It’s the last day of February in 1953. An odd pair – one a tall, lanky 25-year-old American microbiologist, the other a 37-year-old British physicist – burst into the Eagle pub in Cambridge. Interrupting the lunchtime chatter of the patrons at the bar, the elder announces, without the slightest hint of irony, that they “had found the secret of life!”. That morning, 70 years ago, James Watson and Francis Crick finally cracked the double helical structure of deoxyribonucleic acid: DNA.
This tale is recounted in James Watson’s 1968 account of the discovery of the structure of DNA, The Double Helix. I first read the book in the 1990s, after it was recommended by one of my biochemistry lecturers. I remember being quite enthralled by the personal account of Watson’s chaotic approach to his science. It broke a stereotype I had subscribed to, that scientific endeavours have to take a linear, methodical approach. It resonated with me and my own way of working.
Many years later and it was my turn to stand behind the lectern and face a theatre full of young minds. As I clicked through my slides I remembered how deeply The Double Helix had influenced me and considered whether to add it to my own course’s reading list. Back in my office I dusted off my old copy of Watson’s book.
This time round the book had a very different effect. Watson came across as ambitious and brilliant, but also arrogant and happy to openly voice prejudices (a characteristic he displayed throughout his life). Early on in the book, he introduces his collaborators at King's College London, dedicating several pages to denigrating Rosalind Franklin – whose invaluable contribution to the DNA story is now well known. He persistently calls her Rosy, a diminutive that he knew she disliked, describing how her colleague Maurice Wilkins treated her as an assistant. He finishes the chapter by saying “The thought could not be avoided that the best home for a feminist was in another person’s lab.”
Photo 51
Among her other achievements, Rosalind Franklin and her PhD student Raymond Gosling produced one of the most famous images in science: Photograph 51, a diffraction pattern created by shining X-rays through a crystal of DNA. The photo shows a blurry, spotty cross. To those initiated in crystallography, it positively screamed “helix”. But, more subtly, locked within the shape of the cross, and eventually deciphered by Franklin and Gosling, were the precise dimensions of the DNA’s form.
Photo 51 and the detailed structural information it contained became crucial to Watson and Crick’s endeavours. The pair never once conducted an experiment on DNA themselves. Instead, they took a more theoretical approach, gathering all available information and using these data to inform the building of physical, often cardboard, models. The crucial, keystone, piece of data was contained in Photo 51.
The commonly accepted narrative is that the pair obtained the photo not from Franklin, but instead from her colleague Wilkins, who shared the photo without Franklin’s permission or knowledge. The importance of the spotty cross was immediately apparent to Watson, who describes his first glimpse of it in The Double Helix: “The instant I saw the picture my mouth fell open and my heart began to race.” The implication is that Franklin did not appreciate the meaning of the image herself.
Recently, however, professors Matthew Cobb and Nathaniel Comfort unearthed a draft news article for Time magazine from 1953. The article was never published but hints at a different set of events. Writing in Nature on the 70th anniversary of the publication of the original DNA papers in the same journal, Cobb and Comfort describe the draft news article, which was written in consultation with Franklin. It portrays the DNA work as being carried out through an equal collaboration between two teams: one based at King's College London, which included Wilkins and Franklin; the other at the Cavendish laboratories in Cambridge, comprised of Watson and Crick. The London team collected experimental data, whilst the Cambridge duo used the information to build a structural model.
The article describes an exchange of information, including Franklin “checking the Cavendish model against her own X-rays’ data”. In this narrative Franklin is an equal member of a group of four leading scientists. Given that Franklin was a skilled X-ray crystallographer, while Watson was a relative newcomer to the field, this fresh description of events does seem more plausible.
The photo was the framework into which the rest of the DNA puzzle pieces fit. It provided the three-dimensional constraints for those pieces, which when slotted into place revealed the details of the double helix.
Almost a century of research informed this revelation. First, a clear understanding of DNA’s chemistry was required. This gave Watson and Crick the shape of their puzzle pieces and how they interacted with their neighbours. Second, the biological role of DNA needed to be understood. When Watson and Crick started their work, it was not at all clear that DNA carried genetic information. Instead, it was generally suspected that proteins were responsible.
The concept of genetic inheritance begins with Gregor Mendel and his famous work on peas. Over the course of eight years he systematically cultivated, crossed and observed almost 30,000 plants. Eventually, he noticed patterns and arrived at some basic rules of inheritance, including the concepts of recessive and dominant genes. He published his work in 1865, but of course at the time the molecules and mechanisms that underpinned these rules were entirely unknown.
