"Dear M": the transatlantic DNA collaboration of Maurice Wilkins and Leonard Hamilton

This week's post calls attention to a series of correspondence written in the 1950s that documents the DNA research carried by Wilkins and his group at King's College London from 1953 to1960. The correspondence is with Dr Leonard D Hamilton, a British medical researcher and pathologist based in the United States who worked for the Sloan Kettering Institute for Cancer Research and later the Brookhaven National Laboratory. He provided DNA samples to Wilkins at King's from 1952 into the 1960s. As my title suggests the two were firm friends and their letters are refreshingly candid. Although these letters do not document the breakthrough research on the structure of the double helix like the similar correspondence between Wilkins and Crick they do give us a good picture of how Wilkins coped with the news and life thereafter.


DNA Samples: Supply and Demand

In 1953, Leonard Hamilton became the principal provider of DNA for the King's team. Samples had previously been provided by a host of other international scientists such as Rudolf Signer, Erwin Chargaff and Harriet Ephrussi and there was a great pressure to produce better DNA samples now it had been established that DNA was the basis of genes.Wilkins and his team were also under pressure to provide a more detailed double helical model to confirm that the structure was correct and not an equally valid alternative structure.

Figure 1: Photocopy of a letter from Wilkins to Hamilton, dated 28 May 1953: Wilkins thanks Hamilton for the DNA sample taken from a mouse sarcoma and generally expresses an eagerness to press on with further DNA research.

 In the above letter, Wilkins shows his excitement over the diffraction image obtained using the S-180 mouse sarcoma sample. He also expresses the need for greater quantities and variant salts and solutions that becomes a constant theme of this correspondence, as this quotation from a letter from Wilkins on the 9 June 1954 reveals:

"As I thought I made clear, what we need is better DNAs and hence I was very disappointed to find all the samples you sent recently were no better than the usual quality. We have not the time to test laboriously numerous samples in the hope one might be good. The three dry samples were have had already and those in solution, owning to a lack of warning, arrived at this end and were held at the airport for several days and appear to have deteriorated". 

The problem of the supply of demand of DNA were exacerbated by the trans-Atlantic nature of the partnership. Communication was the biggest issue. Before the days of global mass-communication, the main medium for communication was by letter or telegram (international telephone calls had only recently been introduced and were very expensive). The frustration was felt on both sides of the Atlantic especially with the additional pressures of journal and conference deadlines. Despite these stresses, they made progress as this quote from Wilkins on 5 November 1954 states:

"The 10 week exposure came off today and is a great success. it is one of the biggest improvements we have ever had in A pictures and is very much better than the best before. Will send a copy soon and I hope I will spur you on to even better things...Good old Leonard!"

Living in the Shadow of the Watson-Crick Model

One of the reasons why these letters make compelling reading is the scattered references to the discovery of the Double Helix. In the letters we get a contemporary commentary on the initial impact of the discovery and personal opinions on some of the key characters such as Francis Crick, James Watson and Rosalind Franklin. Of particular interest is the response of Hamilton who considered that Wilkins and King's College London Biophysics Unit had been hard done by Watson and Crick's model.

Figure 2: Letter from Leonard Hamilton to Wilkins dated October 12 1954: In this letter, Hamilton describes a visit from Rosalind Franklin and also his plan to air off a little "pro-Wilkins propaganda!" at a nucleic acids conference. 

 From the correspondence, it is clear that the battles and wounds caused by the discovery are still fresh but the scientific interest in the findings ( such as the journal Scientific American in Figure 2) are already calling for a narrative of the discovery. Hamilton's repeated opposition to calling the double helix the Watson-Crick model is an example of this increasing scientific interest and his own attempts to inform the American scientific community of the role that King's Biophysics Unit played in its creation. 

