The Dark Lady of DNA

"She had been getting remarkable results. The only researcher working at high humidity, determined to get the best possible photographs before embarking on interpretation, she took sharp clear pictures that revealed something no one had noticed before. There were two forms of DNA. When hydrated, the figure became longer and thinner. ... All earlier attempts to understand DNA's structure had been looking at a blur of the two forms. ... This achievement was essential to the great discovery that lay in wait."

(page 153)

Rosalind Franklin was one of the primary actors in the search for the structure of the DNA molecule. In 1968 James Watson published The Double Helix, his personal account of the elucidation of the structure of DNA, in which he de-emphasized Rosalind Franklin's critical contributions during the period of discovery, while drawing a negative portrait of her.  Franklin did not receive the Nobel Prize for this discovery, but Watson and Crick did. Why not? Rank villainy? Brenda Maddox does a superb job of sorting out Franklin's complex story.

Franklin, working in the King’s college lab under John Randall, took the influential X-ray crystallographic photo of the B form of DNA, photo 51. Watson and Crick, working in the Cavendish lab under Lawrence Bragg, relied on her information, along with several other lines of evidence and theoretical work, and emulated Linus Pauling by building actual physical models of the molecule of life, finally producing the correct model. They published their model in 1953 in the periodical Nature, along with separate papers by Franklin and Maurice Wilkins of King’s describing the crystallographic evidence. This method of publishing was intended and received as a direct acknowledgement of the critical contribution to the solution made by the various parties. (Think of the periodical Nature as the door of the scientific Wittenberg church.)

Franklin left her work on DNA in 1953 to pursue other topics, handing it over to Wilkins; she died five years later, still four years before the Nobel prize was awarded for the discovery of DNA. Nobel prizes are not awarded posthumously, so Franklin was no longer a candidate for the award. Wilkins was awarded the Nobel prize along with Watson and Crick for the DNA discovery.

The first biographer of Rosalind Franklin was Anne Sayre, who wrote more of a defense of her friend than a balanced history. In her book Rosalind Franklin and DNA, she argued that Franklin was ignored and treated shabbily by the men's club of British science; certainly Watson's tone in The Double Helix supported that hypothesis. (Of course, Watson was indiscriminately harsh to everyone in his book.) Sayre had real difficulty separating her feelings about her friend from a more careful assessment of Franklin's role in the discovery of the structure of DNA. The subsequent book by Brenda Maddox, The Dark Lady of DNA, is much better.

Brenda Maddox’s treatment of Franklin’s story is well-researched, broader, and much more nuanced. Maddox certainly found much to support the idea that at the time, women in science, few in number, and Franklin in particular, bucked up against a great deal of sexist prejudice and dismissal. But she also noted that Franklin herself had had good opportunities and comfortable working relationships in the labs she worked in before and after her DNA work, performing and getting appropriate credit for first rate work, and suggested that some of the problems she encountered, some alluded to by the crass Watson, were specific to her situation in that lab.

Maurice Wilkins led the DNA research efforts at King’s lab prior to her arrival. Franklin, a leading practitioner of X-ray crystallography, was recruited by Randall to join the lab to study protein solutions. Wilkins asked Randall if she could be assigned to the DNA problem, to which he agreed. Yet when she started, new to DNA and building on Wilkins’ research, she proved largely unwilling to work with him. Why?

Randall had deliberately misled Wilkins and Franklin about their roles in the lab, telling the newcomer Franklin but not Wilkins that she alone would now be responsible for the DNA research, and gave her the most up-to-date equipment and the best DNA samples to work with, all of which had been acquired by Wilkins. Randall pitted the two researchers against each other rather than foster cooperation between them. The result was damaging to both of their efforts. It poisoned much of the communication in their lab and between the King’s and Cambridge labs. In particular, Wilkins expected and repeatedly sought collaboration with Franklin, with little success. A persistent bitterness and emnity from Wilkins towards Franklin resulted.

