Thursday, 30 September 2010

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:

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:

Friday, 24 September 2010

DNA Story at King's: The Hidden DNA workers


Fortieth Anniversary at King's College London of the discovery of the structure of DNA in 1993. Pictured are four of the five names commemorated in  the grey plaque on the background wall ( from left-right they are: Raymond Gosling, Herbert Wilson, Maurice Wilkins and Alexander Stokes)


On the unveiling of the grey plaque to commemorate the fortieth anniversary of the discovery of the Double Helix at King's College London, Maurice Wilkins said these words:
"I'd like to emphasize that my presence in front of this plaque is to emphasize all five names there, including that of Rosalind Franklin who is not able to be present".
This magnanimous gesture was not just based on politeness and modesty but reflected the key collaborative effort required to provide the experimental data needed to crack the structure of the double helix. In this blog, I will provide a little background on some of the key collaborators at King's during the early years of the DNA work at King's who have been somewhat overshadowed in DNA history due to the grand narratives of Jim Watson and the biographers of Rosalind Franklin.


Raymond Gosling (born 1926):



Raymond Gosling is relatively well known in the DNA story because of his collaboration with Rosalind Franklin on the X-ray crystallography of DNA. However, Gosling's role in the DNA story pre-dated Franklin's arrival at the lab and it is this work in collaboration with Maurice Wilkins which was also of great importance to the discovery of the double helix. He first joined the lab as a PhD student under the supervision of John Randall in 1949 and began working on the cell nucleus. This approach soon led to Gosling working on studies involving DNA and by 1950 Randall asked Gosling to gather information on ram sperm using X-ray diffraction. These fuzzy pictures were in rough accordance with the X-ray diffraction pictures of DNA by Astbury. The introduction of Signer DNA and the expert manipulation by Wilkins to obtain DNA threads allowed Gosling to improve these initial results and produce X-ray pictures that showed DNA's crystalline structure. With help from Randall, Gosling and Wilkins were able to produce the "Structure A" form of DNA through the bubbling of hydrogen through the camera to prevent air scattering. In early 1951, Rosalind Franklin joined the lab and Gosling was transferred to work under her in a crystallographic analysis of DNA. The crystallographic work of the two provided a key component to obtaining the structure of DNA by vastly improving the crystallographic images and distinguishing structures A and B of DNA. There collaboration continued until Rosalind Franklin left of Birkbeck College in early 1953 and is thankfully well documented  due to the survival of Rosalind Franklin's experimental notebooks (found at the Churchill Archives Centre, Cambridge) and also several articles the two published in Nature and Acta Crystallographica.


Alexander Stokes (1919-2003):
 
  Whilst Gosling was the diligent lab worker, Alex Stokes was the theoretician who provided the crucial mathematical interpretations of the x-ray diffraction studies in order to guide the King's team in the right direction. Stokes was one of the initial appointments into the unit by Randall and came with valuable experience of X-ray crystallography from his time at the Cavendish Lab in Cambridge during the war. What distinguished Stokes from his other colleagues was his consummate ease in translating the patterns created on an X-ray diffraction film into a description of the atomic arrangement using his skills in mathematics. For example, it was Stokes who first noticed in 1950 that the X-ray diffraction photographs of DNA gave an indication of a helical structure by the absence of diffraction along the length of the molecule. Stokes later used complex mathematics in the form of Bessel functions to underline this, by famously working it out on a single train journey from his home in Welwyn Gardens City to London before christening the diagram, " Waves at Bessell-on-sea".



"Waves at Bessell-on-sea" by Alexander Stokes



Herbert Wilson (1929-2008):


Though Herbert Wilson arrived six months before Watson and Crick unveiled the double helix to the world, his work with Maurice Wilkins uncovered essential information regarding the structure of DNA. Wilson arrived at the biophysics unit in September 1952 under tenure of the University of Wales. He soon began X-ray diffraction studies of DNA, nucleoproteins and cell nuclei under the guidance of Maurice Wilkins. The two collaborated on a number of investigations beginning in the autumn of 1952 comparing, under different humidities, different samples of DNA (such as pig thymus, squid sperm, and wheatgerm DNA). Their observations confirmed what Franklin and Gosling had concluded that the phosphate groups were found on the outside of DNA. They then extended the study to look at the effect of undried preparation of live trout sperm to support the hypothesis that the drying process had no affect on the in vivo structure which it subsequently confirmed. The importance of these comparative studies was affirmed by the growing number of samples that were collected that not only showed para-crystalline patterns but also the A-type of DNA. This indicated that the crystalline appearance of DNA was not laboratory induced but occurred in biologically active samples and that the work of Franklin and Gosling would have universal applications.