Wilkins' own initial thoughts and feelings were somewhat more ambigious. For example, his assessment of Francis Crick in the letter shown in Figure 1 states:

"Taken the Watson Crick model with a grain of salt. Francis is quite certain he can solve all the problems of the universe by pure thought and his lack of facts had lost him many friends temporarily until he recovers from DNA hysteria. I am very fond of Francis but he can be a bit much at times and he can be a ruthless careerist when he thinks it suits him. but keep that quiet to ourselves. We both like him a lot so there is no harm saying this to you".

His reaction is in line with his famous letter to Crick on hearing the discovery where he called Crick and Watson a couple of "old rogues" but accepted the model gracefully. Yet in this letter he does admit a degree of resentment over the Crick's "careerist" tendencies but not enough to irreprecibly damage their friendship. 


Finals thoughts

The correspondence between these two friends is of great reading for anyone interested in the story of the double helix and the DNA research carried out at King's College London. By being both a commentary and account of the DNA research undertaken at King's in the fifties the letters acts as an informal guide to the work being carried out and excellent source of information of the different DNA salts and samples. For me, however, the best aspect of the letters is the openess and informality that Wilkins shares with his friend about his life and research.  

Figure 3: Leonard Hamilton and Maurice Wilkins together in the 1960s.

Final words

"Do please reply soon. The nature of the gene depends on it. What piffle. M"

A potted account of the research on DNA at King's College London

In this post, there will be a brief overview of the research carried out here at King's on the structure of DNA. This of course is not a definitive history of the events and interactions which led to the discovery of a double helix. For a more comprehensive scientific history of DNA, I would recommend Robert Olby's book "The Path to the Double Helix: The Discovery of DNA" (1974). My purpose is to introduce some of the techniques and findings that occurred here at King's and relate it to the overall contribution to identifying the structure of DNA.

DNA enters the 'Circus'

The new Biophysics Laboratory created by J T Randall at King's College London was a lively and unconventional institution. Randall's ambition to create a laboratory where physicists could work on biological problems and vice versa were being realised at King's and an assortment of young research workers from diverse scientific backgrounds found their feet in these new disciplines. Maurice Wilkins was one of these workers. His first years at King's had proved fruitless in the field of ultrasonics causing mutations in fruit flies and he swiftly moved on to construct, with his colleagues Bill Seeds and K P Norris reflecting achromatic microscopes which he began to use on ultraviolet and dichroism studies on the Tobacco Mosaic Virus (TMV), nucleic acids and nucleoproteins. During these initial experiments with DNA Wilkins found a significant finding he wrote in 1962:

"While examining oriented films of DNA prepared for ultraviolet dichroism studies, I saw in the polarizing microscope extremely uniform fibres getting clear extinction between crossed nicols...each time that I touched the gel with a glass rod and removed the rod, a thin and almost invisible fibre of DNA was drawn out like a filament of spider's web. The perfection and uniformity of the fibres suggested that the molecules in them were regularly arranged"

Polarising microscope view of DNA fibre stretched at room humidity

The excellent quality of this extracted DNA was not through chance. The sample was supplied by Rudolph Signer, a Swiss biochemist who had been since the 1930s endeavouring to produce high quality extracted DNA. The sample made in 1949 with his student H Schwander made that grade. On the 12 May 1950, Signer was invited to the Faraday Society in Cambridge to discuss his work on preparing DNA samples. At the end of the talk he distributed bottles of his best DNA and Maurice Wilkins was one of the lucky recipients. Wilkins later reflected that this was "a generous act in the best tradition of science!".

Having witnessed the remarkable uniformity of the fibres, Wilkins took the DNA fibres to Raymond Gosling for X-ray diffraction. Gosling was the only person using X-ray diffraction techniques at the time to complement Randall's interest in the X-ray study of ram's sperm heads. Initially the two were unsuccessful  the specimen to the film distance too large and the X-ray tube too weak to yield a pattern but they improvised as Raymond Gosling explains:

"I wound these fibres around a wire frame, forming a dense bundle which on the conventional Raymax tube produced a diffraction pattern recordable in a few hours. If that sounds rather scientific, I must tell you that the 'wire frame' was simply a bent paper clip and the 'dense bundle' was formed by applying Lepages quick setting cement, purchased from Woolworth's in the Strand!"

