Frederick Sanger: Scientist whose pioneering work on DNA sequencing paved the way for mapping the human genome
Wednesday 20 November 2013
Only four people in history have been awarded the Nobel Prize twice. One of them was the biochemist Fred Sanger, who pioneered research into the human genome but who described himself as "just a chap who messed about in his lab".
He won his first Nobel Prize for Chemistry in 1958 for his work on determining the structure of insulin and the second 22 years later for his work on DNA. With his colleagues he developed a rapid method of DNA sequencing – a way to "read" DNA – which became the forerunner for the work on mapping the human genome.
Sanger was born in 1918 in Rendcombe in Gloucestershire, the second son of a GP, Frederick, and his wife Cicely. His father had worked as an Anglican medical missionary in China but had returned to England because of ill health. He converted to Quakerism, and Fred and his older brother Theodore were brought up as Quakers.
Thanks to his father and brother, Sanger said, "I soon became interested in biology and developed a respect for the importance of science and the scientific method." He was educated at Bryanston School, and although he originally intended to follow his father into medicine, he graduated from St John's College, Cambridge in natural sciences in 1939. He described himself as "probably above average but not an outstanding scholar."
As an undergraduate his beliefs were strongly influenced by his Quaker upbringing. He was a pacifist and a member of the Peace Pledge Union, and 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.
He joined Cambridge's Department of Biochemistry in 1940, and as a conscientious objector was allowed to continue his PhD. Initially, under Bill Pirie, he investigated whether edible protein could be obtained from grass, but when Pirie left Sanger began working with Albert Neuberger on the metabolism of the amino acid lysine and a problem relating to the nitrogen content of potatoes; he was awarded his PhD in 1943. Only then did he receive a stipend; until then he supported himself thanks to money from his mother, who was the daughter of a wealthy cotton manufacturer.
New methods of separation and purification made it possible to determine the chemical structure of protein molecules, and Sanger developed methods to determine the order of the building blocks of insulin; this resulted in the Nobel Prize in Chemistry in 1958. In 1962 he moved to the new UK Medical Research Council Laboratory of Molecular Biology.
Following his work on insulin he developed further methods for studying proteins, particularly the active centres of some enzymes, and in about 1960 took on the challenge of determining the order of bases in DNA, known as DNA sequencing. It was known by then that DNA was a linear code – James Watson and Francis Crick had worked out the structure of DNA's double helix and revealed that it held a linear code of base pairs (C, G, T and A), but there was no way to read it, and over the next 15 years Sanger and his team – notably Bart Barrell, Alan Coulson and George Brownlee – developed methods to sequence DNA and RNA.
The team produced the first DNA whole genome sequence, 5,000 letters long, for a virus called phiX174 which grows in bacteria, and went on to sequence the first human genetic material, the 16,000-letter sequence of DNA in mitochondria, the energy factories in our cells. "Dideoxy" or "Sanger" sequencing is still used today to read DNA code – including the 3bn base pairs of the first complete human genome sequence, published in 2003.
In 1980, Walter Gilbert and Sanger shared half of the Nobel Prize for Chemistry "for their contributions concerning the determination of base sequences in nucleic acids". The other half was awarded to Paul Berg for his studies of the biochemistry of nucleic acids.
Sanger said he found it remarkable that a method he developed more than 30 years ago was still in use. Ever modest, he insisted that his focus was always on making the methods work and solving the immediate problems; the greater implications, he said, seemed a long way off at the time. He retired in 1983 to Swaffham Bulbeck near Cambridge. In 1993 the Wellcome Trust named their Sanger Centre in Cambridge after him, and it became the home of the Human Genome Project. He rejected a knighthood, he said, because he didn't want to be called "Sir", but later accepted 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 had recorded his research from 1944 to 1983. In reporting it, Science noted that Sanger was "the most self-effacing person you could hope to meet". Apart from his work, he said his main interests were gardening and "messing about in boats". µ CHRIS MAUME
I got to know Fred Sanger some 60 years ago, writes Tam Dalyell, for the mundane reason that he had rooms as a Fellow at the bottom of a staircase in King's College, Cambridge, and I, as an undergraduate, had a room at the top. Being made jointly responsible by the senior tutor, Patrick Wilkinson, for popping our heads round their doors at night to make sure that two resident elderly fellows, AC Pigou and EM Forster, were OK, brought us together.
Wilkinson complained to me that this was the only College responsibility that Sanger would take on; Sanger drily observed to me: "If I get into the mire of College affairs my work suffers." Indeed, he was the most focussed young man in Cambridge that any of us had met. At the celebration for the 25th anniversary of the discovery of monoclonal antibodies, in the Queen Elizabeth Hall in London, when Sanger was in his eighties, I said to our mutual friend, the Nobel Prize-winner Cesar Milstein, in Fred's presence, that he was the most focussed of men. Milstein replied with a gentle smile, "Still is."
Frederick Sanger, biochemist: born Rendcombe, Gloucestershire 13 August 1918; Medical Research Council Laboratory of Molecular Biology, Cambridge 1961–83; Nobel Prize for Chemistry, 1958, (jointly) 1980; Royal Medal, Royal Society 1969; Copley Medal, Royal Society 1977; CBE 1963, CH 1981, OM 1986; married 1940 M Joan Howe (two sons, one daughter); died 19 November 2013.
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