The Science

Prior to Franklin’s arrival, Wilkins had extended William Astbury’s work on DNA. Wilkins was the first to recognize that DNA could, under the right circumstances, form crystals, and improved the techniques of filming them, taking the first clear pictures. He validated Astbury’s measurement of the helical width, 20 Ångstroms, and the inter-base repeat of 3.4 Ångstroms, and his early pictures hinted at a helical structure.

After Franklin arrived, Wilkins never quite adjusted to the uncomfortable situation. With inferior equipment and material, he still made further crystallographic progress. Working with Alexander Stokes’, they applied Stoke’s helical diffraction theory to his experimental results, and tentatively concluded that DNA was helical.

Franklin, despite the tension in the lab, produced critical experimental results. She was the first to determine that there were two structurally distinct forms of DNA, which she labeled A and B. It is the B form that is found predominantly in nature; previous X-ray photos of DNA were usually blurred due in part to their being a mixture of the A and B forms. Her measurement of the length of the B form helical repeat, 34 Ångstroms, the height of a single complete turn of the helix, was a new discovery.

Her other crystallographic results, including photo 51, provided clearer evidence of the helical structure; provided additional measurements of the helical width and inter-base distance, validating Astbury’s and Wilkin’s measurements; provided more accurate density and humidity measurements (aiding in a determination of the number of chains in the molecule, two); provided clearer arguments and evidence that the bases were in the interior rather rather than on the outside of the molecule; and finally identified the correct symmetry group, which allowed Crick to determine that the two chains were going in the opposite direction of each other. (Interestingly, Franklin did not catch this.)

Crystallography involves shining X-rays through the target crystalline DNA molecule (meaning the molecule had been prepared in a way that the conglomeration of target molecules in the sample were in a very regular structure), which then were scattered in a unique way determined by the internal atomic structure of DNA, exposing film in a spot pattern particular to DNA.

Franklin did make some of her own attempts to solve the structure using mathematical techniques. This analysis of the X-ray patterns was an attempt to work backwards from the spots on the photo and figure out what the structure of the molecule was by the way the light was deflected from the direction of the original source of X-rays, a little bit like a criminologist determining the direction from which a bullet was fired by working backward from the bullet embedded in a wall. The crystallographic analysis is much more complex than the problem the criminologist has, particularly in the case of DNA, composed of many atoms in a complex arrangement, all of which can affect the scattering of the incoming X-rays.

Franklin’s analysis bore fruit, but it did not lead her to to the solution (note 1); ultimately, the crystallographic evidence was itself simply insufficient to fully reveal the structure.

The Importance of Collaboration

"Politeness, Francis Crick said ... is the poison of all good collaboration in science. The soul of collaboration is perfect candor, rudeness if need be."

-Judson, Eighth Day of Creation, p 149

Francis Crick may have said it best, that Rosalind just needed someone to talk things over with, to collaborate with, like he and Watson had fallen into, and then she may well have been able to get past her own sphere of knowledge and approach to find the structure of DNA first. Aaron Klug said something similar, after he had analyzed her notebooks from her DNA research.

Having closed the door to Wilkins, and seeing no value in working with Watson and Crick, whom she saw at the time as rank amateurs, Franklin’s only collaborator in DNA research was her post-doc assistant, Raymond Gosling. Gosling has weighed in on collaborating with Franklin:

"I think you've got to remember that it was difficult for women in science, much more then than it is now. ... She was shy, I think - certainly not the person to let her imagination fire up openly about structural ideas to somebody like Maurice. But we used to have terrific arguments together. Her great strength was that you could have this very frank discussion about the work, and it never got personal, it was objective, and it would push along to reach somewhere. But she would never get like that with Maurice. She would do that with me. And if at that time she had had someone of her own standing to have those frank and fierce discussions with, it might have helped. And I felt repeatedly that Maurice was trying various ways to stimulate Rosalind into saying something about the structure, but she for her part would say, 'We are not going to speculate, we are going to wait, we are going to let the spots on this photograph tell us what the structure is.' And so since there was nobody here Maurice could talk to who was willing to speculate about the structure, he talked to Crick and Watson about it."

(Judson, Eighth Day of Creation, p 149) 

"Now what we have here is a failure to communicate."

