The discovery of insulin

Today marks the 90th anniversary of the first time insulin was used on a human patient.

A brief summary of this event runs as follows: the insulin was injected into a 14-year old diabetic, Leonard Thompson, at Toronto General Hospital. Insulin had been discovered in 1921 at the University of Toronto by Canadian doctor Frederick Banting and American biomedical scientist Charles Best. Thompson's condition had worsened in late 1921 and when he was admitted to hospital he weighed only 65 pounds. With the risk of him slipping into a diabetic coma, Thompson's father let the hospital try the new pancreatic extract for the first time.

As a biography of Thompson on the Science Museum's Brought to Life website notes:

"The extract was an impure form of insulin. Thompson had an allergic reaction, and it had little effect.

A few days later Thompson was injected with a purer form of insulin. This was extracted by the chemist James Collip. Thompson’s blood sugars gradually returned to normal and his diabetic symptoms began to disappear. News of Thompson’s recovery spread, inspiring people with diabetes and their families to write letters to Banting and Best asking for urgent treatment".

So, a medical breakthrough: treatment for diabetes was revolutionised and a terminal disease became treatable. Banting received the Nobel Prize in Medicine in 1923 and as a result of these developments, the lives of millions were changed for the better.

What this quick summary skates over, however, were the politics and powerplays that went on behind the scenes, with disagreements over who could claim success for the development of insulin. What role was played by Prof John Macleod, Professor of Physiology at the University of Toronto, who granted Banting a laboratory at the University to conduct his research (it was with MacLeod, not Best, that Banting shared his Nobel Prize)? And what of Collip, who purified the insulin?

The most detailed account of these discoveries is The discovery of insulin by Michael Bliss (2007 ed), but the Wellcome Library also holds a file of papers which casts an interesting light on these debates.

This comes in the form of copies of letters passed on to the Wellcome Library in 1959 by Sir Henry Dale - Chairman of the Wellcome Trust and also one of the most respected scientists of his time. The letters include accounts of the discovery of insulin by both Banting and MacLeod and illustrate their divergent views. The file also includes a summary of its contents written by Dale himself, offering his own perspective on events.

Leaving aside the actual details of these letters, we'd merely like to flag up this file as an example of how medical breakthroughs have rarely been the result of the efforts of one lone scientist, and that disagreements over recognition by both public and peers can cloud the achievements of scientists.

It's also noteworthy that the papers, whilst focusing on the discovery of insulin and setting out the achievements of Banting, MacLeod, Collip and Best, make very little mention of the use of insulin to treat Leonard Thompson.

Image: Leonard Thompson, from the site 'The Discovery and Early Development of Insulin' from Digital Collections of the University of Toronto

The ‘Spare-part biologist’: Sir Peter Medawar

"He was a big man. That was the first thing that struck you as he strode into the room. A big man - tall and vibrant with life. His sheer presence communicated a sense of power: not political power, not domination, but physical power, above all intellectual power... It was difficult not to be awe-stricken in the company of Peter Medawar" (1)

Such descriptions of Sir Peter Medawar, the Nobel-Prize winning zoologist whose archive has just been digitised, make browsing through his personal papers somehow more tangible. Not all biologists get to appear in Vogue as Medawar did in 1971 (2).

It is a tragedy that Medawar was plagued by persistent strokes later on in life. First struck down dramatically mid-speech in Exeter cathedral in 1969, he persevered through ever disabling health issues to continue to write seven books until his death in 1987. (3)

Some of the most poignant material from Medawar’s papers is those letters that relate to his strokes: correspondence from 1970 includes a series of self-portrait drawings illustrating his recovery from his seizure: one image is marked 'PBM body image 9 July 1970, Pablo Medawar pixit' with spiky fingers and elongated ears.



Other drawings dated ‘May 16’ shows him with enlarged hands and feet and another dated ‘May 26’ with a third leg (possibly a crutch) and just one overgrown ear like protrusion from his head.





Such drawings were part of his traumatic recovery process as explained in his autobiographical work Memoir of a thinking radish (p.157, Oxford University Press, 1986) and revealed, to Medawar at least, an ‘eye defect’ brought on by the stroke. His confidence in his recovery never abated it seems – despite his evident disability, it is a relief to read a note from '9 May' stating repeatedly 'I am feeling better' (4)

The archive will be available to view from 2012. Further details of the digitisation programme can be obtained from the Wellcome Library digitisation project pages.

