Frederick Sanger

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Frederick Sanger

Frederick Sanger2.jpg
Born(1918-08-13)13 August 1918
Died19 November 2013(2013-11-19) (aged 95)
Alma mater University of Cambridge (PhD)
Known forDetermining the amino acid sequence of insulin
Sanger sequencing
Sanger Centre
Scientific career
Fields Biochemistry
Thesis The metabolism of the amino acid lysine in the animal body  (1943)
Doctoral advisor Albert Neuberger [2]
Doctoral students

Frederick Sanger OM CH CBE FRS FAA ( /ˈsæŋər/ ; 13 August 1918 – 19 November 2013) was a British biochemist who twice won the Nobel Prize in Chemistry, one of only two people to have done so in the same category (the other is John Bardeen in physics), [4] 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". [5]


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). [6] He was one of three children. His brother, Theodore, was only a year older, while his sister May (Mary) was five years younger. [7] 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 was not a Quaker. [7]

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. [7] Able to complete his School Certificate a year early, for which he was awarded seven credits, Sanger was able to spend most of 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. [8]

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. [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 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 (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 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. [7] Sanger changed his research project to study the metabolism of lysine [9] and a more practical problem concerning the nitrogen of potatoes. [10] 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. [7]

Research and career

Amino acid sequence of bovine insulin Insulin seq vertical.svg
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 [11] 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. [6]

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. [12] [13] 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 Richard Laurence Millington Synge and Archer John Porter Martin to determine the composition of amino acids in wool. Sanger used a chemical reagent 1-fluoro-2,4-dinitrobenzene (now, also known as Sanger's reagent, fluorodinitrobenzene, FDNB or DNFB), sourced from poisonous gas research by Bernhard Charles Saunders at the Chemistry Department at Cambridge University. Sanger's reagent proved effective at labelling the N-terminal amino group at one end of the polypeptide chain. [14] 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. [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 sequences to deduce the complete structure of insulin. Finally, because the A and B chains are physiologically inactive without the three linking disulfide bonds (two interchain, one intrachain on A), Sanger and coworkers determined their assignments in 1955. [15] [16] 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. [17] This discovery was crucial for the later sequence hypothesis of Crick for developing ideas of how DNA codes for proteins. [18]

Sequencing RNA

From 1951 Sanger was a member of the external staff of the Medical Research Council [6] 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. [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. [18]

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. [19] 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. [20] By 1967 Sanger's group had determined the nucleotide sequence of the 5S ribosomal RNA from Escherichia coli , a small RNA of 120 nucleotides. [21]

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. [22] 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. [23] [24] 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. [25] 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. [3]

In 1977 Sanger and colleagues introduced the "dideoxy" chain-termination method for sequencing DNA molecules, also known as the "Sanger method". [24] [26] 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. [5] The new method was used by Sanger and colleagues to sequence human mitochondrial DNA (16,569 base pairs) [27] and bacteriophage λ (48,502 base pairs). [28] The dideoxy method was eventually used to sequence the entire human genome. [29]

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. [3] Porter later shared the 1972 Nobel Prize in Physiology or Medicine with Gerald Edelman for his work on the chemical structure of antibodies. [30] Elizabeth Blackburn studied for a PhD in Sanger's laboratory between 1971 and 1974. [3] [31] 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. [32]

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 (Physics, 1903 and Chemistry, 1911), Linus Pauling (Chemistry, 1954 and Peace, 1962) and John Bardeen (twice Physics, 1956 and 1972). [4]

The Wellcome Trust Sanger Institute (formerly the Sanger Centre) is named in his honour.

Personal life

Marriage and family

Sanger married Margaret Joan Howe 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." [36]

Later life

The Sanger Institute EBI and Sanger Center, Genome campus, Cambridgeshire.jpg
The Sanger Institute

Sanger retired in 1983, aged 65, to his home, "Far Leys", in Swaffham Bulbeck outside Cambridge. [3]

In 1992, the Wellcome Trust and the Medical Research Council founded the Sanger Centre (now the Sanger Institute), named after him. [37] 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." [37] 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. [37] The Institute now[ when? ] 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. [38] 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." [39]

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. [36] [38] [39]

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. [40]

Sanger died in his sleep at Addenbrooke's Hospital in Cambridge on 19 November 2013. [36] [41] As noted in his obituary, he had described himself as "just a chap who messed about in a lab", [42] and "academically not brilliant". [43]

Selected publications

Related Research Articles

Insulin mammalian protein found in Homo sapiens

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of carbohydrates, especially glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

Nucleic acid polymeric macromolecules

Nucleic acids are the biopolymers, or small biomolecules, essential to all known forms of life. The term nucleic acid is the overall name for DNA and RNA. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. If the sugar is a compound ribose, the polymer is RNA ; if the sugar is derived from ribose as deoxyribose, the polymer is DNA.

Protein Biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells, and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Walter Gilbert American biochemist

Walter Gilbert is an American biochemist, physicist, molecular biology pioneer, and Nobel laureate.

Genomics discipline in genetics

Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes. In contrast to genetics, which refers to the study of individual genes and their roles in inheritance, genomics aims at the collective characterization and quantification of all of an organism's genes, their interrelations and influence on the organism. Genes may direct the production of proteins with the assistance of enzymes and messenger molecules. In turn, proteins make up body structures such as organs and tissues as well as control chemical reactions and carry signals between cells. Genomics also involves the sequencing and analysis of genomes through uses of high throughput DNA sequencing and bioinformatics to assemble and analyze the function and structure of entire genomes. Advances in genomics have triggered a revolution in discovery-based research and systems biology to facilitate understanding of even the most complex biological systems such as the brain.