First multifibre specimen taken on the Raymax tube Unicam Camera, filled with hydrogen (1950)

The above photograph is the one that Maurice Wilkins showed at the Naples conference that so captivated Jim Watson. This was obtained thanks to a suggestion by Randall , by passing hydrogen thought the camera and sealing it where possible to prevent air scattering, which caused a fog on the film. From these images it was possible to demonstrate that the molecule was packed together like cylinders 2.0 nm in diameter and  that the structure was very crystalline. The final study in this initial period was experimenting with the water content of the molecule. By drying and heating the specimen they obtained an amorphous scatter pattern .This contrasted when they repeated the process but wetted the hydrogen at 90% humidity for 12 hours prior to exposure and obtained a crystalline pattern similar tp the example above. This demonstrated that water played a vital role in maintaining an ordered crystalline structure.

X-ray Diffraction Years

In June 1950, the old wartime Siemens X-ray tube broke down leaving the department without a working X-ray diffraction camera. They soon obtained designs for new fine-focus X-ray equipment produced by Ehrenberg and Spear at Birkbeck College. Whilst the camera was being constructed Randall came to the decision that they needed a professional crystallographer to keep the work progressing. Rosalind Franklin was already on her way to the department as a research fellow to work on proteins but Randall expressed in a letter the change in orientation. The letter stated that "as far as the experimental X-ray effort is concerned there will be at the moment only yourself and Gosling..." and  gave no indication of Wilkins' continued involvement on the project. This may account for the grievance that Franklin held from what she viewed as Wilkins interpreting her problem but this issue is in no way definitive and has been heatedly debated along with the wider recognition of Franklin's role ever since. Yet, it is best to leave the issue of Franklin and Wilkins relationship to one side for a moment and recount for what was actually achieved when she joined the department.

One of the first achievements of this collaborations was a vital one in solving the structure of DNA. Franklin brought her expertise to the job by fixing the humidity and the water content of the exposures by passing the hydrogen through saturated aqueous solutions of appropriate compounds through which the hydrogen could bubble into the camera at any given temperature. They soon found that the sodium salt of DNA supplied by Signer could transform into two forms, Structure A and Structure B.

Soon after this discovery, the division between the DNA workers at King's was cemented with Franklin and Gosling continuing to work with the fine focus X-ray tube using Signer DNA to outline the Structure A pattern of DNA whilst Wilkins and Alex Stokes used the old Raymax camera and work on the Structure B pattern using Erwin Chargaff's DNA samples. This situation did not change until Franklin left King's College London in February 1953 with virtually no communication between the two groups.

In October 1951 Wilkins, who had been reading Linus Pauling's famous paper on the protein alpha-helix , wondered why Pauling had not calculated the X-ray diffraction of the structure. After discussing the matter with Stokes he came back the next day with a Bessel function calculation of diffraction of a helix. The remarkable aspect of the 'Waves at Bessel on Sea' diagram was how much it corresponded to the new B diffraction patterns that Franklin was achieving. Franklin reacted furiously to her results being interpreted and the matter was set aside.

The following month November 1951, saw the unveiling of two DNA models: one by Bruce Fraser at King's and the other by Jim Watson and Francis Crick in Cambridge. Both these models were three chained helixes and lacked the key base-pair element. Fraser's model (as described in a previous post) was a closer approximation of the correct version as a fundamental flaw in the first Cambridge model was that the helix was inside out with the bases on the outside due to Watson misjudging the water content. The failure of the Cambridge model put a temporary injunction on the pairs DNA interest, whilst model building was not pursued at King's College London after Fraser left the department shortly after this. 