References:
1. Dipak Nandy, p.1 of an article for p.1 The Runnymede Trust, 1988, file ref: PP/PBM/F.58

2. The article features a shot of him musing at a desk with a cat out of focus in the front, File ref: PP/PBM/D55

3. A full listing of all books authored by Medawar held in the Wellcome Library.

4. File ref: PP/PBM/A.43

Images:

- Photo of Medawar was apparently intended for use in article by Medawar in "Lying Truths" according to pencil inscription on verso ("Lying truths : a critical scrutiny of current beliefs and conventions, Ronald Duncan and Miranda Weston-Smith, Pergamon Press, 1979.

- Self-portrait drawings are dated 1970 from file ref: PP/PBM/A.43

Tour de Francis

The preparation and photography of the Francis Crick archive have provided the digitisation team with a rare and intimate glimpse into the life and thoughts of the Nobel-prize winning scientist. What prevails is a pragmatist, a prolific correspondent, a man of passion for science, of wit and humour and of cutting sarcasm. This thought provoking archive inspired a visit to Cambridge to take a closer look at lasting remains of Crick and Watson’s time there.

Crick moved to Cambridge in 1947 after his stint as a scientist at the British Admiralty. With practically no experience of biology, chemistry or crystallography, he worked at the Strangeways Research Laboratory on the physical properties of cytoplasm in cultured fibroblast cells. He later worked on the x-ray analysis of haemoglobin with first Max Perutz and later Lawrence Bragg at the nearby Cavendish Laboratory under the Medical Research Council.

Our second port of call was Caius College where in 1950 Crick became a PhD research student working on the general theory of X-ray diffraction by a helix. Sadly we were unable to access the dining hall where the commemorative stained glass window (pictured) dedicated to Crick is situated. Efforts to view the window from outside were futile but we were reassured by Crick’s typically modest response to the commemoration in a letter dated February 27 1991 to Dr A Edwards of the College (File ref: PP/CRI/L/1/4/4)

“I was surprised, flattered and delighted to learn that you are considering putting up a window in Hall to commemorate me and the double helix. The main difficulty I see is that Jim Watson was also involved. In fact he was the senior author. I feel that it is essential that he should give his blessing to the project ... There is one very minor point about the design. The double helix is right-handed. A stained glass window will look right-handed from one side and left-handed from the other. However I doubt if this will matter much since the details of the window would probably not be very visible from outside!” (Feb 27 1991)

We did not visit Churchill College on the outskirts of Cambridge since there are no mementoes of note relating to Crick, perhaps due to his resignation just a year after his nomination as a Fellow. Crick, an atheist, had agreed to become a Fellow on the condition that no chapel would be placed there but the College went against this clause and placed a chapel there regardless of the views of Crick and other dissenters. It was not the only time he caused a stir at the college. In a letter dated June 14 2000, Crick recalls another point of contention: “one objection was that some of the women guests might be unsuitable. I pointed out that all clubs expected members not to bring in unsuitable guests, and that several of my uncles would be out of place at High Table. Partly as a result of my arguments it was agreed that women should be allowed to dine. It seemed to me a very C. P. Snow sort of situation”

Crick met James Watson in 1951. He had come from America in search of a like-minded brain to help him solve the mystery of DNA, and hopefully the secret of life. It was an instant meeting of minds. Though self-confessed ‘amateurs’, Crick admitted it was "a great help being two of us" and that their discovery of the double-helix was "not a typical bit of science" (extract from Crick's notes on the DNA revolution given to the San Bernardino County Medical Society's General Membership Meeting, 1 April 1986, file Ref: PP/CRI/K/5/9)

Though ebullient and immodest to his colleagues, Crick was uncomfortable with the attention he received for his achievements and as we saw above, he was always anxious to include Watson in any praise received. He said of the 1993 40th anniversary of the double helix discovery “Why anyone should want to celebrate the 40th anniversary of anything is beyond me but I assume they feared that by the 50th anniversary most of those involved might be dead'”. Though he survived the 50th anniversary in 2003, sadly he died of colon cancer the following year. Following his death, a sculpture by the American sculptor Charles Jencks commemorating Crick and Watson’s achievements was donated by Watson to Clare College Gardens in 2005 where Watson was a former alumnus.

The wording on the sculpture explains their discovery simply:

• "These strands unravel during cell reproduction. Genes are encoded in the sequence of bases."

• "The double helix model was supported by the work of Rosalind Franklin and Maurice Wilkins."

• "The structure of DNA was discovered in 1953 by Francis Crick and James Watson while Watson lived here at Clare."

• "The molecule of DNA has two helical strands that are linked by base pairs Adenine - Thymine or Guanine - Cytosine."

