The discovery of the molecular configuration of DNA is passing from living memory into scientific legend. The tale is well-known: two young scientists at Cambridge University’s Cavendish Laboratory, American James Watson and Englishman Francis Crick, doggedly pursued the problem for two years before assembling a final ‘tinker toy’ model on Watson’s desk one morning in February 1953. Later that day, as they ate lunch at the nearby Eagle pub, Crick declared that they had discovered the secret of life.

In April, a report on the structure was published in Nature. Only Watson and Crick were listed as authors, and only six prior papers were cited. When the duo traveled to Stockholm in 1962 to accept Nobel Prizes for the work, they shared the spotlight with a single colleague, X-ray crystallographer Maurice Wilkins, who had provided a key piece of evidence.

There were, of course, many other contributors, and Watson’s personal account of the discovery, The Double Helix (1968), acknowledged their importance. Watson and Crick were informed, inspired, and motivated by many predecessors and contemporaries, including Wilkins and a small group of biochemists and biophysicists with special interests in the project: Lawrence Bragg, Jerry Donohue, Rosalind Franklin, and Linus Pauling.

Sixty years after the event, the names Watson and Crick are inextricably linked to the double helix, and rightly so. With the exception of Franklin, whose contributions have been amply recognized in recent years — a successful Off-Broadway play and a best-selling biography have celebrated her life and work — the roles of others have been increasingly neglected and overlooked. As readers learned decades ago from Watson’s book, the discovery of the molecular structure of DNA was a great drama, and the plot was propelled at several crucial junctures not by the stars, but by the supporting cast.

Cavendish Laboratory
University of Cambridge, England
March 3, 1953

Having spent the past few days sick at home, Sir Lawrence Bragg sat at his desk to catch up on correspondence and reading. The sixty-two-year-old Nobel Laureate was head of the entire Cavendish Laboratory, but he still pursued his own research, and often took work home at night. He looked the part of the distinguished older scientist — a tweed coat and white mustache rounded out his dark features. He quietly but firmly managed the lab’s strong personalities, and tried to steer their work in productive directions.

Late in the morning, he finally took a break from his administrative chores. He made his way through the Austin Wing, the building that housed the Cavendish Lab, to room 103. Inside, Jim Watson and Francis Crick were bent over a cluster of metal rods and plates arranged into a tower that spiraled up from a desktop. It was their latest model of deoxyribonucleic acid, and they talked confidently about the calculations that had gone into it. Bragg encouraged them to check the structure with someone more knowledgeable in organic chemistry. He could not have known, but he was one of the first people to see the correct configuration of the molecule. Bragg had not helped to build the model, but scientific tools and leadership skills that he had refined over the course of his career were essential to its completion.

William Lawrence Bragg was born in 1890 in Adelaide, Australia. His maternal grandfather was the postmaster general and state astronomer of South Australia, and his father, Sir William Henry Bragg, was an eminent mathematician and physicist, known as a masterful lecturer. Lawrence inherited his family’s gift for science. By the time he was eighteen, the Braggs had moved to England, and he was taking graduate classes in physics at Cambridge while collaborating with his father.

In 1912, German physicist Max von Laue suggested that X-rays aimed at crystals should scatter into characteristic patterns. The Braggs became fascinated by this idea, and began designing experiments to test it.

The elder Bragg designed a device called an X-ray spectrometer that could measure the wavelengths of X-rays. The younger Bragg worked out an equation to fit the diffraction of X-ray beams by crystals. The equation came to be known as Bragg’s Law, and together, the two advances formed the basis of X-ray crystallography. For their innovations, the father and son won the 1915 Nobel Prize for Physics. Lawrence Bragg was twenty-five years old. To this day, he is the youngest Nobel Laureate.

Over the next thirty years, Bragg held several positions, including a professorship at Victoria University in Manchester. He was appointed director of the Cavendish Laboratory in 1937. In The Eighth Day of Creation, a masterful history of molecular biology, Horace Freeland Judson wrote: “Bragg had the quality most essential in the leadership of a great laboratory: an instinct for the grand lines of research that were going to pay out next, and for the men to do them.”

