Frederick Sanger

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Frederick Sanger
PhD
)
Known for
SpouseMargaret Joan Howe[4]
Awards
Scientific career
FieldsBiochemistry
Institutions
ThesisThe metabolism of the amino acid lysine in the animal body (1943)
Doctoral advisorAlbert Neuberger[1]
Doctoral students

Frederick Sanger

FAA (/ˈsæŋər/; 13 August 1918 – 19 November 2013) was a British biochemist who received the Nobel Prize in Chemistry
twice.

He won the 1958 Chemistry Prize for determining the amino acid sequence of insulin and numerous other proteins, demonstrating in the process that each had a unique, definite structure; this was a foundational discovery for the central dogma of molecular biology.

At the newly constructed

Laboratory of Molecular Biology in Cambridge, he developed and subsequently refined the first-ever DNA sequencing technique, which vastly expanded the number of feasible experiments in molecular biology and remains in widespread use today. The breakthrough earned him the 1980 Nobel Prize in Chemistry, which he shared with Walter Gilbert and Paul Berg
.

He is one of only three people to have won multiple Nobel Prizes in the same category (the others being John Bardeen in physics and Karl Barry Sharpless in chemistry),[5] and one of five persons with two Nobel Prizes.

Early life and education

Frederick Sanger was born on 13 August 1918 in

Quakerism soon after his two sons were born and brought up the children as Quakers. Sanger's mother was the daughter of an affluent cotton manufacturer and had a Quaker background, but was not a Quaker.[7]

When Sanger was around five years old the family moved to the small village of

Sieg Heil salute.[9]

In 1936 Sanger went to

Gowland Hopkins with enthusiastic lecturers who included Malcolm Dixon, Joseph Needham and Ernest Baldwin.[7]

Both his parents died from cancer during his first two years at Cambridge. His father was 60 and his mother was 58. As an undergraduate Sanger's beliefs were strongly influenced by his Quaker upbringing. He was a pacifist and a member of the

Newnham College. They courted while he was studying for his Part II exams and married after he had graduated in December 1940. Sanger, although brought up and influenced by his religious upbringing, later began to lose sight of his Quaker related ways. He began to see the world through a more scientific lens, and with the growth of his research and scientific development he slowly drifted farther from the faith he grew up with. He has nothing but respect for the religious and states he took two things from it, truth and respect for all life.[10] Under the Military Training Act 1939 he was provisionally registered as a conscientious objector, and again under the National Service (Armed Forces) Act 1939, before being granted unconditional exemption from military service by a tribunal. In the meantime he undertook training in social relief work at the Quaker centre, Spicelands, Devon and served briefly as a hospital orderly.[7]

Sanger began studying for a

Albert Charles Chibnall and awarded his doctorate in 1943.[7]

Research and career

Amino acid sequence of bovine insulin, with disulfide bridges shown in red.

Sequencing insulin

Neuberger moved to the

Beit Memorial Fellowship for Medical Research.[6]

Sanger's first triumph was to determine the complete

sequence of the two polypeptide chains of bovine insulin, A and B, in 1952 and 1951, respectively.[15][16] Prior to this it was widely assumed that proteins were somewhat amorphous. In determining these sequences, Sanger proved that proteins have a defined chemical composition.[7]

To get to this point, Sanger refined a partition chromatography method first developed by

electrophoresis in one dimension and then, perpendicular to that, by chromatography in the other. The different peptide fragments of insulin, detected with ninhydrin, moved to different positions on the paper, creating a distinct pattern that Sanger called "fingerprints". The peptide from the N-terminus could be recognised by the yellow colour imparted by the FDNB label and the identity of the labelled amino acid at the end of the peptide determined by complete acid hydrolysis and discovering which dinitrophenyl-amino acid was there.[7]

By repeating this type of procedure Sanger was able to determine the sequences of the many peptides generated using different methods for the initial partial hydrolysis. These could then be assembled into the longer

