Frederick Sanger

Frederick Sanger was born on August 13, 1918, in the village of Rendcomb in Gloucestershire, England. His father, also named Frederick, was a general practitioner who had earlier served as a medical missionary in China, and his mother, Cicely, came from a prosperous cotton manufacturing family ^[1]. The household was comfortable, and the young Sanger grew up expecting, at first, to follow his father into medicine.

The family were Quakers, and the Society of Friends shaped Sanger's outlook well into adulthood. He absorbed its emphasis on truthfulness and its opposition to war, convictions that would later lead him to register as a conscientious objector during the Second World War ^[2]. He was educated at Bryanston School in Dorset, where he found he preferred scientific problem solving to the human unpredictability of medicine.

In 1936 he entered St John's College, Cambridge, to read natural sciences. Chemistry and, in his final year, the young discipline of biochemistry captured him. Cambridge's biochemistry department, built up by Frederick Gowland Hopkins, persuaded Sanger that living processes could be explained through chemistry, and he took first class honours in the subject in 1939 ^[1].

When war broke out, Sanger's Quaker convictions led him before a tribunal, which granted him conscientious objector status and allowed him to continue scientific work ^[2]. He stayed in Cambridge, completing a PhD in 1943 on the metabolism of the amino acid lysine under Albert Neuberger, having initially started under a different supervisor who left for wartime duties.

After his doctorate, Sanger joined the group of Charles Chibnall, the new professor of biochemistry at Cambridge, who suggested he examine the free amino groups of insulin ^[3]. Insulin was one of the few proteins available in pure form in quantity, thanks to its medical use in treating diabetes. The prevailing question was fundamental: did a protein have one exact, defined chemical structure, or was it a loose statistical mixture of similar molecules?

Sanger developed a reagent, 1-fluoro-2,4-dinitrobenzene, which attached a yellow label to the end of a protein chain. By labelling, breaking the protein into fragments with acids and enzymes, and separating the pieces by chromatography and electrophoresis, he could deduce the order of amino acids piece by piece ^[3]. The labelling compound became known as Sanger's reagent, and the patient, jigsaw-like strategy became the model for protein chemistry worldwide.

Between 1945 and 1955 Sanger and a small number of colleagues worked out the full amino acid sequence of both chains of bovine insulin, 51 amino acids in all, and established how the chains were linked by disulphide bridges ^[3]. The result settled a foundational argument in biology: proteins are defined chemical entities with a unique, genetically specified sequence. For this work he received the Nobel Prize in Chemistry in 1958, at the age of forty ^[4].

Many scientists would have treated such a prize as a summit. Sanger treated it as a license to start again. In 1962 he moved to the newly opened Medical Research Council Laboratory of Molecular Biology in Cambridge, where colleagues included Francis Crick and Max Perutz, and turned his attention to nucleic acids ^[5]. He first devised ways of sequencing RNA, and his group determined the sequence of a small ribosomal RNA in the 1960s.

The decisive breakthrough came in 1977, when Sanger and his co-workers published the dideoxy chain termination method for sequencing DNA, commonly called Sanger sequencing ^[6]. The technique used modified nucleotides that halt the copying of a DNA strand at known letters, producing fragments whose lengths reveal the sequence. That same year his team read the complete genome of the bacteriophage phiX174, about 5,386 bases, the first DNA genome ever fully sequenced ^[6]. In 1980 he shared the Nobel Prize in Chemistry with Walter Gilbert and Paul Berg, becoming the only person to win the chemistry prize twice ^[4]. Among the achievements most often cited in any account of who was Frederick Sanger, this double recognition sits alongside the practical legacy of his methods, which his laboratory soon applied to human mitochondrial DNA, sequenced in full in 1981 ^[5].

Sanger married Margaret Joan Howe in 1940, and the marriage lasted until her death in 2012. They had two sons and a daughter. He often said that Joan contributed more to his work than anyone else by providing a peaceful and happy home, an arrangement he credited for his ability to concentrate on slow, exacting laboratory problems ^[1].

By temperament he was modest to the point of self-effacement. He described himself as academically unexceptional as a boy and insisted that his success came from persistence at the bench rather than brilliance. He declined a knighthood, reportedly because he did not want to be addressed as Sir, though he accepted appointment to the Order of Merit in 1986, an honour limited to 24 living members ^[7]. Colleagues recalled a man who continued doing his own experiments with his own hands long after most laboratory heads had retreated to offices.

Though raised a Quaker, Sanger gradually lost his religious belief and in later life described himself as an agnostic, while acknowledging that the Quaker regard for truth had marked his approach to science ^[2].

Sanger retired in 1983, at 65, and made the break cleanly. He gave up science altogether and devoted himself to his garden at Far Leys, his home in the village of Swaffham Bulbeck near Cambridge, and to messing about in boats, as he put it. He refused most invitations to lecture or to pronounce on the future of genetics, saying his opinions were no better than anyone else's now that he had left the bench ^[7].

His name, however, kept working. In 1992 the Wellcome Trust and the Medical Research Council founded a large-scale genome research campus near Cambridge and named it the Sanger Centre, later the Wellcome Sanger Institute. He agreed to the naming on the condition, characteristically, that the place had better be good. The institute became the largest single contributor to the Human Genome Project, which relied on industrialised versions of his sequencing chemistry ^[5].

Frederick Sanger died in his sleep at Addenbrooke's Hospital in Cambridge on November 19, 2013, at the age of 95 ^[8]. Obituaries around the world noted the unusual shape of his career: two Nobel Prizes, roughly a hundred publications, no taste whatsoever for celebrity.

Any honest reckoning of Frederick Sanger facts must begin with scale. The chain termination method he introduced in 1977 dominated DNA sequencing for more than three decades and produced the reference human genome announced in 2003 ^[5]. Even after high-throughput technologies displaced it for large projects, Sanger sequencing remained the standard for verifying individual results in clinics and laboratories, and it is still taught to every student of molecular biology ^[6].

His insulin work has an equally durable claim. By proving that a protein has a single defined sequence, Sanger supplied the chemical premise for the idea that genes encode proteins, the framework within which Crick and others formulated the central ideas of molecular biology ^[3]. Two of his own doctoral students and many collaborators went on to distinguished careers, and the Wellcome Sanger Institute continues genome research on a scale he could not have imagined when he was cutting insulin into fragments by hand.

Readers coming to a Frederick Sanger biography for the first time often expect a dramatic personality to match the achievements. What they find instead is a careful, methodical experimentalist who chose hard problems, stayed with them for a decade at a time, and twice changed what biology could do ^[4]. He liked to say that of the three activities open to a scientist, research, teaching, and administration, he was good at only the first. The record suggests he was right, and that it was enough.