At the start of 1952, Franklin, taking the advice of a Paris mentor, Vittorio Luzzati , decided to elucidate the structure of the A pattern using the crystallographic method of cylindrical Patterson function. This laborious method was a way of calculating the Fourier transform of the intensities of the spots on the X-ray films ,and involved measuring different reflexions of the specimen which required a new tilting microcamera to be designed for this process. In order to calculate the Fourier transform, Franklin and Gosling had to consult Beavers and Lipson strips (pictured below). Ray Gosling recalled that:

"These assembled the values of the periodic functions all set out at appropriate intervals and arranged sequentially in a handsomely polished mahogany box. I used to have nightmares...that I had dropped a box of 'strips' on the floor and had to sort them all out in the correct order!"

By the end of 1952, Franklin and Gosling had the preliminary results back for the cylindrical Patterson function of Structure A. Although in hindsight the data from the cylindrical Patterson and then the 3-dimensional Patterson analysis supported a double helix in the A form such a conclusion was not reached by Franklin who before leaving for Birkbeck College had begun to investigate the B form of DNA (with which, as shown in her notebooks, she would come close to solving the structure with). 

The solution to the structure:

On the 7th March 1953, James Watson and Francis Crick finished the model of the double helix. The Cambridge pair started model building again after Watson was inspired on account of being shown 'Photo 51' by Wilkins when he visited King's on the 30th January. Watson deduced that a double helix rather than a triple helix fitted with genetic transference and was supported by the biochemical work of Erwin Chargaff who had discovered that the quantities of the base pairs were equal. On the 12th March 1953 the King's team were invited up to view the model. Wilkins wrote of seeing the model: 

"...a feeling came through to me that the model, though only bits of wire on a lab bench, had a special life of its own. It seemed like an incredible new-born baby that spoke for itself, saying 'I don't care what you think - I know I am right' "

                                                              

 The diagram above on the left hand side shows some of the essential features of the double helix from the original paper by Watson and Crick such as the two sugar-phosphate chains running in opposite directions linked together by hydrogen bonded base-pairs stacked on top of each other. The diagram on the right shows a wire-model of the double helix used by Watson and Crick in their representation of the original double helical model of DNA.                     

Conclusion:

The contribution of the the Biophysics department at King's to the discovery of the structure of DNA was vital. The x-ray diffraction studies and other experimental methods provided the essential properties for Watson and Crick to elucidate the structure.Yet these achievements were not in isolation and needed to be combined with the knowledge acquired from Pauling and Chargaff along with many others to lead to the structure of DNA. The cracking of the structure should not be seen in terms of a race but the culmination of advances in chemistry, biology and physics spanning back to the nineteenth century when Fritz Miescher extracted DNA for the first time. 

Fortieth Anniversary of the Discovery of the structure of DNA. Pictured from left to right are four of the five named workers featured on the commemorative plaque (exception being Rosalind Franklin) they are: Ray Gosling, Herbert Wilson, Maurice Wilkins and Alec Stokes.

                                    

Lost Wilkins-Crick DNA correspondence discovered

Maurice Wilkins is in the news yet again thanks to the discovery of a lost series of correspondence between him and Francis Crick on DNA. It had been previously believed that the early correspondence between him and Francis Crick had been lost in a moment of over-zealous house-keeping. However, due to moving laboratory muddle, part of Francis Crick's papers were mixed with  those of his long-time DNA collaborator, Sidney Brenner while they shared an office in Cambridge. Brenner's papers were recently donated to the Cold Spring Harbor Library Archives, where nine archival boxes of material belonging to Francis Crick came to light.

John Steinbeck, Maurice Wilkins, James Watson and Francis Crick at the 1962 Nobel Prize ceremony (Steinbeck won his for his contribution to literature)

 

The correspondence with Wilkins consists of thirty four letters and three postcards between 1951 and 1964, which include eleven written between 1951 and 1953. The newly discovered letters shed light on the tensions present between the two laboratories, the strained relationship between Wilkins and Rosalind Franklin and the informal arrangements behind the famous note by Watson and Crick to Nature on the structure of DNA. Of particular interest is the complaint regarding Crick's dismissal of the Bruce Fraser DNA model; the anger felt by Randall towards Watson and Crick's involvement in DNA and above all the good humour and wit found in Wilkins letters to Crick that reflect their strong friendship.