Nobel prize in Chemistry in 1958.[20] This discovery was crucial to the later sequence hypothesis of Francis Crick for developing ideas of how DNA codes for proteins.[21]

Sequencing RNA

From 1951 Sanger was a member of the external staff of the

Laboratory of Molecular Biology in 1962, he moved from his laboratories in the Biochemistry Department of the university to the top floor of the new building. He became head of the Protein Chemistry division.[7]

Prior to his move, Sanger began exploring the possibility of sequencing RNA molecules and began developing methods for separating ribonucleotide fragments generated with specific nucleases. This work he did while trying to refine the sequencing techniques he had developed during his work on insulin.[21]

The key challenge in the work was finding a pure piece of RNA to sequence. In the course of the work he discovered in 1964, with Kjeld Marcker, the

tRNA molecule by a group led by Robert Holley from Cornell University, who published the sequence of the 77 ribonucleotides of alanine tRNA from Saccharomyces cerevisiae in 1965.[23] By 1967 Sanger's group had determined the nucleotide sequence of the 5S ribosomal RNA from Escherichia coli, a small RNA of 120 nucleotides.[24]

Sequencing DNA

Main article: DNA sequencing

Sanger then turned to sequencing DNA, which would require an entirely different approach. He looked at different ways of using

autoradiography. The procedure could sequence up to 80 nucleotides in one go and was a big improvement on what had gone before, but was still very laborious. Nevertheless, his group were able to sequence most of the 5,386 nucleotides of the single-stranded bacteriophage φX174.[28] This was the first fully sequenced DNA-based genome. To their surprise they discovered that the coding regions of some of the genes overlapped with one another.[2]

In 1977 Sanger and colleagues introduced the "dideoxy" chain-termination method for sequencing DNA molecules, also known as the "

Sanger method".[27][29] This was a major breakthrough and allowed long stretches of DNA to be rapidly and accurately sequenced. It earned him his second Nobel prize in Chemistry in 1980, which he shared with Walter Gilbert and Paul Berg.[30] The new method was used by Sanger and colleagues to sequence human mitochondrial DNA (16,569 base pairs)[31] and bacteriophage λ (48,502 base pairs).[32] The dideoxy method was eventually used to sequence the entire human genome.[33]

Postgraduate students

During the course of his career Sanger supervised more than ten PhD students, two of whom went on to also win Nobel Prizes. His first graduate student was

antibodies.[34] Elizabeth Blackburn studied for a PhD in Sanger's laboratory between 1971 and 1974.[2][35] She shared the 2009 Nobel Prize in Physiology or Medicine with Carol W. Greider and Jack W. Szostak for her work on telomeres and the action of telomerase.[36]

Sanger's rule

... anytime you get technical development that’s two to threefold or more efficient, accurate, cheaper, a whole range of experiments opens up.[37]

This rule should not be confused with Terence Sanger's rule, which is related to Oja's rule.

Awards and honours

As of 2015, Sanger is one of the only two people to have been awarded the Nobel Prize in Chemistry twice (the other being

Peace, 1962), John Bardeen (twice Physics, 1956 and 1972), and Karl Barry Sharpless (twice Chemistry, 2001 and 2022).[5]

The

Wellcome Trust Sanger Institute (formerly the Sanger Centre) is named in his honour.[2]

Personal life

Marriage and family

Sanger married Margaret Joan Howe (not to be confused with Margaret Sanger, the American pioneer of birth control) in 1940. She died in 2012. They had three children — Robin, born in 1943, Peter born in 1946 and Sally Joan born in 1960.[6] He said that his wife had "contributed more to his work than anyone else by providing a peaceful and happy home."[43]

Later life

The Sanger Institute

Sanger retired in 1983, aged 65, to his home, "Far Leys", in Swaffham Bulbeck outside Cambridge.[2]

In 1992, the

genomic
research centres.