So consumed was Crick with his work on the helix structure of DNA that he had a model of it displayed outside his house on 19-20 Portugal Place also referred to as ‘The Golden Helix’ where he lived with his wife Odile from Autumn 1952.

The helix is not double but single here, a simple symbol of Crick’s momentous discovery the previous year. It was here on 18th October 1962 that Cambridge police were allegedly called to a disturbance involving exploding firecrackers being thrown down to the street. The owners had thrown an extravagant party to celebrate being awarded the Nobel Prize for Physiology or Medicine. (p. 1-2, Francis Crick, Hunter of Life’s Secrets by Robert Olby, Cold Spring Harbour Press, 2009). Crick’s partying spirit made him stand out as Matt Ridley points out in his book (Francis Crick, Discoverer of the Genetic Code, 2006): “Crick stands out among the great scientists of history precisely because he was not eccentric, silent, shy or obsessive. He was gregarious and an extrovert.” Allegedly he was a "dandyish feature on the Cambridge scene” and one of the few academics to have a “subscription to Vogue” (p.63, M. Ridley 2006).

Back in February 28 1953, their discovery was first announced by Crick and Watson in the now famous RAF bar of The Eagle pub, a location which just had to be visited. Within a 2-minute walk from the old Cavendish laboratory the pub's many features include a plaque commemorating the announcement as well as a quote by Watson painted on the adjacent door (table 12 for those whom might wish to visit).

Here, beneath the graffiti covered ceiling (created by the cigarette lighters of RAF and American airmen during World War 2) the two scientists regularly lunched 6 days a week to fuel their work. It is tempting to think they were furiously at work all day and every day but, it seems, life was a little more relaxed: in a speech entitled ‘The Way We Were’ given in 1993 at a Cold Spring Harbour event, Crick talks also about the slower pace of life in the late 50's and how on occasions "if it was a nice afternoon", he and Watson would "go punting up the river" ..."time has shown that none of the great scientists in our time were punters"(File ref: PP/CRI/K/12/2)

And thus concluded our tour of Cambridge …

The Dark Lady of DNA

Rosalind Elsie Franklin was born 90 years ago today, on July 25 1920. Franklin was a biophysicist who produced the now famous x-ray of a DNA molecule known as Photo 51 when she worked at King’s College, London in 1951. The photo formed critical evidence that led to the confirmation of the postulated double helical structure of DNA. The image shown above is from the same series of x-rays and is held by Wellcome Images.

Franklin was rewarded little for her contribution towards the discovery of DNA's structure. Co-discoverers Francis Crick and James Watson from Cambridge University were awarded the 1962 Nobel Prize in Physiology or Medicine for their work on nucleic acids (including DNA) alongside Franklin's colleague Maurice Wilkins. Franklin could not have been awarded in conjunction as she had died four years before, and Nobel Prizes are not awarded posthumously. But some feel that Crick and Francis did not sufficiently acknowledge Franklin for producing her crucial evidence*, and many have observed a bitter rivalry between the three.

The Wellcome Library is currently digitising Crick’s personal papers as part of the Modern Genetics and its Foundations project. Although they later became friends, his letters reveal a strong competitive spirit between himself and Franklin, and a patronising view of "the dark lady of DNA", between 1951 and 1953. In a letter to the science fiction writer Isaac Asimov, Crick says,

"Rosalind was a little difficult to get on with on occasions. She was usually charming but could be a bit spikey" (PP/CRI/D/1/3/1).

Franklin’s biographer, Lynne Elkin, wrote an article entitled 'Rosalind Franklin and the Double-Helix' that was published in March 2003 by Physics Today. She approached Crick for editorial advice. Their correspondence contains snippets of Crick’s dismissive attitude towards Franklin’s contribution: "Rosalind’s grasp of the idea of anti-parallel chains was very fleeting".

He goes on to suggest that he and Watson had already arrived at their conclusion regarding the structure of DNA before they saw Photo 51: "the only detail we learned from the B-photo was that the B form was clearly helical which we had been saying all along". In response, Elkin replies in an email to Crick’s assistant:

"I think that their treatment of REF has been like a sword hanging over their heads for 50 years with Jim being too insensitive to care, but Crick being more human … I have gotten a lot of response by people who very undiplomatically call them thieves and worse."