-Cool Hand Luke

The biggest failure of collaboration was clearly between Wilkins and Franklin. (Ironically, after she left DNA research, Franklin collaborated some both with Crick, and perhaps more surprisingly, with Watson, with whom she worked fruitfully and amicably together on aspects of her tobacco mosaic research.)

Denied Franklin as a collaborator, Wilkins found himself discussing the problems of DNA with Watson and Crick. He communicated regularly with them with full knowledge that they were trying to solve the DNA structure, including sharing some of his own and Franklin’s data. (note 2) Watson and Crick had offered multiple times to bring Wilkins up to speed on the modeling approach, encouraging him to take that approach himself, only to be deflected. Wilkins was slow to see the advantages of the approach, and found himself in a holding pattern, waiting for Franklin to finally depart.

Had she and Wilkins collaborated, they might well have come to the solution together. In fact Wilkins, in his own autobiography, made that very point:

"The discussion in Rosalind's notebook of two-chain DNA with three-eighths separation was from a month or so before the Double Helix model was built. I felt it gratifying that Rosalind had set down those thoughts independently of the new Cambridge work. She did not mention the idea of base-pairing; but I was keen about the importance of that idea, and if she and I had discussed the problem there would have been little to prevent us finding the Double Helix."

(Third Man of the Double Helix, p 221) 

If there is a real bogeyman in this story, it might be John Randall rather than James Watson. His mismanagement of the initial situation, never rectified, seemed no less than gross negligence; he all but ensured that his two main DNA researchers, rather than working together to further a solution, spent too much of their energies fighting with each other, losing what all collaborator’s gain – a synthesis of ideas much greater than what each individually contributed.

In addition, Wilkins and Franklin clearly rubbed each other the wrong way, and found it difficult to work together for reasons beyond sexism and heavy-handed leadership. (The ironical Dark Lady of the book’s title is from a phrase used by Wilkins to describe Franklin.)

The Controversy over Credit

Franklin was only one part of the controversy over who deserved credit for the discovery of DNA. Many, especially some of those more directly involved in the experimental research, were bitter about Watson’s and Crick’s getting there before they did, chief among them Erwin Chargaff, who had been researching nucleic acids, and had discovered one of the critical facts needed to solve the structure: When analyzing DNA from various species, the four organic bases that were part of the DNA polymer showed the same specific ratios, with the number of adenines equaling the number of thymines, and the number of guanines equaling the number of cytosines.

Another, Jerry Donohue, had determined the most probable conformation of those same bases using theoretical quantum mechanical arguments, another critical factor. Both of these men felt that they had claim to a share of the Nobel Prize that went to Watson and Crick. Even Maurice Wilkins, who did share the prize, was unsettled about the role of Watson and Crick. Wilkins had shared King’s research with Watson and Crick, and had even, if reluctantly, given them permission to pursue the problem of the DNA structure. But in the England of the 1950’s, it wasn’t considered quite cricket to use someone else’s research to further one’s own.

Those who felt slighted alluded to the idea that Watson and Crick had taken their work and only put it together. Yet their research had been shared, publicly and privately, particularly by Chargaff, Wilkins and Donohue. Franklin had led a colloquium which Watson attended and to which Crick was invited, and some of her results had been published in a report by the umbrella organization Medical Research Council (MRC), which was designed to share information between their respective labs. Even so, no permission from Franklin was asked by Watson or Crick to use her unpublished data.

The final controversy was triggered by the entry of Linus Pauling into the competition. Already a Nobel Prize winner, he had recently published a proposed model of DNA, built from published facts, like Watson and Crick; but his model was seriously flawed. Pauling had recently determined a sub-structure of a large and complex biological macromolecule, the alpha helix, using such modeling techniques. Bragg feared that Pauling would correct his errors quickly and would scoop his lab again (Bragg’s lab itself barely missed the structure of the alpha helix). Bragg, who had restrained Watson and Crick from moving forward in deference to the King’s lab, gave Watson and Crick permission to go forward again, particularly because he feared that the King’s lab was too dysfunctional to organize a rapid assault on the structure, and the multi-disciplinary approach by Watson and Crick seemed most promising, as it turned out to be.

