Frederick Sanger (; 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), and one of five persons with two Nobel Prizes.

Early life and education

Frederick Sanger was born on 13 August 1918 in Rendcomb, a small village in Gloucestershire, England, 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 four 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 an affluent cotton manufacturer and had a Quaker background, but was not a Quaker. In 1935, prior to heading off to college, Sanger was sent to Schule Schloss Salem in southern Germany on an exchange program. The school placed a heavy emphasis on athletics, which caused Sanger to be much further ahead in the course material compared to the other students. He was shocked to learn that each day was started with readings from Hitler's Mein Kampf, followed by a Sieg Heil salute.

In 1936 Sanger went 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 and obtained a 1st Class Honours. Biochemistry was a relatively new department founded by Gowland Hopkins with enthusiastic lecturers who included Malcolm Dixon, Joseph Needham and Ernest Baldwin. 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. 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. 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 the pharmacy chain 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. 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. 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 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. 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 to the later sequence hypothesis of Francis Crick for developing ideas of how DNA codes for proteins.

Sequencing RNA

thumb|Sanger in 1960

From 1951 Sanger was a member of the external staff of the Medical Research Council 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

Sanger 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 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. 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. 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.

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 Rodney Porter who joined the research group in 1947. Elizabeth Blackburn studied for a PhD in Sanger's laboratory between 1971 and 1974. 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.

Sanger's rule

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

Awards and honours

, Sanger is one of the only two people to have been awarded the Nobel Prize in Chemistry twice (the other being Karl Barry Sharpless in 2001 and 2022), and one of only five two-time Nobel laureates: The other four were Marie Curie (Physics, 1903 and Chemistry, 1911), Linus Pauling (Chemistry, 1954 and Peace, 1962), John Bardeen (twice Physics, 1956 and 1972), and Karl Barry Sharpless (twice Chemistry, 2001 and 2022).

  • Golden Plate Award of the American Academy of Achievement – 2000
  • Citation for Chemical Breakthrough Award from the Division of History of Chemistry of the American Chemical Society – 2016

The Wellcome Trust Sanger Institute (formerly the Sanger Centre) is named in his honour. The institute is 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." 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". He is quoted as saying, "A knighthood makes you different, doesn't it, and I don't want to be different." In 1986 he accepted admission to the Order of Merit, which can have only 24 living members.

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

Global policy

He was one of the signatories of the agreement to convene a convention for drafting a world constitution. As a result, for the first time in human history, a World Constituent Assembly convened to draft and adopt a Constitution for the Federation of Earth.

Selected publications

  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • .
  • . According to the Institute for Scientific Information (ISI) database, by October 2010 this paper had been cited over 64,000 times.
  • .
  • .
  • .
  • .
  • .
  • .
  • .

References

Citations

Bibliography

  • Chapters 4-6 contain the 1992 interview that the author conducted with Sanger.
  • .
  • .
  • . Interviewed by Lewis Wolpert. Duration 1 hour.
  • The Sanger Institute
  • About the 1958 Nobel Prize
  • About the 1980 Nobel Prize
  • Fred Sanger 2001 Video Documentary by The Vega Science Trust
  • Frederick Sanger interviewed by Alan Macfarlane, 24 August 2007 (video), also available on . Duration 57 minutes.
  • Frederick Sanger archive collection – Wellcome Library finding aid for the digitised collection.