amino acids) chain folds up into a helical arrangement held together by hydrogen bonds between groups on the same chain. Wilkins, who had been friends with Crick since 1947, had told him that the diameter of the DNA molecule was thicker than what would be the case if only one polynucleotide chain were present. This made him think that it was a compound helix composed of several polynucleotide chains twisted about each other. Wilkins actually suspected that three polynucleotide chains were used to construct the helix; he did not, however, share Crick and Watson's belief that Pauling's model building game would quickly solve the structure, at least not until further X ray results were obtained. Their conversations were also centred on Rosalind Franklin, a physical chemist, who had studied the structure of carbons using X-ray diffraction methods and had arrived at King's College, becoming Wilkins' colleague, in that same year, 1951.
During her first year of work, Franklin made important improvements in the preparation of the DNA fibres and assembled a new X-ray tube with Gosling, being able to obtain sharper diffraction patterns. Franklin also made a crucial advance showing that, depending on the water content of the fibre specimen, two forms of the DNA molecule actually existed, which she later labelled A and B, also defining the conditions for the transition between them. The two forms of DNA give radically different diffraction patterns, corresponding to slight structural differences mainly related to the arrangement of their ribose units, as was later clarified. It became clear that all previous workers had been working with a mixture of the two forms, thus explaining for the first time the difficulties of earlier attempts to decipher such mixtures in terms of a single phase. In Franklin's draft notes, prepared for a colloquium on her past six month's work she gave in November 1951 at King's College, it is clearly stated that both DNA forms are likely to be a helical bundle of two or three chains. She realised, too, that any correct model must have the phosphate groups on the outside, accessible to water. The group of chains would be linked together by hydrogen bonds between the bases that would be in the centre of the molecule.
Watson was invited by Wilkins to participate in Franklin's seminar of November 1951, after which Crick cross-examined him about what he had grasped from the talk. But Watson was in trouble. He had not taken any notes and he did not know enough of the crystallographic jargon; some of the reported data later proved to be faulty. Still, they decided they had enough elements to start in earnest their collaboration and test their ideas on the possible structure of DNA. Inspired by Pauling's technique, they began to build a three-dimensional stick-and-ball model, also based on what Watson remembered about the structural information from Franklin's seminar. After a week, in late November 1951, Wilkins, Franklin, and other colleagues were invited to Cambridge to see a tentative three-chain model of the DNA molecule, with the phosphates on the inside and with the bases pointing outwards, which Watson and Crick had just built. Franklin immediately expressed complete disagreement, saying that the correct DNA model must contain at least ten times more water than was found in their model. She also insisted that the sugar-phosphate backbones must be on the outside, not the inside. After this failure, Lawrence Bragg, the head of the Cavendish Laboratory, firmly vetoed any further work on DNA, and no attempt was made to appeal the verdict. Crick returned to his protein studies for his thesis and Watson turned to the other form of nucleic acid - RNA, ribonucleic acid - in the tobacco mosaic virus, but he dedicated to learn more theoretical chemistry and to leaf through journals, hoping that possibly there existed a forgotten clue to DNA. The book he studied the most was Pauling's classic The Nature of the Chemical Bond that Crick had recently bought. Pauling was the world authority on the structural chemistry of ions, so that Watson hoped that “somewhere in Pauling's masterpiece the real secret would lie." A second copy of the book was Crick's gift to Watson for Christmas 1951.
The tetranucleotide hypothesis stated that DNA was a simple molecule composed of a boring repetition of each of its four constituent “bases” attached to a sugar-phosphate backbone. In 1947, Erwin Chargaff had discovered an important regularity related to the bases: although their sequence along the polynucleotide chains was complex and the base composition of different DNA's varied considerably from species to species, for particular pairs of nucleotides - adenine and thymine, guanine and cytosine - the two nucleotides are always present in equal proportions. A real breakthrough in Crick and Watson's enterprise occurred in 1952, when Chargaff visited Cambridge and inspired Crick with a description of his experiments, that Crick had not known of. Shortly before meeting Chargaff, Crick had asked the young Cambridge mathematician John Griffith to calculate what attractive forces there would be between the bases and he had found out that adenine attracted thymine, and guanine attracted cytosine. Crick was quite satisfied, because this meant that this preferential attraction between the two couples would give rise to complementary replication. The idea of a complementary scheme that had been circulating around in the circle of theoretical geneticists intrigued by gene duplication, was now taking a more concrete sense. Thus, in June 1952, Crick had become aware of a fundamental piece of the jigsaw: base pairing could be the cause of the Chargaff rules -- the one-to-one ratio-- and, on the basis of Griffith's calculations, a structural relationship between pairs of bases might explain them.