The Molecular Configuration of Nucleic Acids", twenty six people along with organisations that contributed. Along with those mentioned already they also include from King's Sir John Randall, Bill Seeds, Bruce Fraser, Geoffrey Brown, Gerald Oster, Watson Fuller and Struther Arnott.

Tuesday, 21 September 2010

The Biophysics Research Unit

King's Biophysics Department Prospective (1962)

In understanding the role of Maurice Wilkins and King’s in the discovery of the double helix it is necessary to explore the background of the Biophysics Research unit. This Medical Research Council (MRC) funded group was crucial in the discovery due to its unique status as the only interdisciplinary biophysics laboratory in the UK.  Its self-consciously hybridised and almost dilettante approach to science bore fruit not just with the landmark discovery of DNA but also in regards to the pioneering muscle work of Jean Hanson and the research on collagen under J T Randall.


Biophysics in a Bombsite:

The Department owes its creation to the vision and direction of Sir Professor John Randall. He had been appointed Wheatstone Professor of Physics at King’s  in 1946 and part of his initiative was to have a separate biophysics department alongside the existing Physics department. It was Randall’s fantastic aptitude to wheel and deal that secured government funding for the unit through the Medical Research Council in 1946. This was shortly followed by Rockefeller Foundation granting funds for special apparatus such as electron microscopes and X-ray diffraction apparatus. Whilst money was not a problem the physical devastation of the Second World War was.

Construction work begins on re-building the Physics laboratories at the Strand Campus (1950)

The impact of German bombs had left a crater 58 feet long and 27 feet deep and had completely destroyed the Physics laboratories in the basement of the quadrangle. Randall described the facilities as appalling but pressed the College for new rooms which he obtained in 1950 and was shortly followed in 1952 with an even better space in the form of the reconstructed quad laboratory in the Strand. Recruiting staff for the new unit was also relative ease with Randall transporting the core of his staff from his old St Andrews Department, including Maurice Wilkins who became his right hand man. Although established scientists were unwilling to join Randall’s venture he did manage to attract bright young scientists who were interested in interdisciplinary work. The likes of Jean Hanson, Geoffrey Brown, Bruce Fraser and Raymond Gosling joined the department in these early years.


The “Circus”:

Although the biophysics unit at King’s was the bright young thing of the British physics scene this did not lead automatically to stellar success. The staff had to find their feet in new disciplines as physicist tried to be a biologist and vice versa. Randall in his 1951 Royal Society lecture on the unit described the lab as “an experiment in co-ordination centred in a University physics laboratory”. As an experiment, some failure was expected but this however was seen by some, such as Maurice Wilkins as not a bad thing: “If our programme had been thought out more clearly in advance they would unavoidably have been dominated by existing ideas as a result would not have provided the fullest opportunity for new ideas to arise”. In Maurice’s own case is own failure with ultrasonics led to microscopic work on sperm heads that convinced him in 1950 that DNA held genetic material. The enthusiasm and spirit of innovation is perhaps best captured by this a further recollection by Maurice:

In one room in 1948 I remember two physicists setting up reflecting ultraviolet microscopes with a technician grinding and polishing quartz coverslips, a physicist trying to construct a high voltage electron microscope for direct study of thin tissue culture cells, another physicist smashing cell nuclei in a blender to make ‘Mirshy chromosomes’ and a biological technician handling tissue cultures under the expert supervision of Honor Fell”.


This frantic inter-disciplined laboratory was not the only reason why it began to be referred to as “Randall’s Circus” in King’s corridors. The spirit of the lab was maintained by hilarious Christmas parties with irrelevant songs, dances and once an opera being performed that pointed out the absurdities of the lab and made everyone laugh. This was complemented by the annual summer cricket match where J T Randall would take centre stage with his solid batting displays.



 The collaborative, congenial and diverse scientific skills of the biophysics unit helped advance science in several directions during this period. It should be remembered that the discovery of DNA was not down to a few individuals but a number of scientists from around the world.


Christmas in a Biophysics Laboratory when you don't have enough decorations at hand- here J T Randall is depicted as Father Christmas whilst on his right hand side, Maurice Wilkins makes an angelic appearance (1960s)

Maurice Wilkins: A brief biography


Maurice Wilkins (1916-2004): New Zealand born Nobel Prize winning biophysicist

The Nobel Prize winning biophysicist is chiefly known for his experimental work that led to Watson and Crick discovering the correct double helical structure of DNA. The importance of Wilkins, and that of the King’s biophysics department in the discovery of DNA has been somewhat overshadowed by the dynamic duo from Cambridge ( even to the extent that the publisher of Wilkins’s autobiography thought to mention in choosing the title, “The Third Man of the Double Helix”). This is a disservice to both pioneering DNA work at King’s which paved the way for its discovery and which as an institute spent the next decade after the discovery confirming the validity of the Watson-Crick model.




