Frederick Sanger OM CH CBE FAA was a British biochemist who won the Nobel
Prize for Chemistry twice, one of only two people to have done so in the same
category, the fourth person overall with two Nobel Prizes, and the third person
overall with two Nobel Prizes in the sciences. 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". 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. He was one of three children.
His brother, Theodore, was only a year older, while his sister May 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 a wealthy cotton
manufacturer and had a Quaker background, but Cicely 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 was 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. Able to complete his School
Certificate a year early, for which he was awarded seven credits, Sanger was
able to spend most his last year of school experimenting in the laboratory
alongside his chemistry master, Geoffrey Ordish, who had originally studied at
Cambridge University and been a researcher in the Cavendish Laboratory.
Working with Ordish made a refreshing change from sitting and studying books
and awakened Sanger's desire to pursue a scientific career.
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. It was a relatively new department founded by
Gowland Hopkins with enthusiastic lecturers who included Malcolm Dixon,
Joseph Needham and Ernest Baldwin. 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. Under the Military
Training Act 1939 he was provisionally registered as a conscientious objector,
and again under the National Service 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. 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. Research
= 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 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. Sanger's first triumph was to determine
the complete amino acid sequence of the two polypeptide chains of bovine
insulin, A and B, in 1952 and 1951, respectively. 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.
To get to this point, Sanger refined a partition chromatography method first
developed by Richard Laurence Millington Synge and Archer John Porter Martin to
determine the composition of amino acids in wool, and used a chemical reagent
fluorodinitrobenzene, a compound now known as the "Sanger Reagent". Sourced
from Bernhard Charles Saunders in the Chemistry Department at Cambridge
University, the reagent proved effective at labelling 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 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.
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. Finally, because the A and B
chains are physiologically inactive without the three linking disulfide
bonds, Sanger and coworkers determined their assignments in 1955. 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. 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.
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
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 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.
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 and bacteriophage λ.
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. Porter later shared the 1972 Nobel Prize in Physiology or
Medicine with Gerald Edelman for his work on the chemical structure of
antibodies. 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. Marriage and family
Sanger married Margaret Joan Howe in 1940. They had three children — Robin,
born in 1943, Peter born in 1946 and Sally Joan born in 1960. He said that
his wife had "contributed more to his work than anyone else by providing a
peaceful and happy home." Later life
Sanger retired in 1983, aged 65, to his home, "Far Leys", in Swaffham Bulbeck
outside Cambridge. In 1992, the Wellcome Trust and the
Medical Research Council founded the Sanger Centre, 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 in person on 4 October 1993, with a staff of fewer
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. Sanger said he found no evidence for a
God so he became 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". 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 the award of an
Order of Merit, which can have only 24 living members.
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.
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".
Awards and honours As of 2015, Sanger is the only person to
have been awarded the Nobel Prize in Chemistry twice, and one of only four
two-time Nobel laureates: The other three were Marie Curie, Linus Pauling
and John Bardeen. The Wellcome Trust Sanger Institute is
named in his honour. Selected publications by Frederick
Sanger References
Further reading Brownlee, George G.. Fred Sanger, double
Nobel laureate: a biography. Cambridge, UK: Cambridge University Press. ISBN
978-1-107-08334-9. Chapters 4-6 contain the 1992 interview that the author
conducted with Sanger. Finch, John, A Nobel Fellow on every
floor: a history of the Medical Research Council Laboratory of Molecular Biology,
Cambridge: Medical Research Council, ISBN 978-1-84046-940-0 .
García-Sancho, Miguel. "A new insight into Sanger's development of sequencing:
from proteins to DNA, 1943–1977". Journal of the History of Biology 43:
265–323. doi:10.1007/s10739-009-9184-1. Sanger, F.; Dowding, M., Selected Papers
of Frederick Sanger: with commentaries, Singapore: World Scientific, ISBN
981-02-2430-3 . External links
The Sanger Institute About the 1958 Nobel Prize
About the 1980 Nobel Prize Fred Sanger 2001 Video Documentary by
The Vega Science Trust National Portrait Gallery
Frederick Sanger interviewed by Alan Macfarlane, 24 August 2007, also
available on Video on YouTube. Duration 57 minutes.
Interviews with Nobel Prize–winning scientists: Dr Frederick Sanger, British
Broadcasting Corporation, c. 1985 . Interviewed by Lewis Wolpert. Duration 1
hour. Frederick Sanger archive collection -
Wellcome Library finding aid for the digitised collection.