In bioinformatics, sequence analysis is the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alignment, searches against biological databases, and others. Since the development of methods of high-throughput production of gene and protein sequences, the rate of addition of new sequences to the databases increased exponentially. Such a collection of sequences does not, by itself, increase the scientist's understanding of the biology of organisms. However, comparing these new sequences to those with known functions is a key way of understanding the biology of an organism from which the new sequence comes. Thus, sequence analysis can be used to assign function to genes and proteins by the study of the similarities between the compared sequences. Nowadays, there are many tools and techniques that provide the sequence comparisons and analyze the alignment product to understand its biology.

Nucleic acid sequence succession of nucleotides in a nucleic acid

A nucleic acid sequence is a succession of base-pairs signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA or RNA (GACU) molecule. By convention, sequences are usually presented from the 5' end to the 3' end. For DNA, the sense strand is used. Because nucleic acids are normally linear (unbranched) polymers, specifying the sequence is equivalent to defining the covalent structure of the entire molecule. For this reason, the nucleic acid sequence is also termed the primary structure.

Reading frame

In molecular biology, a reading frame is a way of dividing the sequence of nucleotides in a nucleic acid molecule into a set of consecutive, non-overlapping triplets. Where these triplets equate to amino acids or stop signals during translation, they are called codons.

Single-nucleotide polymorphism Single nucleotide position in genomic DNA at which different sequence alternatives exist

A single-nucleotide polymorphism is a substitution of a single nucleotide that occurs at a specific position in the genome, where each variation is present at a level of more than 1% in the population.

Marshall Warren Nirenberg American biochemist and geneticist

Marshall Warren Nirenberg was an American biochemist and geneticist. He shared a Nobel Prize in Physiology or Medicine in 1968 with Har Gobind Khorana and Robert W. Holley for "breaking the genetic code" and describing how it operates in protein synthesis. In the same year, together with Har Gobind Khorana, he was awarded the Louisa Gross Horwitz Prize from Columbia University.

DNA sequencing process of determining the nucleic acid sequence – the order of nucleotides in DNA

DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The advent of rapid DNA sequencing methods has greatly accelerated biological and medical research and discovery.

History of genetics

The history of genetics dates from the classical era with contributions by Pythagoras, Hippocrates, Aristotle, Epicurus, and others. Modern genetics began with the work of the Augustinian friar Gregor Johann Mendel. His work on pea plants, published in 1866, established the theory of Mendelian inheritance.

Phi X 174 A single-stranded DNA virus that infects bacteria

The phi X 174 bacteriophage is a single-stranded DNA (ssDNA) virus that infects Escherichia coli, and the first DNA-based genome to be sequenced. This work was completed by Fred Sanger and his team in 1977. In 1962, Walter Fiers and Robert Sinsheimer had already demonstrated the physical, covalently closed circularity of ΦX174 DNA. Nobel prize winner Arthur Kornberg used ΦX174 as a model to first prove that DNA synthesized in a test tube by purified enzymes could produce all the features of a natural virus, ushering in the age of synthetic biology. In 1972-1974, Jerard Hurwitz, Sue Wickner, and Reed Wickner with collaborators identified the genes required to produce the enzymes to catalyze conversion of the single stranded form of the virus to the double stranded replicative form. In 2003, it was reported by Craig Venter's group that the genome of ΦX174 was the first to be completely assembled in vitro from synthesized oligonucleotides. The ΦX174 virus particle has also been successfully assembled in vitro. Recently, it was shown how its highly overlapping genome can be fully decompressed and still remain functional.


Dideoxynucleotides are chain-elongating inhibitors of DNA polymerase, used in the Sanger method for DNA sequencing. They are also known as 2',3' dideoxynucleotides, and abbreviated as ddNTPs.

1-Fluoro-2,4-dinitrobenzene chemical used for polypeptide sequencing

1-Fluoro-2,4-dinitrobenzene is a chemical that reacts with the N-terminal amino acid of polypeptides. This can be helpful for sequencing proteins.

HMGA1 protein-coding gene in the species Homo sapiens

High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.

MT-ND6 A mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

Mitochondrial dicarboxylate carrier mammalian protein found in Homo sapiens

The mitochondrial dicarboxylate carrier (DIC) is an integral membrane protein encoded by the SLC25A10 gene in humans that catalyzes the transport of dicarboxylates such as malonate, malate, and succinate across the inner mitochondrial membrane in exchange for phosphate, sulfate, and thiosulfate by a simultaneous antiport mechanism, thus supplying substrates for the Krebs cycle, gluconeogenesis, urea synthesis, fatty acid synthesis, and sulfur metabolism.

The Colworth Medal is awarded annually by the Biochemical Society to an outstanding research biochemist under the age of 35 and working mainly in the United Kingdom. The award is one of the most prestigious recognitions for young scientists in the UK, and was established by Tony James FRS at Unilever Research and Henry Arnstein of the Biochemical Society and takes its name from a Unilever research laboratory near Bedford in the UK, Colworth House.

Maxam–Gilbert sequencing

Maxam–Gilbert sequencing is a method of DNA sequencing developed by Allan Maxam and Walter Gilbert in 1977–1980. This method is based on nucleobase-specific partial chemical modification of DNA and subsequent cleavage of the DNA backbone at sites adjacent to the modified nucleotides.


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Further reading