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Frederick Sanger

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Frederick Sanger
Frederick Sanger2.jpg
Born (1918-08-13) 13 August 1918
Gloucestershire, England, United Kingdom
Residence United Kingdom
Nationality British
Fields Biochemist
Institutions University of Cambridge
Laboratory of Molecular Biology
Alma mater University of Cambridge
Doctoral advisor Albert Neuberger
Doctoral students Rodney Robert Porter
Liz Blackburn
Known for Amino acid sequence of insulin, dideoxy method of sequencing DNA
Notable awards Nobel Prize in Chemistry (1958)
Copley Medal (1977)
Nobel Prize in Chemistry (1980)

Frederick Sanger, OM, CH, CBE, FRS ( / ˈ s æ ŋ ər /) (born 13 August 1918) is a British biochemist who was twice the recipient of the Nobel Prize for Chemistry, the only person to have been so. In 1958 he was awarded a Nobel prize in chemistry "for his work on the structure of proteins, especially that of insulin". In 1980, Walter Gilbert and Sanger shared half of the chemistry prize "for their contributions concerning the determination of base sequences in nucleic acids". The other half was awarded to Paul Berg "for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA".

He is the fourth person to have been awarded two Nobel Prizes, either individually or in tandem with others.

Early life and education

Frederick Sanger was born on 13 August 1918 in Rendcomb, a small village in Gloucestershire, the second son of Frederick Sanger, a general practitioner, and his wife, Cicely Sanger (née Crewdson). He was one of three children. His brother, Theodore was only a year older while his sister May (Mary) was five years younger. His father had worked as an Anglican medical missionary in China but returned to England because of ill health. He was 40 in 1916 when he married Cicely who was 4 years younger. Sanger’s father converted to Quakerism soon after his two sons were born and brought up the children as Quakers. Sanger’s mother was the daughter of a wealthy cotton manufacturer and had a Quaker background but Cicely herself was not a Quaker.

When Sanger was around five years old the family moved to the small village of Tanworth-in-Arden in Warwickshire. The family were reasonably wealthy and employed a governess to teach the children. In 1927, at the age of nine, he was sent to the Downs School a residential preparatory school run by Quakers near Malvern. His brother Theo was a year ahead of him at the same school. In 1932, at the age of 14, he was sent to the recently established Bryanston School in Dorset. This used the Dalton system and had a more liberal regime which Sanger much preferred. At the school he liked his teachers and particularly enjoyed scientific subjects.

He achieved good results in the School Certificate examinations and in 1936 moved as an undergraduate to St John's College, Cambridge to study natural sciences. His father had attended the same college. For Part I of his Tripos he took courses in physics, chemistry, biochemistry and mathematics but struggled with physics and mathematics. Many of the other students had studied more mathematics at school. In his second year he replaced physics with physiology. He took three years to obtain his Part I. For his Part II he studied biochemistry. It was a relatively new department founded by Gowland Hopkins with enthusiastic lecturers who included Malcolm Dixon, Joseph Needham and Ernest Baldwin. Sanger graduated with a first class degree in 1939.

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 Peace Pledge Union. It was through his involvement with the Cambridge Scientists’ Anti-War Group that he met his future wife, Joan Howe, who was studying economics at Newnham College. They courted while he was studying for his Part II exams and married after he had graduated in December 1940. With the onset of the Second World War in 1939, he was granted unconditional exemption from military service as a conscientious objector.

Sanger began studying for a PhD in October 1940 under N.W. "Bill" Pirie. His project was to investigate whether edible protein could be obtained from grass. After little more than a month Pirie left the department and Albert Neuberger became his adviser. Sanger changed his research project to study the metabolism of lysine and a more practical problem concerning the nitrogen of potatoes. His thesis had the title: "The metabolism of the amino acid lysine in the animal body". He was examined by Charles Harington and Albert Charles Chibnall and awarded his doctorate in 1943.


Amino acid sequence of bovine insulin

Sequencing insulin

Neuberger moved to the National Institute for Medical Research in London but Sanger stayed in Cambridge and in 1943 joined the group of Charles Chibnall, a protein chemist who had recently taken up the chair in the Department of Biochemistry. Chibnall had already done some work on the amino acid composition of bovine insulin and suggested that Sanger look at the amino groups in the protein. Insulin could be purchased from Boots and was one of the very few proteins that were available in a pure form. Up to this time Sanger had been funding himself. In Chibnall's group he was initially supported by the Medical Research Council and then from 1944 until 1951 by a Beit Memorial Fellowship for Medical Research.