Sanger said he found no evidence for a God so he became an agnostic.[45] In an interview published in the Times newspaper in 2000 Sanger is quoted as saying: "My father was a committed Quaker and I was brought up as a Quaker, and for them truth is very important. I drifted away from those beliefs – one is obviously looking for truth, but one needs some evidence for it. Even if I wanted to believe in God I would find it very difficult. I would need to see proof."[46]

He declined the offer of a

Order of Merit, which can have only 24 living members.[43][45][46]

In 2007 the British Biochemical Society was given a grant by the Wellcome Trust to catalogue and preserve the 35 laboratory notebooks in which Sanger recorded his research from 1944 to 1983. In reporting this matter, Science noted that Sanger, "the most self-effacing person you could hope to meet", was spending his time gardening at his Cambridgeshire home.[47]

Sanger died in his sleep at Addenbrooke's Hospital in Cambridge on 19 November 2013.[43][48] As noted in his obituary, he had described himself as "just a chap who messed about in a lab",[49] and "academically not brilliant".[50]

Global policy

He was one of the signatories of the agreement to convene a convention for drafting a

Constitution for the Federation of Earth.[53]

Selected publications

References

Citations

  1. S2CID 72943723
    .
  2. ^
    doi:10.1098/rsbm.2015.0013
    .
  3. doi:10.1038/503442a
    .
  4. ^ "The Nobel Prize in Chemistry 1958".
  5. ^ a b "Nobel Prize Facts". Nobelprize.org. Retrieved 1 September 2015.
  6. ^ a b c d "The Nobel Prize in Chemistry 1958: Frederick Sanger – biography". Nobelprize.org. Retrieved 10 August 2020.
  7. ^ a b c d e f g h i j "A Life of Research on the Sequences of Proteins and Nucleic Acids: Fred Sanger in conversation with George Brownlee". Biochemical Society, Edina – Film & Sound Online. 9 October 1992. Archived from the original on 13 March 2014. Retrieved 29 April 2013.. Subscription required. A 200 min interview divided into 44 segments. Notes give the content of each segment. [dead link]
  8. ^ Marks, Lara. "Sanger's early life: From the cradle to the laboratory". The path to DNA sequencing: The life and work of Fred Sanger. What is Biotechnology. Retrieved 1 September 2015.
  9. ISBN 978-3-319-54707-7
    .
  10. ^ "The Nobel Prize in Chemistry 1980".
  11. ^ Sanger, Frederick (1944). The metabolism of the amino acid lysine in the animal body (PhD thesis). University of Cambridge.
  12. ^ Neuberger & Sanger 1942; Neuberger & Sanger 1944
  13. American Academy of Achievement
    .
  14. S2CID 85124201
    . Section on insulin starts on page 153.
  15. ^ Sanger & Tuppy 1951a; Sanger & Tuppy 1951b; Sanger & Thompson 1953a; Sanger & Thompson 1953b
  16. ^ Sanger, F. (1958), Nobel lecture: The chemistry of insulin (PDF), Nobelprize.org, retrieved 18 October 2010. Sanger's Nobel lecture was also published in Science: Sanger 1959
  17. ^ Marks, Lara. "Sequencing proteins: Insulin". The path to DNA sequencing: The life and work of Fred Sanger. What is Biotechnology. Retrieved 1 September 2015.
  18. ^ Ryle et al. 1955.
  19. PMID 12399368
    .
  20. ^ a b "The Nobel Prize in Chemistry 1958: Frederick Sanger". Nobelprize.org. Retrieved 8 October 2010.
  21. ^ a b Marks, Lara. "The path to sequencing nucleic acids". The path to DNA sequencing: The life and work of Fred Sanger. What is Biotechnology. Retrieved 1 September 2015.
  22. ^ Marcker & Sanger 1964
  23. S2CID 40989800
    .
  24. ^ Brownlee, Sanger & Barrell 1967; Brownlee, Sanger & Barrell 1968
  25. ^ Sanger et al. 1973