 The new Nature article by Alexander Gann and Jann Witkowski, entitled "The lost correspondence of Francis Crick" gives excellent insight into the letters and a chance to view samples of the correspondence:

http://www.nature.com/nature/journal/v467/n7315/full/467519a.html

One or two other news articles also worth perusing are: 

An article on the discovery and context around the letters can also be read on the Guardian website: http://www.guardian.co.uk/science/2010/sep/29/letters-dna-double-helix-francis-crick

 To hear an interview with Raymond Gosling's witty and informed take on the newly discovered letters for BBC Radio 4's Today programme:

http://www.bbc.co.uk/blogs/today/tomfeilden/2010/09/scientific_feuds.html

The Randall Letters: The DNA Story at King's Revisited

The exciting aspect of our cataloguing project is the potential surprise and revelations that might occur when going through Maurice Wilkins' uncatalogued papers. Of particular interest is anything relating to DNA and in particular to the "DNA story" that followed. This topic has been well mined and publicised due to the buzz and controversy of Jim Watson's account, The Double Helix, first published in 1968. Whilst the book has been lauded for being the first personalised autobiographical book on a major scientific discovery the book offended many of the key protagonists, especially Maurice Wilkins and Francis Crick. It was however, the treatment of Rosalind Franklin that created the biggest outrage and caused a chain of events that would eventually lead to this obscure scientist being lauded as one of the greatest female scientists of the century. This constant re-assessment of the DNA narrative had an affect on Maurice Wilkins who had to constantly redress the issue throughout his life.

One of the key trails of thought that Wilkins had after becoming aware only after reading in Robert Olby's book, The Path to the Double Helix (1974), was that Rosalind Franklin was misinformed of her position in her correspondence with Randall. The letters stated that she would be working with Gosling on the problem and it did not mention that Wilkins would still be working on the project. This was further implied by his non-appearance at the first meeting with Franklin due to him being on holiday in Wales. These events allowed Wilkins to gain some understanding of her later behaviour in telling him to leave the DNA work to her and to "get back to your microscopes!". He further speculated that this failure to notify Franklin of his continued interest in DNA was not an oversight but a deliberate attempt by Randall to get in on the DNA research. Wilkins justified this by the fact had a long term research interest in DNA dating from the forties and had initial given him the task of using X-ray diffraction on squid sperm heads. Whether this was the case is difficult to speculate but fortunately we have found in Maurice Wilkins's personal papers letters from Randall written in 1951 that support his assessment.In a letter dated on the 5th June 1951 ,whilst Wilkins's was in Naples, Randall wrote:

"I shall be in direct charge of any X-ray work on sperm: I planned this particular experiment a long time ago and would like to see it through. As you know, I tried unsuccessfully to get you and others interested in the optical properties of sperm and sperm nucleoprotein in 1948-49 and met with very indifferent response (and the wrong answer!)"

He added:

" I am inclined to think I have been far too generous of my time and mental effort in feeding the laboratory with apparatus, people, and ideas, and that it is time I took charge of more definitive programme myself"

The letter seems to corroborate Wilkins' view that Randall wanted to have greater authority and input in the DNA project and was frustrated by the slow progress being made.

 Although this letter seems to confirm Maurice Wilkins' assessment about Randall's domination being detrimental to DNA research at King's. We are fortunate to also have extracts from Randall's own account in a letter to Wilkins from 1976:

Letter received from J T Randall to Maurice Wilkins, dated 5th January 1976

The letter is refreshing as it gives candid comments on several aspects that crop up regarding DNA work at King's such as the treatment of women, the atmosphere in the lab, relationship between Franklin and Wilkins. From the above, what stands out is that Randall emphasizes the point that it was Wilkins initial absence from the first meeting that proved fateful and if he were present his "standing in relation to DNA and your interest in it" would have been recognised.

Many more documents regarding the story of DNA are being unearthed in the papers of Maurice Wilkins, including letters and opinions from Francis Crick and Raymond Gosling along with Wilkins's own detailed research for his autobiography.