Further to the letters, the Library has more material on Franklin and the discovery of DNA. Wellcome Film holds a recording of the 1987 television film, The Race for the Double Helix. This dramatisation features Jeff Goldblum as Watson and Juliet Stevenson as Franklin. Wellcome Images’ historical collection includes this "funeral card" produced by Franklin and colleague Raymond Gosling, sent to Maurice Wilkins. It is a satirical observation on the unlikelihood of the A-DNA model. An explanation of their joke is here.

As the digitisation project proceeds, we hope more gems like this will be uncovered in the Library’s collections.

*Correction: An earlier version of this post stated that Crick and Watson published Photo 51 in the 1953 Nature paper without crediting Franklin. This is incorrect. A similar x-ray diffraction photograph is printed alongside their paper, but belongs to another paper by Wilkins, who does mention Franklin. The photograph in Wilkins' paper was taken by himself. We apologise for this oversight". (Correction made: 25th August 2010).


Authors: Julia Nurse and Louise Crane

Sir James Black (1924-2010)

Sir James Black, Nobel-Prize winning pharmacologist, died on Sunday at the age of 85.

Between 1978 and 1984, Black was Director of Thereapeutic Research at the Wellcome Research Laboratories (these laboratories being part of the research wing of the Wellcome Foundation, the pharmaceutical business co-founded by Sir Henry Wellcome).

His Nobel Prize - awarded in 1988 for Physiology or Medicine - was shared with Gertrude B. Elion and George H. Hitchings, for their work on drug development (Elion and Hitchings also had strong ties to the Wellcome Foundation, working for almost all of their professional careers for the American wing of the business).

Obituaries have hailed Sir James Black's achievements, particularly his work on beta-blocker drugs (Black is credited with discovering them in 1962). Such drugs now play in a vital role in the treatment of heart attacks and angina.

The Wellcome Library holds a number of items relating to Black. The Wellcome Foundation Archive contains a selected amount of material, with editions of Foundation News (the organisation's in-house publication) contextualising Black's work during his 6 years with the Foundation.

Black also contributed to two Wellcome Witness seminars: Peptic Ulcer: Rise and Fall (Vol. 14) and Clinical Pharmacology in the UK, c. 1950–2000: Influences and institutions (Vol. 33), (these being seminars at which "...significant figures in twentieth-century medicine are invited to discuss specific discoveries or events in recent medical history"). Copies of these works are held by the Wellcome Library and are also freely available online.

Nobel Prize Winners in the Wellcome Library

The award of the Nobel Prizes for 2009 has recently been in the news. Collections in Archives and Manuscripts in the Wellcome Library include the catalogued and available material of over a dozen Nobel Laureates from 1902 onwards, varying from a few letters or research notebooks to very extensive collections of personal papers:

• Henri Becquerel (1852-1908), physics, 1903 (MS.8642)
• Professor Sir Ernst Boris Chain (1906-1979), medicine, 1945 (PP/EBC)
• Francis Harry Compton Crick (1916-2004), physiology and medicine, 1962 (PP/CRI)
• Marie Curie (1867-1934), physics, 1903, chemistry, 1911 (MSS.1978-1979, MS.7811)
• Sir Henry Hallett Dale (1875-1968), physiology and medicine, 1936 (PP/HHD, MS.8552, WF)
• Prince Louis Victor de Broglie (1892-1987), physics, 1929 (MSS.1359 - 1361)
• Paul Ehrlich (1854-1915), medicine, 1908 (PP/EHR)
• Sir Alexander Fleming (1881-1955), medicine, 1945 (MS.7809)
• Professor Archibald Vivian Hill (1886-1977), physiology and medicine, 1922 (GC/74)
• Sir Peter Brian Medawar (1915-1987), physiology/medicine, 1960 (PP/PBM)
• Élie (Ilya) Ilyich Metchnikoff (1845-1916), medicine, 1908 (MS.7311)
• Sir Ronald Ross (1857-1932), medicine, 1902 (GC/59, MS.7495)
• Dr Frederick Sanger (b. 1918), chemistry, 1958, 1980 (SA/BIO/P)

Information on Nobel winners can also be found among institutional records.

• The membership of the Physiological Society (SA/PHY) included 14 Nobel Laureates.
• The records of the Biochemical Society (SA/BIO) include, besides a substantial collection of Frederick Sanger material, items on other Nobel Laureate members.
• The records of the Wellcome Foundation (WF) include material on the several members of staff who were awarded the Nobel Prize.

There is often also correspondence with Laureates, about nominations of specific individuals, and with the Nobel Academy in other collections of personal papers and records of organisations. The papers of Ronald Hare (PP/HAR), who wrote on the discovery of penicillin, and of Robert Gwyn Macfarlane (PP/RGM), who published biographies of Sir Alexander Fleming and Sir Howard Florey, include a substantial amount of material on these Laureates of 1945 in physiology and medicine.