Sanger's first triumph was to determine the complete amino acid sequence of the two polypeptide chains of bovine insulin in 1951. 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. For this purpose he used the "Sanger Reagent", fluorodinitrobenzene ( FDNB), to react with the exposed amino groups in the protein and in particular with the N-terminal amino group at one end of the polypeptide chain. He then partially hydrolysed the insulin into short peptides (either with hydrochloric acid or using an enzyme such as trypsin). The mixture of peptides was fractionated in two dimensions on a sheet of filter paper: first 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 which 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. 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 sequences to deduce the complete structure of insulin. Sanger's principal conclusion was that the two polypeptide chains of the protein insulin had precise amino acid sequences and, by extension, that every protein had a unique sequence. It was this achievement that earned him his first Nobel prize in Chemistry in 1958. This discovery was crucial for the later sequence hypothesis of Crick for developing ideas of how DNA codes for proteins.

Sequencing RNA

From 1951 Sanger was a member of the external staff of the Medical Research Council and when they opened 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. Soon after his move he started looking at the possibility of sequencing RNA molecules and began developing methods for separating ribonucleotide fragments generated with specific nucleases. One of the problems was to obtain a pure piece of RNA to sequence. In the course of this he discovered in 1964, with Kjeld Marcker, the formylmethionine tRNA which initiates protein synthesis in bacteria. He was beaten in the race to be the first to sequence a 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. By 1967 Sanger's group had determined the nucleotide sequence of the 5S ribosomal RNA from Escherichia coli, a small RNA of 120 nucleotides.

Sequencing DNA

He then turned to sequencing DNA which would require an entirely different approach. He looked at different ways of using DNA polymerase I from E. coli to copy single stranded DNA. In 1975 together with Alan Coulson he published a sequencing procedure using DNA polymerase with radiolabelled nucleotides that he called the "Plus and Minus" technique. This involved two closely related methods that generated short oligonucleotides with defined 3' termini. These could be fractionated by electrophoresis on a polyacrylamide gel and visualised using autoradiography. The procedure could sequence up to 80 nucleotides in one go and was a big improvement on what 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. 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.

In 1977 Sanger and colleagues introduced the "dideoxy" chain-termination method for sequencing DNA molecules, also known as the "Sanger method". 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. The new method was used by Sanger and colleagues to sequence human mitochondrial DNA (16,569 base pairs) and bacteriophage λ (48,502 base pairs). The dideoxy method was eventually used to sequence the entire human genome.

He is thus far (2012) the only person to have been awarded two Nobel Prizes in Chemistry, and one of only four two-time Nobel laureates: the other three were Marie Curie (Physics, 1903 and Chemistry, 1911), Linus Pauling (Chemistry, 1954 and Peace, 1962) and John Bardeen (twice Physics, 1956 and 1972).

Marriage and family

Sanger married Margaret Joan Howe in 1940. They have three children: Robin, born in 1943, Peter born in 1946 and Sally Joan born in 1960.

Later life

The Sanger Institute

Sanger retired in 1983 to his home, "Far Leys", in Swaffham Bulbeck outside Cambridge and next to Sanger Wood.

In 1992, the Wellcome Trust and the Medical Research Council founded the Sanger Centre (now the Sanger Institute), named after him. The Institute is located on the Wellcome Trust Genome Campus near Hinxton, only a few miles from Sanger's home. He agreed to having the Centre named after him when asked by John Sulston, the founding director, but warned, "It had better be good." It was opened by Sanger himself on 4 October 1993, with a staff of less than 50 people, and went on to take a leading role in the sequencing of the human genome. The Institute now has over 900 people and is one of the world's largest genomic research centres.

He has lost his religious faith and calls himself an agnostic. 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."

He declined the offer of a knighthood as he did not wish to be addressed as "Sir" but later accepted the award of an Order of Merit.

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 remarkable research from 1944 to 1983. In reporting this matter, Science magazine noted that Sanger, "the most self-effacing person you could hope to meet", was now spending his time gardening at his Cambridgeshire home.