His early life and education:

 Maurice was born in Pongaroa, New Zealand in December 1916 where he lived happily until the age of six before his father, a medical practitioner, moved his family to England in 1923. Whilst living in Birmingham, Wilkins began to display his characteristic ingenuity and craftsmanship as he built his own telescopes and microscopes to pursue his interests in astronomy and optics. He won a scholarship to St John’s College, Cambridge in 1935 to study physics but due to both his eclectic tastes in physics and his preoccupation with university politics he obtained a low second degree in 1938. Although disappointed by the result, Wilkins’s eclecticism and good fortune allowed him to join his former tutor, Mark Oliphant, at Birmingham. Oliphant had been impressed by Wilkins’s ability and interest in thermoluminescence and phosphorescence and set him up as the research student for a certain, John Randall- whom Wilkins would enjoy a fruitful, if not fractious thirty year collaboration. Wilkins made rapid progress in Birmingham obtaining his PhD in luminescence in 1940.
He was subsequently recruited into the Ministry of Home Security and Aircraft Production to work on the improvement of radar screens. In 1944, Wilkins followed Oliphant to the University of California at Berkeley, to work on the Manhattan project. Although Maurice played a small role within the project he became increasingly concerned about the ethical implications of atomic weapons and like many of his colleagues turned away from atomic physics to pursue biophysics inspired to some extent by Erwin Schrodinger's book, What is Life? (1944). 


King’s College London: 
After returning from California after the war, Maurice decided to rejoin Randall’s research group at first at St Andrew’s University in 1945. This group then moved in 1946 to King’s College, London where Randall was appointed the Wheatstone professor of physics and had obtained funding from both the Medical Research Council (MRC) and the Rockefeller institute for a new Biophysics Research Unit. This new MRC unit was fairly unprecedented with interdisciplinary work within science not being a common occurrence. Maurice was integral in the early years of the institution with innovative work in adapting microscopes to use optical, ultraviolet and infra-red light. He turned to studying DNA, on Randall’s bequest in 1950. Working closely with the PhD student, Raymond Gosling and the mathematician, Alec Stokes they started to produce the first crystalline diffraction patterns for DNA. This formative period convinced Wilkins that DNA had a clear crystalline symmetry and could be readily pursued. It was whilst at a conference in Naples in 1951, that Wilkins showed a slide of their results that excitedly transfixed a previously bored and distracted Jim Watson as he realised that the structure of DNA was possible to study.
  Later that year, Wilkins was joined by Rosalind Franklin to work on X-ray diffraction experiments on DNA. The need for a professional crystallographer was essential for progress on the structure but due to misunderstanding over each others role the two fell out splitting the laboratory where Franklin and Gosling would continue working on the X ray diffraction of the A Crystalline Signer DNA whilst Wilkins and Alec Stokes (and later Herbert Wilson too) would work on the “B” form though without access to the Signer which was a remarkably pure form of extracted calf thymus DNA. Franklin and Gosling produced enhanced the quality of the X-ray diffraction photos thanks largely to Franklin’s expertise in crystallography with the vital “photo 51” being taken in May 1952 as a consequence. The teams effectively worked in isolation and it was not until 1953 when Franklin had left for Birkbeck College that any unified King’s response occurred. By then it was too late. Watson and Crick cracked the structure of DNA in March 1953. Somewhat unfortunately,the spur for Jim Watson's new attempt at model building had been seeing the marvellously clear helical pattern of "photo 51" and deciding to discard experimental data pointing to three chains and opt for two.

 Yet, to Maurice’s credit rather than throw in the towel he and the department of King’s continued to work on DNA. The process of checking the validity of the model was required especially with the constant bombardment of competing models appearing during the fifties and sixties. The work was painstaking and the refinement of the Watson - Crick Model took seven years. The toil was however worth it with the Albert Lasker Award being given to Maurice, Watson and Crick in 1960 and a general indication that a Nobel Prize would be soon on the cards.  