Those that came before
To find the very beginning of the thread that ties DNA with inheritance and culminates in Crick’s lunchtime proclamation in the Eagle pub, we have to go back a little earlier, and travel to Tübingen, Germany. There, a laboratory led by Felix Hoppe-Seyler was busy establishing itself as the first research group in Europe dedicated to understanding the chemistry of life. At the time, this largely meant focusing on proteins, a relatively recently discovered class of biological molecule.
Hoppe-Seyler was a prestigious and inspiring character, who frequently changed the course of careers of aspiring scientists. Johann Friedrich Miescher had already graduated as a medical doctor but was persuaded by Hoppe-Seyler to turn from medicine towards research and join his lab (which was actually a converted kitchen) to work on physiological chemistry, as it was then known. The young Miescher was tasked with extracting proteins from leukocytes, or white blood cells. This was a rather unenviable project given that the most viable source of leukocytes was pus-soaked bandages picked out of the buckets in surgical wards. Nevertheless, Miescher diligently toiled, isolating several proteins and also something else.
Something that had a quite different chemical composition, lacking in sulfur and plentiful in phosphorous. Something that was only found in the nucleus of cells. In reference to its source, he named the material “nuclein”. Some years later, one of Miescher’s students demonstrated that nuclein was acidic and so renamed it nucleic acid: the NA in DNA.
Meanwhile, the ever-energetic Hoppe-Seyler had upped sticks and established himself as a professor of chemistry in Strasbourg. There, he turned the head of yet another medic. The task for the convert, Albrecht Kossel, was to better understand the chemistry of Miescher’s molecule. Kossel soon worked out a formula for nuclein: C₂₉N₄₉N₉O₂₂P₃. This didn’t reveal much about the molecule’s structure. Nevertheless, Kossel’s interest was piqued. Over the course of 16 years he set about isolating the chemical components that came together to form nuclein.
One component had already been isolated from bird guano, or excrement, and had been given the name “guanine”. For the rest, Kossel needed thousands of kilos of animal organs rich in nuclein. So, he formed a relationship with a local slaughterhouse which provided him with a steady stream of pancreas and thymus. From these organs, Kossel eventually isolated “adenine”: a name derived from the Greek “adenas” meaning “gland” (in reference to the pancreas) and “ine” meaning “contains nitrogen”. From calf thymus he extracted two more compounds which he named “thymine” (after “thymus”) and “cytosine” (from “cyto” meaning cell). This nomenclature is the names of the four fundamental bases that make up DNA. And so, Kossel gave us the DNA alphabet; the letters ATGC, now so familiar to us.
Having isolated the building blocks of DNA, it fell to a prolific chemist, Phoebus Levene, to work out the chemistry linking them together. Over a period of two decades at the beginning of the 20th century, Levene investigated the building blocks of nucleic acids and revealed that they are composed of just three distinct chemical components. A phosphate group, a five carbon sugar, and one of the four bases (guanine, adenine, cytosine and thymine). Just as importantly, Levene also worked out how the components were linked together to form what he called “nucleotides”.
Despite DNA being under their noses (and up them too, given the prevalence of bird poo and offal), none of the big players – including Kossel, Miescher and Levene – understood its true significance. They were still convinced that only proteins were large and complicated enough to carry genetic information. Their research on DNA, therefore, was a sideline. Many believed it to be a storage molecule for phosphorous, or maybe a structural molecule.
Paving the way
Others very nearly uncovered DNA’s true role. As early as 1927, the great Russian biologist Nikolai Koltsov came uncannily close to the truth in his description of the mechanism by which DNA replicates and stores information. He predicted that inheritance would occur via a “giant hereditary molecule” consisting of “two mirror strands that would replicate in a semi-conservative fashion using each strand as a template”. But despite his extraordinary insight into the mechanisms of inheritance, Koltsov was not able to go against the dominant scientific thinking of the time, and like everyone else presumed that proteins were the agents that stored genetic information.
But the dogma was slowly shifting. The idea that DNA might have a role in inheritance was beginning to be expressed. One frequently overlooked voice was that of Florence Bell. In 1939, she was a PhD student in the lab of William Astbury, a professor in Leeds with a prestigious reputation for his work on the structure of fibres. In Bell’s doctoral thesis, which was focused on the X-ray diffraction of nucleic acids, she wrote: “Possibly the most pregnant development in molecular biology is the realisation that the beginnings of life are closely associated with the interaction of proteins and nucleic acids.”
Bell’s work paved the way for Rosalind Franklin and Raymond Gosling. She produced the first X-ray images of DNA. The images are blurry because, unbeknownst to Bell and Astbury (and everyone else), DNA could take two subtly different structures, and their sample contained a mixture of both. Nevertheless the image revealed that DNA adopted a regular structure and allowed them to determine some key dimensions of the molecule, specifically the distances between the As, Ts, Gs and Cs, in each step of the DNA ladder.
Bell and Astbury’s Nature paper in 1938 described these DNA nucleotides as being stacked like “a pile of pennies”. This information fed directly into Watson and Crick’s models. Unfortunately, Bell’s work was curtailed by the outbreak of the Second World War. She joined the Women’s Auxiliary Air Force as a radio operator, later married a US serviceman, emigrated and worked as an industrial chemist in Texas.
There is a strange footnote to the history of the Astbury lab. Following the war and having lost valued researchers such as Bell (whom he had tried his best to retain), Astbury rebuilt his group and in 1951 received fresh samples of DNA. He directed another PhD student, Elwyn Beighton, to shine X-rays through them, just as Bell had done over a decade before. This new sample contained just one form of DNA, and so it was much sharper than Bell’s images. Beighton’s photograph is near enough identical to Photo 51, but precedes it by a year. Bizarrely, however, Astbury showed very little interest in the photo and so never published or even presented it at a meeting. Had he done so, the Nobel prizes and familiar names associated with the structure of DNA might have been quite different.
Too little, too late
A breakthrough was needed. It came in 1944 when Oswald Avery, Colin Macleod and Maclyn McCarty carried out a meticulous study showing that the characteristics of a bacterium could be altered by “transforming” it with DNA and only DNA. The final nail in the coffin was the theory of protein-based inheritance, hammered home by Martha Chase and Alfred Hershey with their famous “blender experiment” in the early 1950s.
At the time it was known that bacteriophages (viruses that infect bacteria) are comprised of a protein shell encapsulating DNA. Chase and Hershey “tagged” the protein and DNA, by introducing radioactive isotopes of sulfur to the protein, and radioactive phosphorous to the DNA. This labelling system allowed them to follow the whereabouts of the different molecules. They then infected bacteria with their radioactive phages.
The phage rapidly proliferated inside the infected bacteria, indicating some form of genetic material had been transmitted to the bacteria. Traces of radioactivity could only be detected in bacteria that had been infected with labelled DNA, and not the labelled protein, clearly indicating that DNA and only DNA had been injected into the bacteria. The pair went on to categorically prove that DNA originated from the phage by whizzing the broth of newly infected bacteria in a modified kitchen blender. This knocked the phage off the surface of the bacteria. When they then looked for the location of the labelled protein, it was in solution, along with the now empty phage capsules, whilst the labelled DNA had been injected into the bacteria.
Thus, Chase and Hershey conclusively showed that DNA was the molecule of inheritance. Hershey went on to win a Nobel Prize in 1969. Sadly, in yet another story of women losing out, Martha Chase went on to lose her job and leave science, at the age of 37. Little more of her life is on record, apart from a few obituaries when she passed away in 2003.
Without Chase and Hershey’s insights into the secrets of life, it is doubtful that James Watson and Frances Crick would have put so much effort into DNA. When Hershey died in 1997, Watson said in a memorial article that “the Hershey-Chase experiment . . . made me ever more certain that finding the three-dimensional structure of DNA was biology’s next important objective.”
In recent times, more light has been thrown on the contribution of women scientists to the story of DNA. However, it can feel like too little, too late. It took the best part of 70 years for Rosalind Franklin’s contributions to be fully appreciated. Often described as the “Dark Lady of DNA”, Franklin has now been the subject of multiple biographies. In 2015, Nicole Kidman played her in a West End show named “Photograph 51” after Franklin’s famous image.
It is a shame that Martha Chase and Florence Bell, who provided equally important insights and influence, are not as widely recognised. The pivotal blender experiment does bear Chase’s name, but most people who are familiar with the experiment are unaware that Chase was a woman. Meanwhile, Florence Bell remains almost entirely unknown.
In The Double Helix, Watson claims it was Crick who rushed into a nearby pub and blurted out that they had found the “secret of life”. The announcement in the Eagle pub has since gone down in scientific history. According to Gosling, when Rosalind Franklin heard about it a few days later, she commented, “We all stand on each other’s shoulders.” Quite whose shoulders she meant we cannot know, but I like to think she was paying tribute to the likes of Bell, Chase, Gosling, Miescher, Kossel, Levene and many more besides.
Editor's note: This article was updated on 9 May 2023 after new information about the story of Photo 51 came to light.
This piece is from the New Humanist spring 2023 edition. Subscribe here.