At that time, the American microbiologists Alfred Hershey and Martha Chase had completed their decisive set of experiments showing that when the phage infects its bacterial host, only its DNA enters the cell. The phage protein remained outside, devoid of any further function in the reproductive process. It provided evidence that the DNA component of the phage particle, not the protein, carries the genetic information. During their work, completed in early 1952, they established that DNA directs the biosynthesis of enzymes and thus controls the biochemical processes of the cell. From these results it could be inferred that nucleic acids had important biological roles that were connected with protein synthesis. Hershey continued to work along this line and in 1969 he would share the Nobel Prize in Physiology or Medicine with Max Delbrück and Salvador Luria “for their discoveries concerning the replication mechanism and the genetic structure of viruses.”
According to Watson's memoir, The Double Helix, learning about the Hershey-Chase experiment in the spring of 1952 drove them to intensify their efforts to work out the structure of DNA. But Pauling, too, was becoming eager to solve the three-dimensional structure of DNA, as he had already done with other biological molecules. In the summer of 1952, as soon as he learned about the Hershey-Chase experiments, suggesting that hereditary continuity is carried by the nucleic acid and not the protein, he immediately switched his attention to DNA, feeling that it should be possible to decipher the structure of this substance by building models along similar lines to those used in his protein work. Pauling's son, Peter, who was at the time working with Crick and Watson as a graduate student in the Cavendish Laboratory got a letter from his father before Christmas 1952. It contained the long-feared news that Pauling now had a structure for DNA, even if no details were given on what he was up to. They were eager to know what his model looked like. Towards the end of January 1953 they learned that a manuscript on DNA had been written, a copy of which would soon be sent to Peter and to Lawrence Bragg.
During the last week of January 1953, Crick and Watson finally saw the draft of Pauling’s already submitted paper. It described the DNA molecule as a triple-stranded helix, very reminiscent of the three-stranded model Watson and Crick had abandoned fourteen months before. The three strands were twisted around each other in ropelike fashion, with the phosphoric acid groups triangularly arranged in the centre and with the various bases pointed outward. The analysis was unfortunately based on rather poor photographs published many years before by Astbury and on equally poor photographs made in Pauling’s laboratory. After reading the summary and the introduction, Watson soon came to the figures showing the locations of the essential atoms. Something was not right. He realised that the phosphate groups in Pauling's model were not ionised, but that each group contained a bound hydrogen atom and so had no net charge. Everything he knew about nucleic-acid chemistry indicated that phosphate groups never contained bound hydrogen atoms. Virologists and organic chemists in Cambridge reassured Watson that DNA is an acid, so of course the phosphate groups must be ionised. Moreover, the structure ignored Chargaff's rules and in general it gave no clue to its own reduplication. Crick and Watson felt that thanks to Pauling's failure, they still had a chance to interpret the structure first. Crick immediately explained to Perutz and Kendrew that “no further time must be lost on this side of the Atlantic.” When his mistake would become known, Pauling would not stop until he had captured the right structure. They now felt in open competition with the world-famous chemist Linus Pauling. As soon as the paper would be spread around the world, it would be only a matter of days before the error would be discovered. They had up to six weeks before Pauling was in full-time pursuit of DNA.
The next year, Pauling would be awarded the Nobel Prize in Chemistry 1954 “for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances.” In 1962, for his opposition to weapons of mass destruction, he was awarded the Nobel Peace Prize, becoming the only person ever to receive two undivided Nobel Prizes.
The three-dimensional structure of DNA
In the meantime, at King's College in London, Wilkins had continued his experiments working on sepia sperm and getting much clearer patterns than the previous year. They very clearly offered strong evidence for a helical structure for DNA. Franklin, too, had continued to work on her step-by-step detailed analysis of her diffraction data. At the end of January 1953, Watson visited Kings' College and Wilkins showed him what became famous as picture B51, an X-ray picture of the B form of DNA, that Franklin had obtained in May 1952. In his book The Double Helix Watson himself recalled that it was a memorable moment: “The instant I saw the picture my mouth fell open and my pulse began to race.” The pattern was so much simpler than that of the A-form. The black cross of reflections that dominated the picture could arise only from a helical structure, also giving several of the vital helical parameters. The characteristic feature of the B-form is the X-shaped pattern of streaks arranged in a set of layer lines, from which it could be directly deduced that DNA in this form is a helix with an axial repeat of 34 angstrom and an axial spacing between nucleotides of 3.4 angstrom. Franklin, however, had chosen to concentrate on the difficult analysis of the more complicated A-form, which offered the possibility of an objective crystallographic analysis, because of the greater wealth and precision of the diffraction data available. If correctly interpreted, the A pattern would yield more precise information about the DNA molecule. She was actually able to determine the dimensions and symmetry of the unit cell and embarked on the calculation of the Patterson maps in an attempt at solving the structure.