With Science comes Great (or Social) Responsibility:

Whilst the DNA aspect of this project is self evident, the ‘social responsibility’ requires explanation. This phrase embodies Maurice’s dual pursuit of a scientific profession but with a social consciousness. This distinct direction was present from his Cambridge student days where his anti-war activities led to him investigating the effect of incendiary bombs (the devastation that they ensured had only just been witnessed during the Spanish Civil War). Despite, and in some ways because of his work on the Manhattan project, Maurice became an ardent opponent of the proliferation of nuclear weapons and a member of organisations such as CND and Pugwash. In 1968, his opposition to biological and chemical weapons led him into contact with Hilary and Stephen Rose and together they set up the British Society for Social Responsibility in Science with Maurice serving as President. The initial aims of the society were to challenge the belief that science was a ‘pure knowledge’ that only caused harm through its application and therefore ridding the scientist any mental anguish on the ethical implications of this research. This reductionist approach to science was abhorrent to Maurice who believed the practice of science to be embedded with human values and should therefore be made to be held accountable for its impact on society. His passionate belief that the broader implications of science should be taught led to the creation of the “Social impact of the biosciences” which is run to this day in the Biophysics department here at King’s.

Fortieth Anniversary celebration of the discovery of the structure of DNA (1993). Pictured (left-right), Raymond Gosling, Herbert Wilson, Maurice Wilson, Alexander Stokes.


Wednesday, 8 September 2010

DNA model building: The Fraser Model

Model building by Watson and Crick famously led to them being the first to that discover the structure of DNA was in fact in the form of a double helix. It was the orientation and the manipulation of the central spine of base-pairs that proved essential to solving the structure. However, this approach to solving the structure of DNA was not unique. Model building was in vogue in the world of biophysics, thanks to the pioneering work of Linus Pauling on helical proteins. Previous DNA models had been already attempted by William Astbury and Sven Furberg but they were not based on the more accurate experimental results of the King's Biophysics department and were therefore inaccurate as they were calculated to comprise of only one chain. The first attempted model to use the experimental results of the King's biophysics department was built in late 1951 by Robert 'Bruce' Fraser. Fraser was at the time a research student in William Price's spectroscopy group, and had been asked by Maurice Wilkins to try his hand in building a DNA model.

Annual Physics Cricket Match: pictured (left-right) unknown, Margaret M'Ewen, Maurice Wilkins,
Bill Seeds, Bruce Fraser, Mary Fraser,
Raymond Gosling (standing) and Geoffrey
Brown, 1951.(KDBP/PH/1-311)


Maurice Wilkins recalls in his autobiography being beckoned by Fraser to view his helical model of DNA:

"Bruce had done a good job: the model was very interesting. The three helical chains had the right pitch, diameter and angle, and were linked together by hydrogen bonds between the flat bases which were stacked on each other in the middle of the model".

The model illustrated well the general understanding of DNA in the lab: the structure was helical based on the work of Wilkins and Alex Stokes; the phosphates were on the outside as indicated by Rosalind Franklin; the stacked central core of bases, or "pile of pennies" as shown by the x-ray diffraction photographs first achieved by William Astbury. However, whilst the model showed many of the correct characteristics in retrospect, it also reflected certain errors current at the time. A three chain structure was based on the water content and density data for DNA.Whilst both Wilkins and Franklin could not envisage anything less than three with that information (and had both separately told Fraser that the model had to be three chained) the Fraser model contradicted the X-ray diffraction data by showing the three chains to be equally spaced. The hydrogen bonding between the bases was also incorrect and the structure did not fit with Chargaff's 1:1 base ratios. The end result of the model was one of collective frustration as it summed up how the King's group had become trapped in the belief of a three chain structure and with no guidance as to how to construct it.

 The model was never published, Bruce and Mary Fraser left the lab shortly afterwards and moved to Australia in 1952. There was a final act of drama as Maurice Wilkins urgently cabled Fraser in 1953 asking him to write up his model asap for publication in Nature.

Telegram received by Maurice Wilkins from Bruce Fraser regarding publication of note on DNA model ( annotation by Maurice Wilkins)
 
Fraser worked throughout the night to finish his note on the model, but Maurice Wilkins decided in the end not to submit it for publication alongside the other papers for Nature in March 1953 as it compared unfavourably with the Watson-Crick model. Maurice Wilkins later regretted his decision as the Fraser model showed for the historical record how advanced the thinking was at King's. Below are copies of the original note:











To read more about Bruce Fraser and his DNA model there is an excellent interview with him on the Australian Academy of Science website: http://www.science.org.au/scientists/interviews/f/bf.html

An earlier and more comprehensive blog on Bruce Fraser and his model is also available on the Linus Pauling blog: http://paulingblog.wordpress.com/2009/04/16/the-fraser-structure-of-dna/