  26. ^ Sanger & Coulson 1975
  27. ^ a b Sanger, F. (1980). "Nobel lecture: Determination of nucleotide sequences in DNA" (PDF). Nobelprize.org. Retrieved 15 September 2019.
  28. ^ Sanger et al. 1977
  29. ^ a b Sanger, Nicklen & Coulson 1977.
  30. ^ a b "The Nobel Prize in Chemistry 1980: Paul Berg, Walter Gilbert, Frederick Sanger". Nobelprize.org. Retrieved 8 October 2010.
  31. ^ Anderson et al. 1981
  32. ^ Sanger et al. 1982
  33. PMID 24380948
    .
  34. ^ "The Nobel Prize in Physiology or Medicine 1972". Nobelprize.org. Retrieved 1 September 2015.
  35. ^ Blackburn, E. H. (1974). Sequence studies on bacteriophage ØX174 DNA by transcription (PhD thesis). University of Cambridge. Archived from the original on 5 March 2016. Retrieved 4 July 2015.
  36. ^ "The Nobel Prize in Physiology or Medicine 2009". Nobelprize.org. Retrieved 1 September 2015.
  37. ^ "Schlessinger, David" (PDF). National Human Genome Research Institute (NHGRI, genome.gov). March 2018.
  38. ^ "The ABRF Award for Outstanding Contributions to Biomolecular Technologies". Association of Biomolecular Resource facilities. Archived from the original on 6 August 2020. Retrieved 11 August 2020.
  39. American Academy of Achievement
    .
  40. ^ "Summit Overview Photo". Awards Council member and Nobel Prize laureate Dr. Charles H. Townes presenting the American Academy of Achievement's Golden Plate Award to British biochemist Dr. Frederick Sanger, recipient of two Nobel Prizes in Chemistry, at the 2000 Summit in Hampton Court.
  41. ^ "2016 Awardees". American Chemical Society, Division of the History of Chemistry. University of Illinois at Urbana-Champaign School of Chemical Sciences. 2016. Retrieved 14 June 2017.
  42. ^ "Citation for Chemical Breakthrough Award" (PDF). American Chemical Society, Division of the History of Chemistry. University of Illinois at Urbana-Champaign School of Chemical Sciences. 2016. Retrieved 14 June 2017.
  43. ^ a b c "Frederick Sanger, OM". The Telegraph. 20 November 2013. Archived from the original on 12 January 2022. Retrieved 20 November 2013.
  44. ^ a b c "Frederick Sanger". Wellcome Trust Sanger Institute. Archived from the original on 7 April 2011. Retrieved 12 October 2010.
  45. ^
    ISBN 978-1-86094-288-4
    .
  46. ^ a b Ahuja, Anjana (12 January 2000). "The double Nobel laureate who began the book of life". The Times. London. p. 40. Archived from the original on 11 December 2008. Retrieved 18 October 2010 – via warwick.ac.uk.
  47. S2CID 220092058
    .
  48. ^ "Frederick Sanger: Nobel Prize winner dies at 95". BBC.co.uk. 20 November 2013. Retrieved 20 November 2013.
  49. ^ "Frederick Sanger: Unassuming British biochemist whose pivotal and far-reaching discoveries made him one of a handful of double Nobel prizewinners". The Times. London. 21 November 2013. p. 63.
  50. ^ "Frederick Sanger's achievements cannot be overstated". The Conversation. 21 November 2013.
  51. ^ "Letters from Thane Read asking Helen Keller to sign the World Constitution for world peace. 1961". Helen Keller Archive. American Foundation for the Blind. Retrieved 1 July 2023.
  52. ^ "Letter from World Constitution Coordinating Committee to Helen, enclosing current materials". Helen Keller Archive. American Foundation for the Blind. Retrieved 3 July 2023.
  53. ^ "Preparing earth constitution | Global Strategies & Solutions | The Encyclopedia of World Problems". The Encyclopedia of World Problems | Union of International Associations (UIA). Retrieved 15 July 2023.

Bibliography

External links

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