Watson did not engender any excitement in Wilkins and that same evening, as he rode back to Cambridge, he sketched what he could remember of the B form's diffraction pattern. By the time he was back, he had decided that the range of possible densities in the molecule did not, after all, rule two chains out. The next day, Watson reported to Perutz and Bragg about what he had learned during his visit in London, running through the details of the B form and making a rough sketch to show the evidence that DNA was a helix that repeated its pattern every 34 angstroms along the helical axis. Watson then said that he was going to ask a Cavendish machinist to make models of the purines and pyrimidines, and remained silent, waiting for Bragg's reaction. Bragg made no objection and encouraged him to get on with the job of building models.
Unleashed from Bragg's earlier ban, Watson began to build tentative models as soon as he received the first group of atoms. Every evening, after he got back to his rooms, Watson tried to puzzle out the mystery of the bases: “My aim was somehow to arrange the centrally located bases in such a way that the backbones on the outside were completely regular - that is, giving the sugar-phosphate groups of each nucleotide identical three-dimensional configurations. But each time I tried to come up with a solution I ran into the obstacle that the four bases each had a quite different shape. Moreover, there were many reasons to believe that the sequences of the bases of a given polynucleotide chain were very irregular. Thus, unless some very special trick existed, randomly twisting two polynucleotide chains around one another should result in a mess... There was also the vexing problem of how the intertwined chains might be held together by hydrogen bonds between the bases.” In the meantime they learned from Wilkins that he, too, was going to work on model building, so they asked him whether he would mind if they started to play about with DNA models. Wilkins' answer was no, so they went ahead.
A most lucky coincidence opened the way to the final stage of the race. In the second week of February, Perutz showed Crick a progress report from King's College, which included Franklin's report to that Committee of December 1952. Wilkins himself had mentioned the existence of such a report, which was not meant to be confidential, but should help in establishing contact between the different groups of people working for the Council in the same field. It confirmed much of what they already knew, but a highly significant piece of information that Crick derived from the report was that Franklin had identified the A-form as having a face-centred monoclinic cell with the space symmetry group C2. Up to that moment, everyone had assumed that the component chains lay parallel, all pointing in the same direction. A lucky coincidence led Crick to grasp the significance of this crucial piece of information: C2 was the same space group as that of oxyhaemoglobin, the material he was supposed to be studying. This meant that the motif units occur in pairs (related by the two-fold axes) with one pointing upwards and the other downwards. As the A- and B-forms can be interconverted simply by changing the level of hydration, Crick argued that they must be very similar in structure. The dimensions of the unit cell proved that the axis of symmetry between paired elements of the structures was perpendicular to the long axis of the cell, suggesting two chains running in opposite directions, definitely excluding a three-chain structure. If the A-form had an anti-parallel double-stranded structure, the B-form must be the same and the chains had to be twisted at twice the rate, so that the repeat distance was a complete 360° turn for each helix, while the repeat distance for a parallel double-chain structure is 180° turn for each strand. Discovery of the characteristic symmetry of the molecule immediately settled the spatial arrangement of the backbones as they spiralled up the outside around the core. Watson was now convinced of Franklin's claim made more than 1 year earlier that the sugar-phosphate chains must be on the outside of the molecule. But how were the bases to be fitted inside the two helices? And how were Chargaff's ratios to be accounted for in the model?