Further information on these holdings can be found via the searchable online catalogue of Archives and Manuscripts.

Proteins and Prizes

Wellcome Image Award winner and current Wellcome Trust grant holder, Venkatraman (Venki) Ramakrishnan, has been named as one of the winners of the Nobel Prize in Chemistry 2009.

Venki's computer-generated molecular model of a ribosome, showing its 3D structure in great detail, impressed the judges of the Wellcome Image Awards in 2008. It is for his research on the structure and function of the ribosome, which converts DNA information into proteins, that the Nobel Prize has been awarded.

Specifically, it is Venki's use of X-ray crystallography to map the atomic structure that has been recognised. This technique has advanced from the standard X-ray, early examples of which are held in the Library's collections.

Venki's Wellcome Award-winning image, the accompanying protein-synthesis animation and a recording of Venki describing his image, background and research are available online.

Author: Louise Crane

Breaking the Mould

As part of their War Beneath the Skin season, BBC4 last night broadcast Breaking the Mould: The Story of Penicillin.

Details:

"Whilst it is widely recognised that Alexander Fleming was the man who discovered penicillin, the truth is a bit more complicated than that and the extraordinary story of Professor Florey is hardly known.

Set against the background of the early years of the Second World War, this factually-based drama shows how it was Professor Florey and his team who persevered against incredible odds to make penicillin an applicable medicine, whilst refusing to patent it for commercial gain.

A revealing, poignant and witty character-driven account of a miraculous scientific breakthrough, Breaking The Mould tells the little known story of Professor Florey and the team of unsung heroes from the prestigious Dunn School of Pathology at Oxford University who were behind the discovery of penicillin, that changed the world of medicine forever".

A number of the Wellcome Library’s archive collections have a direct link to the story of penicillin’s development. These include the papers of Norman Heatley, including his laboratory notebooks and correspondence with Florey; Ernst Chain, who shared the 1945 Nobel Prize in Physiology applied to Medicine with Fleming and Florey; and Sir Edward Mellanby, Secretary of the Medical Research Council during the period, and an important figure in connecting the disparate research communities working in this field.

That the mass production of penicillin in this country was achieved during the Second World War was due in no small part to the creation in 1941 of the Therapeutic Research Corporation (TRC), a consortium of five leading UK drug companies. One of the members was the Wellcome Foundation Ltd, and the papers relating to the involvement of the company in the TRC are part of the Wellcome Foundation Archive.

Breaking the Mould is available to watch through the BBC’s iPlayer.

Happy birthday, Paul Ehrlich!

Paul Ehrlich (1854-1915) was a leading medical researcher of the late nineteenth and early twentieth centuries particularly famed for his work in bacteriology and immunology. He won the Nobel Prize for Medicine in 1908. He is best remembered for 'Dr Ehrlich's Magic Bullet', Compound 606, the arsephanemine drug salvarsan discovered in 1909, which provided a cure for syphilis,.

Shortly after the Second World War, Gunther Schwerin, one of his grandsons, located Ehrlich's copybooks in Germany, and sent them, along with other material, to the Wellcome Historical Medical Museum in London for safekeeping. While they were there, his former secretary Martha Marquardt, who was also his biographer, and the co-editor of the four volumes of his collected papers, one of the few people able to read his handwriting, prepared seven sets of typewritten transcripts. These carbons are the 3rd set (of 4) copies, formerly in the possession of Sir Henry Dale, and presented by him to the Library early in 1958. The originals, and 3 sets of copies, are now held with the Paul Ehrlich archive in the Rockefeller Archive Center, New York, by whose kind permission this particular set of copies is made available in the Wellcome Library

There are 6 series, representing both copies of letters sent by him, and experimental notebooks. There are not complete sets of transcripts for all of these: in some cases the originals themselves appear to no longer exist. According to a letter from Dr E A Underwood, Director of the Wellcome Historical Medical Museum, to Gunther Schwerin, 25 Mar 1963 (WA/HMM/CO/Eau/13), there are some misreadings by Marquardt of scientific terms in the originals, as, although she was capable of deciphering Ehrlich's writing, she was not herself a scientist.

Ehrlich's name is one of those on the frieze of names of the most distinguished figures in medical science, created in 1913 for the Wellcome Historical Medical Museum when it was based in Wigmore Street. The frieze is now viewable around the gallery of the Wellcome Library Reading Room at 183 Euston Road