Over the course of his career, Bragg had become intrigued with the idea that X-ray crystallography could be used to sketch out the structures of complex biomolecules, such as proteins, lipids, carbohydrates, and nucleic acids. The Cavendish had long been known for research in classical and nuclear physics, but with Bragg at its helm, the laboratory began applying the instruments and methodologies of the field to problems in the life sciences.

The dull gray brick of the Austin Wing could have been mistaken for a factory, but inside, it was alight with creativity. It housed the famous Cavendish Laboratory, established in 1874, where Ernest Rutherford described the structure of the atom, James Chadwick discovered the neutron, and John William Strutt explained why the sky is blue. British science writer Egon Larsen once called the place “a nursery of genius.” For a brief period during World War II, it housed government researchers, but by the time Francis Crick and Jim Watson took up residence in a ground floor room, it had been repopulated with civilians and, and, thanks largely to Lawrence Bragg, was setting the pace for postwar research in biophysics.

By the early 1950s, researchers had found — unexpectedly — that DNA is the molecular carrier of hereditary information across generations. Most had assumed that proteins were involved. A protein is a complex assemblage of amino acids. A piece of DNA, by contrast, is simple in composition. How could a substance so plain convey the genetic instructions for building complex organisms?

The mystery gave scientists a reason to investigate the molecule’s form and function. Bragg was drawn to the challenge, along with many others, including Linus Pauling at the California Institute of Technology. Pauling had recently earned acclaim for working out the three-dimensional shape of the alpha helix, a structural motif common to many proteins, and had lately displayed an interest in DNA. Sniffing competition, Bragg encouraged Watson and Crick to pursue the structure in 1951. The Rockefeller Foundation provided supporting funds for research in both laboratories.

The scientific stakes were high, so Bragg kept a close eye on the project and his young protégés. He even pressured them to abandon it when their first model proved unworkable. He wanted the Cavendish to be the first to the goal, but he also wanted to avoid embarrassing gaffes. When Watson and Crick put the finishing touches on their final design, Bragg checked and re-checked its correspondence with the available evidence, and when the paper disclosing the discovery was complete, he wrote a laudatory cover letter to the editors of Nature. Several years later, he nominated his charges for a Nobel Prize.

Naples Zoological Station
Naples, Italy
May 1951

Maurice Wilkins stood at the front of a lecture room, facing rows of seated scientists. He walked his audience through the steps needed to make crystals of DNA. His blonde hair was parted far to one side and his characteristic round glasses were perched on his nose. He had received the DNA from Rudolf Signer, he explained, at a conference in London the previous year. With help from a graduate student at King’s College, where Wilkins was a professor, he had spun the strands into tight fibers and bombarded them with X-rays.

At the end of his presentation, Wilkins flashed an image onto the projection screen. A blur of dots and lines whirled in circles around a hole in the center. It was far from crisp, but it had some semblance of organization. The crystallographers in the room understood that only a crystal would give rise to such a pattern. The image had a profound effect on at least one member of the audience. “Suddenly I was excited about chemistry,” James Watson wrote later. “Before Maurice’s talk I had worried about the possibility that the gene might be fantastically irregular. Now, however, I knew that genes could crystallize; hence they might have a regular structure that could be solved in a straightforward fashion.”

Maurice Wilkins was a physicist. Like many of his contemporaries, he was inspired to tackle the big biological questions posed in Erwin Schrödinger’s 1944 book, What is Life? Schrödinger asked how the physical laws that govern matter at the atomic level are translated into biological order in emergent phenomena such as cells and organisms. He postulated the presence of a material code that directs the workings of living cells.

Through World War II, Wilkins had worked on radar and radioactivity, but Schrödinger’s theorizing sparked his curiosity. He was in good company. Future Nobel Laureates Max Delbrück and Salvador Luria also made the switch from physics to biology, along with others, such as Leo Szilard, who had become disillusioned by the wartime association of physical science and weaponry.

In 1946, Wilkins accepted a position in a new biophysics unit at King’s College London, and commenced X-ray studies of biomolecules. In 1950, he collaborated on DNA with Rudolf Signer, an organic chemist at the Universität Bern. Signer possessed highly purified strands of DNA that his student, Hans Schwander, had extracted from calf thymus.