During the last week of February, Jerry Donohue, sharing the office with Crick, Watson and Peter, set them on the right track concerning the correct position of hydrogen atoms, essential for cross-bonding. He was an excellent structural chemist, a world expert, like Pauling, in hydrogen bonds. His comments allowed Watson to fit in adenine-thymine as a pair, and also guanine-cytosine. All this information played a key role in Watson's final insight: the adenine-thymine bond was exactly as long as the cytosine-guanine bond. An adenine-thymine pair held together by two hydrogen bonds was identical in shape to a guanine-cytosine pair held together by at least two hydrogen bonds. Two irregular sequences of bases could be regularly packed in the centre of a helix if a purine always hydrogen-bonded to a pyrimidine. The hydrogen bonds formed naturally, making the two types of base pairs identical in shape. Chargaff's ratios now automatically arose as a consequence of Watson's base-pairing scheme, standing out as a consequence of a double-helical structure for DNA. Always pairing adenine with thymine and guanine with cytosine meant that the base sequences of the two intertwined chains were complementary to each other. Given the base sequence of one chain, that of its partner was automatically determined. The mystery was solved. Conceptually, it was very easy to visualise how a single chain could be the template for the synthesis of a chain with the complementary sequence. Crick was so excited that he told everyone that they had found the secret of life.
When the metal plates of the bases were ready, Watson made a model in which for the first time all the DNA components were present. He arranged the atoms in positions that satisfied both the X-ray data and the laws of stereochemistry. Because of the helical symmetry, the locations of the atoms in one nucleotide would automatically generate the other positions. The resulting helix was right-handed with the two chains running in opposite directions. Their three-dimensional metal skeleton of atoms assembling a double helix was finished in early March. Bragg was delighted and immediately caught on to the complementary relation between the two chains and saw how an equivalence of adenine with thymine and guanine with cytosine was a logical consequence of the regular repeating shape of the sugar-phosphate backbone. Wilkins was the first people outside of Cambridge to see it. According to the model, the double helix of the DNA molecule consists of two antiparallel strands of deoxyribose phosphate (alternating units of sugar and phosphate) on the outside, joined by complementary pairs of bases within the helix. As stated by Chargaff, adenine is paired with thymine, guanine with cytosine, and the bases to one another by hydrogen bonds. When Franklin saw the model, she had enough elements to understand that it was a reasonable model, because in the meantime she had arrived very near to the solution, as can be inferred from her notebooks and from two papers sent to press before she knew of the Watson-Crick model. After a whole afternoon of difficult conversation about how much the King’s work had helped Watson and Crick, they agreed that Wilkins and his colleagues would publish their data jointly with Watson and Crick’s announcement in three papers with continuous pagination in Nature. The three papers appeared on 25 April 1953, grouped together under the title “Molecular Structure of Nucleic Acids”. In their paper Crick and Watson acknowledged that they had been ”stimulated by ... the unpublished results and ideas” of Wilkins and Franklin. Gosling and Franklin added a short note describing the helical evidence in the B photographs, and Wilkins co-authored his paper with Stokes and H. R. Wilson. They made a preliminary description of the experimental evidence for the polynucleotide chain configuration being helical and existing in this form when in the natural state. During the following 10 years Wilkins led a team that performed a range of meticulous experiments to establish the helical model more rigorously.
After Watson and Crick had seen the two King's College papers showing how strongly X-ray evidence supported their structure, they wrote a second article published on May 30 containing the first clear statement on DNA carrying the genetic code: “... it therefore seems likely that the precise sequence of bases is the code which carries the genetic information”. It also offered a mechanism of replication: “If the actual order of the bases on one of the pair of chains were given, one could write down the exact order of the bases on the other one, because of the specific pairing. Thus one chain is, as it were, the complement of the other, and it is this feature which suggests how the deoxyribonucleic acid molecule might duplicate itself.” The complementarity of the two strands in the structure provided a mechanism for inheritance, in that each single strand could act as a template for assembling its complement - leading to two identical duplex molecules. The information is in the sequence of the bases.
In 1962, Crick, Watson, and Wilkins were jointly awarded the Nobel Prize in Physiology or Medicine for “discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material.”
Unfortunately, by that time Rosalind Franklin had died. After moving to Bernal's laboratory at Birkbeck College, Rosalind Franklin did very fruitful work on the tobacco mosaic virus and also began work on the poliovirus. In the summer of 1956, she became ill with cancer and died less than two years later at the age of 37.
The discovery of the DNA three-dimensional structure gradually emerged as an event with great heuristic consequences and the steady accumulation of new evidence for the double helix made it apparent that this was a transforming milestone in the evolution of biological science. The elucidation of the genetic code launched the new subjects of molecular genetics and, combined with biochemistry, the molecular biology of the gene. The following decades saw what has been called the genetic revolution in biotechnology, after the development of many powerful methods tools for handling and manipulating DNA that led to great advances in understanding the regulation of gene expression and eventually to the human genome project and to the comparative genomes of other organisms. The image of the DNA double helix itself has turned into one of the icons of the 20th century.
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