Why Rosalind Franklin Should Have Won The Nobel Prize

In 1962, the Nobel Prize in Physiology and Medicine for discovering the twisted-ladder structure of deoxyribonucleic acid (DNA) was awarded to James Watson, Francis Crick and Maurice Wilkins. 

The result was due to a collaboration between two leading research team in the UK. The first was the Cavendish Laboratory, Cambridge, consisting Sir William Bragg, Jim Watson, Francis Crick, and John Kendrew and Max Perutz, and the other at King’s College, led by Sir John Randall, Maurice Wilkins, Raymond Gosling and Rosalind Franklin. 

The work from these teams revolutionised the modern field of molecular biology and genetics. However, only three of these scientists could forever rest in the light of glory – and one of these victors should have be Dr Rosalind Franklin. 

 

Watson and Crick had no evidence on what DNA looked like

Granted, Watson and Crick were early to recognise that the key to inheritance was understanding the three-dimensional form of DNA. In 1951, the pair hoped to solve the DNA structure by building molecular models based on existing experiments. From the work of Phoebus Levene and Alexander Todd, they knew that DNA mainly consisted of a repeating deoxyribose sugar-phosphate backbone, which was made of individual nucleotide building blocks (Levene et al., 1919; Todd, 1958).

They were also aware that DNA was the fundamental genetic material due to the works of Avery et al. (1944). They knew that DNA could be modelled into single-stranded alpha helices thanks to Linus Pauling (1948), and that the four DNA bases – the purines adenine (A) and guanine (G), and the pyrimidines cytosine (C) and thymine(T) – vary significantly between species, as described by Erwin Chargaff et al. (1950).

However, no comprehensive image of the structure existed in those days, aside from the two dimensional X-ray diffraction images taken by Astbury and Bell in the late 1930’s, which themselves were of crude quality.

 

This aluminium template representing the base thymine (T) is part of Crick and Watson’s model of DNA (Wikimedia Commons).

 

She corrected Watson and Crick’s incorrect DNA model

By combining Crick’s knowledge of physics and X-ray crystallography with Watson’s background in bacterial genetics, the pair composed a physical 3D representation of DNA. However, their initial models were far from accurate: some contained triple helices, whereas others showed the four bases protruding outward instead tucked between the backbones. Furthermore, their models incorrectly displayed guanine and thymine in enol instead of keto forms and did not follow Chargaff’s rules of base pairing, showing adenines bound to adenines. Their model gave no clear insight into the self replicative nature of DNA, since the nucleotide ladders ran parallel, instead of anti-parallel. Some of these errors were due to misunderstandings in basic chemistry, such as the configuration of elements in thymine and guanine (specifically, the carbon, nitrogen, hydrogen, and oxygen rings).

Regardless, the researchers presented their model to the King’s College team. It’s  faults were obvious to Rosalind Franklin, an expert X-ray crystallographer studying DNA with state of the art X-ray cameras.

She pointed the lack of evidence available for the proposed helix configuration, voiced that the model should contain more water molecules, and was sceptical of the electrostatic sodium bridges in Watson’s and Crick’s DNA model.

Franklin’s feedback made the Cavendish team to rightfully retaliate back to the drawing board.

 

Franklin unraveled the correct DNA form

Franklin’s own work at the time further reveals her superior understood the nature of the molecule. In 1952, 16 months before Watson and Crick published their Nobel winning structure, Franklin took one of the most advanced X-ray images of DNA to date. I have had the privilege to meet Anne Sayre, a personal friend of  Franklin, who has kindly sent me some of Franklin’s early notes on this photograph 51.

According to Franklin, the x-shaped diffraction pattern seen in the image suggests “a helical structure (which must be very closely packed) containing 2, 3 or 4 co-axial nucleic acid chains per helical unit, and having the phosphate groups near the outside.” Franklin calculated the exact diameter and double helical structure of the right-handed “B-form” DNA molecule. She presented her findings on the B and A-DNA forms at a symposium and correctly stated that the phosphate backbone lay on the outside of the structure: “Conclusion: Big helix in several chains, phosphates on the outside, phosphate‐phosphate inter-helical bonds disrupted by waste phosphate links available to proteins.” Only several months later Watson and Crick catch on to any of these observations.