Awards and honours

  • Fellow of the Royal Society - 1954
  • Commander of the Order of the British Empire - 1963
  • Order of the Companions of Honour - 1981
  • Order of Merit (Commonwealth) - 1986
  • William Bate Hardy Prize - 1976
  • Nobel Prize in Chemistry - 1958, 1980
  • Corday–Morgan Medal - 1951
  • Royal Medal - 1969
  • Gairdner Foundation International Award - 1971
  • Copley Medal - 1977
  • G.W. Wheland Award - 1978
  • Louisa Gross Horwitz Prize - 1979
  • Albert Lasker Award for Basic Medical Research - 1979
  • Association of Biomolecular Resource Facilities Award - 1994

Selected publications by Frederick Sanger

  • Neuberger, A.; Sanger, F. (1942). "The nitrogen of the potato". The Biochemical journal 36 (7–9): 662–671. PMC  1266851. PMID  16747571. //
  • Neuberger, A.; Sanger, F. (1944). "The metabolism of lysine". The Biochemical journal 38 (1): 119–125. PMC  1258037. PMID  16747737. //
  • Sanger, F. (1945). "The free amino groups of insulin". The Biochemical journal 39 (5): 507–515. PMC  1258275. PMID  16747948. //
  • Sanger, F. (1947). "Oxidation of insulin by performic acid". Nature 160 (4061): 295–296. doi: 10.1038/160295b0. PMID  20344639.
  • Porter, R.; Sanger, F. (1948). "The free amino groups of haemoglobins". The Biochemical journal 42 (2): 287–294. PMC  1258669. PMID  16748281. //
  • Sanger, F. (1949). "Fractionation of oxidized insulin". The Biochemical journal 44 (1): 126–128. PMC  1274818. PMID  16748471. //
  • Sanger, F. (1949). "The terminal peptides of insulin". The Biochemical journal 45 (5): 563–574. PMC  1275055. PMID  15396627. //
  • Sanger, F.; Tuppy, H. (1951a), "The amino-acid sequence in the phenylalanyl chain of insulin. 1. The identification of lower peptides from partial hydrolysates", Biochemical Journal 49 (4): 463–481, PMC  1197535, PMID  14886310.
  • Sanger, F.; Tuppy, H. (1951b), "The amino-acid sequence in the phenylalanyl chain of insulin. 2. The investigation of peptides from enzymic hydrolysates", Biochemical Journal 49 (4): 481–490, PMC  1197536, PMID  14886311.
  • Sanger, F.; Thompson, E.O.P. (1953a), "The amino-acid sequence in the glycyl chain of insulin. 1. The identification of lower peptides from partial hydrolysates", Biochemical Journal 53 (3): 353–366, PMC  1198157, PMID  13032078.
  • Sanger, F.; Thompson, E.O.P. (1953b), "The amino-acid sequence in the glycyl chain of insulin. 2. The investigation of peptides from enzymic hydrolysates", Biochemical Journal 53 (3): 366–374, PMC  1198158, PMID  13032079.
  • Sanger, F.; Thompson, E.O.p.; Kitai, R. (1955), "The amide groups of insulin", Biochemical Journal 59 (3): 509–518, PMC  1216278, PMID  14363129.
  • Ryle, A.P.; Sanger, F.; Smith, L.F.; Kitai, R. (1955), "The disulphide bonds of insulin", Biochemical Journal 60 (4): 541–556, PMC  1216151, PMID  13249947.
  • Brown, H.; Sanger, F.; Kitai, R. (1955), "The structure of pig and sheep insulins", Biochemical Journal 60 (4): 556–565, PMC  1216152, PMID  13249948.
  • Sanger, F. (1959), "Chemistry of Insulin: determination of the structure of insulin opens the way to greater understanding of life processes", Science 129 (3359): 1340–1344, Bibcode 1959Sci...129.1340G, doi: 10.1126/science.129.3359.1340, PMID  13658959.
  • Milstein, C.; Sanger, F. (1961), "An amino acid sequence in the active centre of phosphoglucomutase", Biochemical Journal 79 (3): 456–469, PMC  1205670, PMID  13771000.
  • Marcker, K.; Sanger, F. (1964), "N-formyl-methionyl-S-RNA", Journal of Molecular Biology 8 (6): 835–840, doi: 10.1016/S0022-2836(64)80164-9, PMID  14187409.
  • Sanger, F.; Brownlee, G.G.; Barrell, B.G. (1965), "A two-dimensional fractionation procedure for radioactive nucleotides", Journal of Molecular Biology 13 (2): 373–398, doi: 10.1016/S0022-2836(65)80104-8, PMID  5325727.