Wilkins put Signer’s DNA in an X-ray tube and snapped photos. The results were grainy but patterned. They showed that DNA could be crystallized. The work established Wilkins instantly as one of England’s leading molecular biologists. “At the time,” Watson wrote in The Double Helix, “molecular work on DNA in England was, for all practical purposes, the personal property of Maurice Wilkins.”

When Watson and Crick took up their modeling project, the Cambridge and London teams kept in contact through letters, phone calls, and occasional meetings. In November 1951, when Watson and Crick had assembled their first (incorrect) model of DNA, they invited Wilkins to Cavendish to take a look. In January 1953, when Watson visited London, Wilkins showed him a photograph of DNA, taken at King’s by Rosalind Franklin, a research fellow in his charge, which clearly indicated a helical structure. And a month later, when Watson and Crick had assembled yet another model — this time the correct double helix — they again invited Wilkins to Cambridge to review it.

Wilkins was later asked why Watson and Crick won the race to solve the structure. “I was a bit slow on the base pairing, I must admit,” he told Horace Freeland Judson. “I knew about Chargaff’s results, but I didn’t cotton on to the fact of a structural implication. Rosalind Franklin put me onto the wrong track. She said the structure couldn’t be helical.” Despite the error, Wilkins shared in the 1962 Nobel Prize.

Wilkins continued to study nucleic acids until his retirement in 1981. He confirmed the structure of the double helix with improved images, and then turned his focus to the functioning of the central nervous system. He also took advantage of his public visibility to advocate for nuclear disarmament.

After many retellings of the discovery, Wilkins’s contributions have become obscured by his famously rocky relationship with Franklin, but the first image showing the crystalline structure of DNA was created before Franklin joined his lab, and the informative crosstalk between Kings and the Cavendish involved the lab chief mainly, and not the research fellow. Franklin deserves credit, but Wilkins played an independent role.

He wrote about the messy interpersonal details in his autobiography, The Third Man of the Double Helix: “…this discussion of mistakes and muddles may lead nonscientists to believe that science is not reliable. Science can and does solve important problems for humanity, but it may take much hard work and hard discussion before the truth is pulled out of the muddle.”

Biochemist Erwin Chargaff became interested in DNA in 1944, when Oswald Avery’s findings indicated that it was the stuff of genes. He investigated whether the chemical composition of DNA is the same in every organism, and learned that it isn’t — he found variations in quantities of nucleotide bases (adenine, thymine, cytosine, and guanine) across DNA samples from different species.

Chargaff also observed interesting empirical regularities: although percentages of the four nucleotides were not equal and varied considerably, ratios of pyrimidine (adenine and thymine) and purine bases (cytosine and guanine) were invariant and very nearly 1:1. These relationships are now known as Chargaff’s Rules. The observations hinted strongly to Watson and Crick that DNA molecules incorporate nucleotides on the basis of either like-with-like or complementary base pairing.

According to Watson, Crick’s final test of the correct model involved a check against alternative base pairing schemes: “His quickly pushing the bases together in a number of different ways did not reveal any other way to satisfy Chargaff’s rules.”

King’s College
London, England
Summer 1951

Her hands moved expertly as she hunched over a large camera in the dark basement X-ray room. Her sleek black hair was pulled back tightly; her dark eyes focused intently as she added salt solutions to a tiny cuvette of DNA. The key to getting good pictures, she had discovered, was controlling the humidity inside the camera. With added water, the nucleic acid formed long, thin fibers. It was basic chemistry — she wondered why no one had tried it before. Now that she had it figured out, the structure seemed near at hand.

The work was slow — an image could take hundreds of hours to produce — but she was determined. She conducted trial after trial, refining her techniques. But while the pictures became clearer, she still struggled to understand them.

Rosalind Franklin was born in London in 1920. She found her passions early in life: science, math, hiking, and travel. As an undergraduate physical chemistry major at Cambridge, she immersed herself in her studies. Mineralogy, especially, captured her interests, and a strong undergraduate performance qualified her for a doctoral fellowship. The year was 1941; England was at war.

Franklin stayed on at Cambridge, studying the porosity of coal for the British Coal Utilisation Research Board. She received a PhD for the work, and in 1947, accepted a position in Paris at the Laboratoire Central des Services Chimiques de l’État. There she became skilled at analyzing coals and carbons using X-ray crystallography. In 1950, she sought a return to England and began applying for research fellowships.