A- and B- DNA X-ray diffraction patterns (Wikimedia Commons).

 

Furthermore, Franklin used her data to solve the A-DNA structure in another organism. Her A-form images had better crystalline dot patterns, compared to the B-DNA, which allowed for unambiguous, albeit tedious, structural analysis using Patterson functions. After Randall had decided to end the DNA research at King’s College, Franklin analyzed the tobacco mosaic virus structure at Birkbeck College. Based on her previous knowledge, she demonstrated the helix structure of A-form viral RNA between 1953-58.

Therefore it seems likely that Franklin had solved the B-form DNA helix structure without the help of her colleagues, had she obtained more research time at Cambridge.

 

Watson and Crick had significant outside help

Unlike Franklin’s work, Watson and Crick’s model building was influenced by the council of other academics. The American physical chemist Jerry Donohue in particular made a significant correction to the Watson and Crick’s DNA model by pointing out the incorrect carbon, nitrogen, hydrogen and oxygen rings of thymine and guanine. Donohue’s advice caused Watson to rearrange the hydrogen atoms in their base models such that they bonded to nitrogen instead of oxygen. This form enables the neat A-T and C-G pairing suggested by Chargaff’s rules, and fits the bases inside the sugar-phosphate DNA backbone, forming a twisting double helix ladder.

How long until Watson and Crick had figured this out themselves is a topic for endless speculation.

 

Watson and Crick stole and published Franklin’s data

The double helix structure was supported by Franklin’s images, which dubiously fell in the hands of Watson and Crick. In early 1953, Wilkins took some of Franklin’s x‐ray photographs of the B-formed DNA without her knowledge and showed them to Watson. Also unknown to Franklin, the men obtained a write‐up copies of Franklin’s work from her other colleague, Max Perutz. Franklin’s work confirmed that the two backbones were held together by complementary base pairing, with the four bases wound around a common axis in a crucially antiparallel configuration. Her findings clearly re-awakened DNA model work at the Cavendish Lab. By the end of March the same year, Watson and Crick built a final version of the B-DNA structure.

Before publishing, they ruthlessly presented the work to Franklin, who was completely unaware how her work had shaped the model. In addition, her credit was diluted in the published DNA paper in Nature Magazine, in which her name appeared as a side mention, bundled together with those of her co-workers at King’s College.

 

Evidence of personal conflict

Although Watson and Crick published the first DNA structure, I am baffled by a rumour of Maurice Wilkins being the third Nobel Prize candidate. Despite producing his own X-ray images of B-DNA, Wilkin’s and Perutz’ contribution to the DNA structure discovery seems to have been delivering Franklin’s work to the Cavendish Lab. However, being an old wartime friend of Crick’s may have made Wilkins a more favorable working partner, rather than their less amenable female colleague. In fact, personal quarrel between Franklin, Watson and Crick may have fuelled the belittlement of her contribution. Further, Franklin’s criticism of Watson and Crick’s first model may have been a humiliating setback, which fuelled resentment and the revenge-like justification for using Franklin’s X-ray images without her knowledge.

 

To conclude…

Evidence suggests that the evolution of Watson and Crick’s DNA model depended on the profound work of Rosalind Franklin. Her x-ray images enabled the correct modelling of the antiparallel double DNA helix, and without it Watson and Crick would perhaps still be in the dark. However, teamwork and data sharing enabled Watson and Crick to solve the structure faster than Franklin. Franklin gathered and analysed her data by herself, often competing against colleagues even within her own lab, and chose the long, systematic rout in finding the B-DNA structure.

So we should beg the question – what is the purpose of the Nobel Prize?

Is it a symbol of scientific excellence and advancement, and deep impact left to society as a whole, or a trophy given to those who reached the finish line? Acknowledging Franklin’s work would have been a vocation against data theft, a protest against toxic scientific competition, as well as a victory for the hard labouring female scientists of our time. By contrast, awarding the Nobel to Watson, Crick and Wilkins encouraged the sexist atmosphere present among geneticists and discouraged future female scientists to trust and prosper alongside their male colleagues.

We can only hope that the future scientific committees will reward diligence rather than velocity.

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