  • Brownlee, G.G.; Sanger, F.; Barrell, B.G. (1967), "Nucleotide sequence of 5S-ribosomal RNA from Escherichia coli", Nature 215 (5102): 735–736, Bibcode 1967Natur.215..735B, doi: 10.1038/215735a0, PMID  4862513.
  • Brownlee, G.G.; Sanger, F. (1967), "Nucleotide sequences from the low molecular weight ribosomal RNA of Escherichia coli", Journal of Molecular Biology 23 (3): 337–353, doi: 10.1016/S0022-2836(67)80109-8, PMID  4291728.
  • Brownlee, G.G.; Sanger, F.; Barrell, B.G. (1968), "The sequence of 5S ribosomal ribonucleic acid", Journal of Molecular Biology 34 (3): 379–412, doi: 10.1016/0022-2836(68)90168-X, PMID  4938553.
  • Adams, J.M.; Jeppesen, P.G.; Sanger, F.; Barrell, B.G. (1969), "Nucleotide sequence from the coat protein cistron of R17 bacteriophage RNA", Nature 223 (5210): 1009–1014, Bibcode 1969Natur.223.1009A, doi: 10.1038/2231009a0, PMID  5811898.
  • Barrell, B.G.; Sanger, F. (1969), "The sequence of phenylalanine tRNA from E. coli", FEBS Letters 3 (4): 275–278, doi: 10.1016/0014-5793(69)80157-2, PMID  11947028.
  • Jeppesen, P.G.; Barrell, B.G.; Sanger, F.; Coulson, A.R. (1972), "Nucleotide sequences of two fragments from the coat-protein cistron of bacteriophage R17 ribonucleic acid", Biochemical Journal 128 (5): 993–1006, PMC  1173988, PMID  4566195.
  • Sanger, F.; Donelson, J.E.; Coulson, A.R.; Kössel, H.; Fischer, D. (1973), "Use of DNA Polymerase I Primed by a Synthetic Oligonucleotide to Determine a Nucleotide Sequence in Phage f1 DNA", Proceedings of the National Academy of Sciences USA 70 (4): 1209–1213, Bibcode 1973PNAS...70.1209S, doi: 10.1073/pnas.70.4.1209, PMC  433459, PMID  4577794.
  • Sanger, F.; Coulson, A.R. (1975), "A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase", Journal of Molecular Biology 94 (3): 441–448, doi: 10.1016/0022-2836(75)90213-2, PMID  1100841.
  • Sanger, F.; Nicklen, S.; Coulson, A.R. (1977), "DNA sequencing with chain-terminating inhibitors", Proceedings of the National Academy of Sciences USA 74 (12): 5463–5467, Bibcode 1977PNAS...74.5463S, doi: 10.1073/pnas.74.12.5463, PMC  431765, PMID  271968. According to the Institute for Scientific Information (ISI) database, by October 2010 this paper had been cited over 64,000 times.
  • Sanger, F.; Air, G.M.; Barrell, B.G.; Brown, N.L.; Coulson, A.R.; Fiddes, C.A.; Hutchinson, C.A.; Slocombe, P.M. et al. (1977), "Nucleotide sequence of bacteriophage φX174 DNA", Nature 265 (5596): 687–695, Bibcode 1977Natur.265..687S, doi: 10.1038/265687a0, PMID  870828.
  • Sanger, F.; Coulson, A.R. (1978), "The use of thin acrylamide gels for DNA sequencing", FEBS Letters 87 (1): 107–110, doi: 10.1016/0014-5793(78)80145-8, PMID  631324.
  • Sanger, F.; Coulson, A.R.; Barrell, B.G.; Smith, A.J.; Roe, B.A. (1980), "Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing", Journal of Molecular Biology 143 (2): 161–178, doi: 10.1016/0022-2836(80)90196-5, PMID  6260957.
  • Anderson, S.; Bankier, A.T.; Barrell, B.G.; De Bruijn, M.H.; Coulson, A.R.; Drouin, J.; Eperon, I.C.; Nierlich, D.P. et al. (1981), "Sequence and organization of the human mitochondrial genome", Nature 290 (5806): 457–465, Bibcode 1981Natur.290..457A, doi: 10.1038/290457a0, PMID  7219534.
  • Anderson, S.; De Bruijn, M.H.; Coulson, A.R.; Eperon, I.C.; Sanger, F.; Young, I.G. (1982), "Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome", Journal of Molecular Biology 156 (4): 683–717, doi: 10.1016/0022-2836(82)90137-1, PMID  7120390.
  • Sanger, F.; Coulson, A.R.; Hong, G.F.; Hill, D.F.; Petersen, G.B. (1982), "Nucleotide sequence of bacteriophage λ DNA", Journal of Molecular Biology 162 (4): 729–773, doi: 10.1016/0022-2836(82)90546-0, PMID  6221115.
  • Sanger, F. (1988), "Sequences, sequences, and sequences", Annual Review of Biochemistry 57: 1–28, doi: 10.1146/, PMID  2460023.
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