A friend at King’s College suggested that she take up the study of large biological molecules, because it was an expanding area of research. Franklin wrote back: “I am, of course, most ignorant about all things biological, but I imagine most X-ray people start that way.” After a visit to King’s, she accepted an invitation from John Randall, the head of the biophysics unit, to study protein structures.

By the time she arrived, however, Maurice Wilkins, the assistant lab director, had convinced Randall that she should work on DNA. Wilkins expected collaboration, but Franklin demanded autonomy. Her experience at King’s and her working relationship with Wilkins suffered as a result.

Franklin quickly made an important discovery: DNA takes two crystalline forms. Relatively low humidity produces the dry ‘A’ form; more moisture produces the wet ‘B’ form. Higher water content elongates the fiber. Researchers had not previously controlled for humidity. They had haphazardly mixed the forms in samples, and were left with blurry X-ray images.

Franklin’s observation allowed her to produce crisper photographs, but she shared them only reluctantly. She sought ownership and control of her work while Wilkins continued to insist that the she had been hired to contribute to the lab’s collective effort. Tensions mounted. In an attempt to defuse the situation, Randall split responsibilities: Wilkins would tackle the B form of DNA, and Franklin the A form.

Eventually, Franklin arranged to transfer her fellowship from King’s to Birkbeck College at the University of London. Wilkins wrote to Crick, “I hope the smoke of witchcraft will soon be out of our eyes.” By this time, Franklin had taken photos of the A form from every conceivable angle, but she never saw a double helix. Calculations in her lab notebooks suggest that she envisioned a molecule with three or four winding chains.

In January 1953, Watson visited King’s. Wilkins showed him Franklin’s clearest image of DNA — photograph 51, taken the previous spring. Watson later recalled his visceral reaction: “The instant I saw it my mouth fell open and my pulse began to race.” He saw a double helix.

Photograph 51

At Birkbeck, Franklin abandoned DNA for structural studies of the tobacco mosaic virus. Again, she generated images of unsurpassed clarity. Her untimely death from ovarian cancer in 1958, perhaps caused by exposure to X-rays, cut short a distinguished scientific career. Only posthumously was her work on DNA publicly recognized. Her photographs were key pieces of evidence in the search for the structure of DNA.

In 1944, microbiologist Oswald Avery reported experimental results that led to an astounding conclusion. Avery was conducting microbiological research at the Rockefeller University Hospital in New York with two different strains of pneumococcus bacteria, a smooth-coated ‘S’ strain that causes pneumonia in mice and a rough-coated ‘R’ strain that does not.

One day, purely by accident, he transferred heat-killed S cells to a colony of R bacteria. He found, unexpectedly, that when the culture was injected into mice, they developed pneumonia. Somehow the R strain had been transformed and the S strain had been reproduced. Avery ran through an exhaustive battery of tests to isolate the causal agent(s). His findings indicated that the “transforming principle” was DNA. The experiments did not convince many of Avery’s colleagues. It was generally assumed that only complex molecules such as proteins could carry hereditary information. Geneticists were simply not prepared to accept that genes were made out of a humble nucleic acid.

Avery’s claim was corroborated in 1952 by the famous Hershey-Chase blender experiment performed at Cold Spring Harbor Laboratory on Long Island. Alfred Hershey and Martha Chase, worked with E. coli and bacteriophage, a virus that infects bacteria. They labeled the protein coats of the virus with S35, an isotope of sulfur, and the viral DNA with P32, an isotope of phosphorus, before introducing the virus to bacterial cultures. After incubation, they employed an ordinary kitchen implement, a Waring blender, as a centrifuge. They observed that most of the S35-labeled viral proteins were separated from the bacteria, but the P32-labeled viral DNA was not. On the basis of this evidence, Hershey and Chase proposed tentatively that viral DNA is injected and incorporated in bacterial cells but viral proteins are not. They surmised, in addition, that viral DNA alone accounts for bacteriophage reproduction. Skepticism about DNA’s genetic role became harder to sustain.

Cavendish Laboratory
University of Cambridge, England
mid-December 1952

Peter Pauling, a dashing twenty-one-year-old American student, sauntered into the Cavendish Laboratory. He had received a letter from his father, chemist Linus Pauling, and was eager to share its contents. Though many of their letters revolved around travel plans, cars, and the money that Peter needed to live in England, this one had scientific news. Linus Pauling’s Caltech lab had proposed a molecular structure for DNA. The news filled the Cavendish upstarts with anxiety. They had no details on Pauling’s new structure, and felt a sudden sense of urgency to conclude their own work as soon as possible.

By 1952, Linus Pauling had already achieved scientific eminence. He had been accepting the field’s highest honors for nearly two decades, and would soon receive a Nobel Prize for his research into the nature of chemical bonds. His work had paralleled Bragg’s for many years. Both had employed X-ray crystallography to determine biochemical morphologies. Pauling had resolved in three dimensions the fundamental structures that constitute proteins, and he had characterized the forces that hold them together.

Pauling’s preoccupation with proteins made him late to the DNA party: “I knew the contention that DNA was the hereditary material, but I didn’t accept it. … I thought that proteins probably are the hereditary material rather than nucleic acids — but that of course nucleic acids played a part. In whatever I wrote about nucleic acids, I mentioned nucleoproteins, and I was thinking more of the protein than of the nucleic acids.”

In The Double Helix, Watson describes Pauling as a constant adversary — he wanted to “beat him at his own game.” Pauling later downplayed the significance of his project: “We weren’t working very hard at it. I didn’t know there was competition — I wasn’t involved in any race.” It was only in occasional conversation and correspondence that Pauling considered the importance of DNA or thought about its structural properties.

For a month in late 1952, however, he gave the problems serious attention. He did not have much data, but still pondered and sketched possible structures. In the December 1952 letter to his son, who was working at the Cavendish, Pauling alluded to a structure that wound three strands into a helix — a model not unlike that proposed by Watson and Crick before they were redirected by Franklin. On December 19, 1952, Pauling wrote to Scottish biochemist Alexander Todd: “We have, we believe, discovered the structure of the nucleic acids.” The structure was, he added, “really a beautiful one.”

On the final day of the year, Pauling and colleague Robert Corey submitted the three-strand DNA manuscript to the Proceedings of the National Academy of Science. In January, Pauling sent copies to Cambridge. Watson and Crick got hold of one, examined the work, and were relieved to find that it contained errors. Pauling’s diagrams showed phosphate groups with neutralizing hydrogen atoms attached, which meant that the proposed molecule had no net charge — it wasn’t an acid. Somehow, the master had a made a fundamental error.

On January 30, Watson visited Wilkins’s lab and saw photograph 51. He and Crick made a final push to deduce the structure, now confident that it was a double helix. Today, Pauling is remembered as a great scientist who made many outstanding contributions to physical chemistry. His triple helix model of DNA wasn’t among them, but it spurred Watson and Crick to the finish line.

Physical chemists began studying crystals (solids comprising repeating arrangements of atoms), in the nineteenth century. Around the turn of the twentieth, physicists discovered and began working with X-rays, a form of electromagnetic radiation. In 1912, the two areas were combined by the English father-and-son Bragg team, and German contemporaries, who showed how and why crystals scatter X-ray beams in distinctive and predictable ways. Suddenly, scientists had a way to represent the invisible and to characterize atomic structures of interest.

In subsequent decades, English researchers applied the technique broadly and laid foundations for Wilkins and Franklin’s DNA studies. In the 1920s, John Desmond Bernal began working under the elder Bragg at the Royal Institution in London. After solving the structure of graphite, he moved to the Cavendish and became the first investigator to record X-ray images on film, and the first to crystallize biomolecules.

In the 1930s, two of Bernal’s students undertook protein studies that led eventually to Nobel Prizes: Dorothy Crowfoot Hodgkin worked on pepsin, vitamin B, and insulin; Max Perutz characterized hemoglobin. During the same period, ‘textile physicist’ William Astbury conducted X-ray studies of fibrous substances at the University of Leeds. In the course of examining keratin, wool, fingernails, and hair, he developed techniques for measuring helices. In 1937, he looked at DNA and took the first steps toward elucidating its structure. He identified patterned repeats in the molecule and determined that its constitutive bases lay flat and 0.34 nanometers apart.

X-ray crystallography remains an indispensable tool in molecular biology, physical chemistry, and drug discovery.

Cavendish Laboratory
University of Cambridge, England
February 27, 1953

Inspired by Franklin’s photograph, Watson sat in his office, arranging and rearranging cardboard cutouts. He had been staying up late at night, reading chemistry textbooks and making sketches. Now he was trying to reproduce his latest sketch in three dimensions. Watson believed that two connected strands wound around each other, but he was struggling to configure the nucleotide bases correctly. To his office mate, Jerry Donohue, he looked to be fumbling with a jigsaw puzzle.

Jerry Donohue earned a PhD in physical chemistry at Caltech in 1947, under Pauling’s tutelage. He subsequently stayed on in his mentor’s laboratory, conducting research on hydrogen bonds in organic crystals. In the fall of 1952, he accepted a fellowship from the Guggenheim Foundation to spend a year at the Cavendish, where he shared an office with Watson and Crick.

Donohue and Pauling continued to collaborate, despite the distance, and sent each other frequent letters with research updates. From this correspondence, Pauling became aware of Watson and Crick’s research on DNA, and Donohue kept abreast of Pauling’s. Initially, Donohue had little interest in DNA — he told Horace Freeland Judson that when he arrived in Cambridge, he “didn’t even know what a nucleic acid was” — but he was gradually drawn into the race.

For much of February, Watson had been working on a new model of DNA. “The real stumbling block,” he wrote in his book, “was the bases.” If the structure comprised a sugar-phosphate backbone on the outside, as Franklin insisted, then the bases had to be on the inside. It was “a frightful problem.” Watson couldn’t figure out how to connect chains with irregular sequences of bases. At night, he sat alone in his room, poring over a textbook, J. N. Davidson’s The Biochemistry of Nucleic Acids, in hopes of resolving the issue.

By the end of the month, Watson believed he had done it. He was convinced that DNA molecules consist of two chains with identical base sequences held together by hydrogen bonds. He saw that such a model could explain the transmission of hereditary information: two intertwined strands held together by like-with-like base pairing could be unwound, and each strand could serve as a template for the synthesis of a new double strand.

On the morning of February 27, Watson and Donohue were alone in the office (Crick generally arrived late). Donohue was expert on the very problem that had consumed Watson, the formation of hydrogen bonds. When Watson described his latest idea, Donohue saw immediately that it was impossible.

Nucleotides are tautomeric. They can alternate between two chemical forms, keto and enol, each with distinctive characteristics and properties (the difference lies in where hydrogen and oxygen atoms attach to the compounds). Watson had assumed that when stacked in a double helix, nucleotides exist in the enol form, giving them one particular shape and size. By the 1950s, chemists had agreed, and Donohue knew, that they ordinarily appear in the more stable keto form. Davidson’s textbook was out of date. The correction meant that Watson’s double helix with like-to-like pairing couldn’t be right.

After Donohue brought Watson up to date on nucleotide chemistry, the final model came together quickly: the placement of hydrogen atoms in the keto form made the bases available for complementary pairing in the interior. The structure explained Chargaff’s rules and suggested a mechanism for replication.

Donohue informed Pauling, in a letter dated March 20, that Watson and Crick had constructed “a very ingenious nucleic acid structure.” The discovery of the double helix was an interdisciplinary achievement. Prior to Donohue’s intervention, Watson and Crick were on a path not to scientific glory, but to an embarrassing mistake.

Afterword

The brief paper disclosing the structure was published in the April 25 issue of Nature. It included a reference to Pauling’s article and acknowledged contributions from Donohue, Wilkins, and Franklin. Two supporting papers from King’s College followed immediately in the same issue: one by Wilkins, the other by Franklin, with photographic evidence on the A and B forms of DNA.

The three papers make up perhaps the most important series in the history of biology. The discovery of the molecular structure of DNA led to revolutionary changes in science and society. In 1953, Watson and Crick could not have imagined the full implications of their achievement, but they saw a glimmer. “We knew,” Watson later wrote, “that a new world had been opened…”

— article by Sarah C. P. Williams

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