Perhaps surprisingly, Rosalind Franklin did not hold the attitudes of Chargaff or Dononue or Wilkins. Franklin had completed the move from King’s to Birkbeck college under John Bernal in the spring of 1953, just after the DNA solution was announced. Having left her DNA work, by most accounts because she was unhappy with her working situation rather than her disinterest in the subject, she made no public nor private argument over the matter of priority or credit, even though her research contributed critical experimental information needed to solve the structure.

The Nobel Prize

It is possible that Franklin would have received the Nobel prize had she lived. Yet beyond the initial simultaneous publications in Nature, Watson, Crick and Wilkins did little to promote the importance of her work in the discovery of the DNA structure while she was alive. Was this deliberate, part of an early campaign to minimize her chances for a Nobel? Probably not. The candidates for the 1962 prize were largely determined after her death in 1958.

In any event, the Nobel Prize does not generally reflect the collaborative nature of leading edge science. Even large individual contributions to knowledge are made on the shoulders of giants, as Newton so famously pointed out. Yet Alfred Nobel’s prizes are limited to a few, so cannot reward all who contributed, whether large or small.

The discovery of the structure of DNA, a seminal event in the field of molecular biology, was indeed produced from the work of many researchers over a long span of time, the most notable perhaps (where to start? who to leave out?):

• Miescher’s characterization of nucleic acid;
• organic crystallographic work by the Bragg’s, Max von Laue and Linus Pauling;
• John Griffith’s pneumococcal transformation by nucleic acid;
• Oswald Avery’s identifying DNA as the transforming agent;
• Alfred Hershey and Martha Chase’s demonstration that DNA was the genetic component of bacteriophage viruses;
• Erwin Chargaff’s careful determination of organic base ratios;
• Jerry Donohue’s identification of organic base conformations;
• William Astbury, Wilkins and Franklin’s crystallographic work on DNA;
• and finally the puzzle solving Watson and Crick, who put all of these pieces together to describe the correct physical model of DNA.

Only some of these people received Nobel prizes for their efforts. Of those eligible, Griffith, Avery, Chase, Chargaff, Donohue, and Astbury were not awarded the Nobel prize. Miescher lived before the Nobel prize was established, and Franklin, as already noted, died before she could be considered. Roughly half of this list were left out.

Her Legacy

Did Franklin deserve a Nobel prize for her work on the structure of DNA? Unquestionably, in this reader’s eyes. Would she have received it had she lived? There was certainly ample argument for her nomination, buttressed by her simultaneous publication in Nature alongside Watson and Crick’s announcement of DNA’s structure, and by the pieces of experimental evidence that she alone produced that were critical parts of the solution.

In some ways, Rosalind Franklin’s story is a tragedy, a life quite possibly brought short by cancer induced by her heavy overexposure to X-rays, but it is first the tale of a brilliant physical chemist who contributed a great deal to science in her short life, extending scientific understanding of the structure of DNA, of coal, and of the tobacco mosaic virus. Full recognition of her contributions came late, but she is deservedly celebrated today.

 

---

Notes

1. Today, with the availability of powerful computers, this is a more accessible technique for large molecules, but was extremely time-consuming and difficult in the 1950’s, made no easier by the fact that it was done manually. Using similar techniques in the same era, Perutz and Kendrew solved the structure of hemoglobin, another large and even more complex biomolecule; it took them better than twenty years.

2. Too much has been made of the fact that Wilkins, two months before the structure was determined, showed Watson Franklin’s photo 51, as if he were sharing someone else’s research. In fact, Franklin had already handed over her research to Wilkins, as she had ceased her DNA research at King’s and already taken a new position at Birkbeck’s college. (Even after leaving the research, she continued to work on the final summaries and papers with Gosling). Wilkins had every right to show the photo to Watson. Wilkins himself later regretted showing the photo to Watson, for his own reasons: He had started positioning his team to resume full-on assault of the DNA problem. He was waiting for Franklin to finish up her summaries before resuming. Ironically, this turned out to be March 7th, the very day that Watson and Crick were finalizing their successful model.

3. Other books recommended on the subject of the discovery of the structure of DNA: