Women’s History Month – Rosalind Franklin

March is Women’s History Month. Rosalind Franklin was  a key figure in the discovery of DNA’s structure. She was an X-Ray Crystallographer who was working at King’s College in the UK at the same time as Watson and Crick who were at Cambridge. This all took place during the transition of King George VI of England and Queen Elizabeth. At the time, biologists knew there were such things as nucleic acids in cell nuclei and that genes were the “stuff of inheritance” but scientists were clueless as to how DNA was structured and “what was a gene”. Remember that patterns of predictable inheritance of genes had been worked out by Gregor Mendel decades before in the late 1800’s but in the early 1950’s nobody knew what a gene was. Watson (British) and Crick (a visiting USA researcher) were attempting to determine the structure of DNA. They were virtually doing it in their spare time as they had other research roles at The Cavendish Laboratory at Cambridge. They were more-or-less stuck, their physical models of DNA just did not fit (i.e., the physical constraints of the molecules Adenine, Thymine, Cytosine and Guanine along with deoxyribose (5-carbon sugar) and Phosphorus did not arrange properly). Watson traveled to King’s College because he and Crick had heard about Franklin’s successes in using X-ray crystallography to determine the shape of DNA. Rosalind Franklin’s supervisor at King’s College was Maurice Wilkins. Franklin was opposed to prematurely building theoretical models, until sufficient data were obtained to properly guide the model building. Wilkins gave Watson a more-or-less unauthorized peak at Franklin’s’ famous “Photograph 51” (below).

While returning on the train to Cambridge Watson scribbled down a diagram based upon his brief viewing of Photograph 51. When he showed his drawing to Crick it was a watershed moment because Watson immediately recognized it as a double helix. Crick had taught himself the mathematical theory of X-ray crystallography. Also, Crick’s access to a progress report by Franklin late in 1952 made Crick confident that DNA was a double helix with antiparallel chains (for students of Genetics, see the technical addendum below).

Watson and Crick finished building their model on 7 March 1953. To be fair Watson might not have completed the model if he had not got a vital tip from the son of U.S. scientist Linus Pauling. Pauling senior in the U.S. was also attempting to define the structure for DNA. Pauling’s son was visiting in Cambridge and told Watson that he was using the wrong forms of the four bases and he should talk to Jerry Donohue, an American crystallographer who was also working at Cambridge at the time. The bases occur in “enol” and “keto” forms which affects their size and symmetry. Watson and Crick had been building their model with “enol” shapes that did not fit. When Watson started cutting out cardboard molecules using “keto” dimensions it worked! A beautiful, symmetrical, twisted and tilted double helix emerged!

Watson and Crick together developed a model for a helical structure of DNA, which they published on 25 April 1953 in the journal “Nature.” Franklin viewed their model in early April. She was gracious and remarked on its beauty and simplicity. She also published an article of her X-ray work in the same issue of Nature (this was an arrangement to recognize properly her contributions).

In 1962 the Nobel Prize was subsequently awarded to Crick, Watson, and Wilkins (they had been nominated in 1960 and 1961). Nobel rules now prohibit posthumous nominations (though this statute was not formally in effect until 1974) or splitting of Prizes more than three ways.  Later, Franklin commenced deciphering the structure of the polio virus while it was in a crystalline state but was forced to end her work due to her rapidly failing health. Rosalind Franklin died in 1958 from cancer.  After her death, her research group headed by Klug completed the polio virus work and published the results in 1959. Klug was the sole winner of the Nobel Prize in Chemistry 1982 for his work he started while working for Franklin. This work was exactly what Franklin had started and which she introduced to Klug, and it is highly likely that, if she were alive, she would have shared Klug’s Nobel Prize. Rosalind Franklin’s photo called “Photograph 51” probably was the single most important discovery which accelerated the discovery of DNA’s molecular structure. What followed was Crick’s “Central Dogma” where the bases of DNA dictate the bases of RNA which in turn define the sequence of amino acids in proteins. 

Actress Nicole Kidman portrayed Rosalind Franklin on stage in “Photograph 51” Kidman won at the 2015 London Evening Standard theatre awards for her portrayal of the overlooked DNA scientist Rosalind Franklin in “Photograph 51.”

Life Story (also known as The Race for the Double Helix in the United States) is a 1987 television historical drama which depicts the progress toward, and the competition for, the discovery of the structure of DNA starring a young Jeff Goldblum as Jim Watson (the US half of Watson and Crick).

Addendum For Genetics Students

Antiparallel means that one side of the DNA is oriented 5’ to 3’ and the other 3’ to 5’ where 3’ and 5’ are Carbon molecule positions on the 5-carbon sugar molecule deoxyribose in DNA. In other words, the two sides are pointed in opposite directions. 

The X-Ray Crystallography (photograph 51) performed by Dr. Franklin showed that DNA was 20 Angstroms wide and that bases were 3.4 Angstroms apart. Every 10 bases or every 34 Angstroms DNA makes one complete turn. The complete turn includes what are termed “minor grooves” and “major grooves.” In deoxyribonucleic acids (DNA), the nucleotide bases guanine and thymine are in keto form, and adenine and cytosine are in amino form (20 Angstrom width for the pairs).  Dr. Franklin had also reported that the dark shadows outside the X-pattern in Photograph 51 were likely due to Phosphorus being on the outside of the DNA molecule (i.e., the outside of the double helix with the bases being in the inside).

Watson and Crick were familiar Chargaff’s observation that the molar amounts of A and T are always equal, as are G and C in DNA. The trick was building a model for the molecule. Watson and Crick were building models using the wrong tautomers (e.g., enol and imino forms) of the bases (since those were the structures in textbooks) until the organic chemist Jerry Donohue (a laboratory partner) told them to use the keto form of thymine and guanine  and the amino forms of adenine and cytosine. In the enol/imino forms these two bases could not fit a 20 A DNA molecule. But in the keto/amino forms they fit the 20 Angstrom model predicted by Photograph 51.