Frederick Sanger

British biochemist

• Born: August 13, 1918
• Birthplace: Rendcombe, Gloucestershire, England
• Died: November 19, 2013

Two-time Nobel Prize-winner Sanger was the first to determine the exact structure of proteins and went on to become the founder of practical genomic analysis.

Early Life

Frederick Sanger (SAN-gur) was born into a Quaker family. His father, Frederick Sanger, Sr., was a general practitioner, and his mother, Cicely Crewsden Sanger, was the daughter of a successful cotton manufacturer. The young Sanger attended Bryanston School in Blandford, Dorset, from 1932 to 1936 before going to St. John’s College, Cambridge, where he obtained a bachelor’s degree in natural science in 1939. World War II broke out shortly thereafter, but because he was a Quaker, he was excused from military service on conscientious grounds and stayed on at Cambridge as a postgraduate. He completed his PhD in 1943, after studying the amino acid lysine.

Sanger’s initial intention encouraged by his older brother, Theodore, had been to follow his father into medicine, but he had become interested in fundamental problems in biochemistry even before his doctoral studies took shape. Biochemistry would be the area to which he dedicated his future research. He lived a quiet, modest, and disciplined life, in full accordance with his Quaker principles, and it was the highly exceptional patience, persistence, and focus of his endeavor that led him to undertake and successfully complete scientific tasks that were inordinately complicated and required great dedication. He married Margaret Joan Howe in 1940, with whom he had two sons, Robin (b. 1943) and Peter (b. 1946), and a daughter, Sally Joan (b. 1960). The family always lived near Cambridge, eventually settling in the village of Swaffham Bulbeck.

Life’s Work

After obtaining his doctorate, Sanger was awarded the Beit Memorial Fellowship for Medical Research, which he held until 1951. He joined a group of researchers headed by A. C. Chibnall, a recently appointed professor of biochemistry, who was attempting to find ways of analyzing the chemical composition of biochemically significant proteins. Chibnall asked Sanger to find a means of attaching a chemical label to the end of a peptide chain in order to ascertain that proteins were, as had been theorized, made up of chains of amino acids.

In 1945, Sanger discovered that dinitrophenol (DNP) could form bonds with nitrogen atoms in amino acids that were stronger than the peptide bonds holding the chain together. This process allowed proteins to be broken into smaller components, which could then be separated and analyzed using a chromatographic technique recently developed by Archer Martin and Richard Synge. In 1949, Sanger made a further discovery that allowed the disulfide bridges that hold distinct peptide chains together thus determining the folding of complex protein molecules to be broken. He and Hans Tuppy immediately set out to determine the exact structure of the hormone insulin. Tuppy left the project in 1950 and left Sanger to complete the complex task alone. It took him until 1955, but it was the breakthrough that earned him his first Nobel Prize in Chemistry in 1958.

When Sanger moved to a different laboratory in Cambridge he formed a strong friendship with his Cambridge colleague Francis Crick, one of the discoverers of the structure of deoxyribonucleic acid (DNA). Their conversations led Crick to form the “sequence hypothesis,” which proposed that the genetic code took the form of sequences of the four bases contained in pairs within the DNA double helix. Each group of bases formed a template for a particular amino acid, which could then be strung together on single-stranded molecules of ribonucleic acid (RNA) to form peptide chains. While Crick published the hypothesis, Sanger set out to find a means of determining the sequence of bases in nucleic acid molecules.

In the early 1960s, Sanger perfected a method of initiating the spontaneous replication of a nucleic acid chain thus cloning the chain and then blocking it, which enabled him to produce small derivative chains of variant length, which could then be separated and analyzed using an acrylamide gel. The overlapping ends of the short chains could then be matched up so that the sequence of the whole chain could be determined. An alternative method was developed simultaneously by Walter Gilbert and Allan Maxam, who used enzymes to cut the replication process short. However, Sanger’s chain termination (or dideoxy) method was initially more convenient for long-chain analysis. Again, putting the technique into practice required enormous patience and dedication.

In 1978, Sanger and his coworkers, who included Bart Barrell, Alan Coulson, and George Brownlee, determined the 5,375-base-long sequence of a bacterial virus, phi-X174, thus founding the science of genomics. Sanger and Gilbert shared half of the 1980 Nobel Prize in Chemistry, the other half going to Paul Berg. The migration patterns formed in the acrylamide gel became known as DNA fingerprints, and their distinctiveness allowed them to be developed for use as a means of identification in forensic science.

Sanger remained at Cambridge throughout his career, but his status shifted over time. He was on the staff of the Medical Research Council (MRC), the body responsible for allocating government research funding in his field from 1951 until his retirement in 1983, and in 1962 he moved into the MRC’s Cambridge Laboratory of Molecular Biology. He became a fellow of the Royal Society in 1954 and went on to win a considerable number of honors, including an appointment as Commander of the Order of the British Empire (CBE) and the Order of Merit in 1986. He was made an honorary member of the American Academy of Arts and Sciences in 1958 and an honorary member of the American Society of Biological Chemists in 1961. In 1969 he was awarded the Royal Medal of the Royal Society and won several other similar awards. He also received honorary doctorates from several universities, including Oxford and Strasbourg (both in 1970). He never became a public figure, though, always remaining modest and retiring. He listed his interests in autobiographical sketches, such as the one on the Nobel Foundation’s Web site, as gardening and “messing about in boats.” Sanger died in November 2013.

Significance

The technical foundation stones that Sanger set in place were critical to science. The key techniques he developed were greatly streamlined by subsequent technologists, and his method for nucleic acid sequencing would become automated; the work that took him years took a matter of hours with this automation. The speed of sequencing facilitated the completion of the Human Genome Project (HGP) and allowed DNA fingerprinting to become the cornerstone of modern criminal investigations.

Tasks that were so difficult and time consuming during Sanger’s days of research have become routine, and their application has wrought fundamental changes in the understandings of biochemistry. In 1992 the Wellcome Trust set up a specialist laboratory at Hinxton, near Cambridge, to undertake Britain’s contribution to the HGP. The Wellcome Trust named the laboratory the Sanger Centre (and, later, the Sanger Institute). Sanger is a worthy member of the highly select group of individuals who have won two Nobel Prizes, the others being Marie Curie, Linus Pauling, and John Bardeen.

Bibliography

Batiza, Ann Finney. Bioinformatics, Genomics, and Proteomics: Getting the Big Picture. Philadelphia: Chelsea, 2006. Print. Foreword by Mullis. An introduction to the world of biotechnology in the twenty-first century. Good for readers with no background in biochemistry.

García-Sancho, Miguel. "A New Insight Into Sanger’S Development of Sequencing: From Proteins to DNA, 1943–1977." Journal of the History of Biology 43.2 (2010): 265–323. Academic Search Complete. Web. 12 Dec. 2013.

Hollar, Sherman. Pioneers in Medicine: From the Classical World to Today. New York: Britannica, 2013. Print.

Judson, H. F. “Frederick Sanger, Erwin Chargaff, and the Metamorphosis of Specificity.” Gene 135 (1993): 19–23. Print. A historical article placing Sanger’s work in the context of the contemporary development of molecular biology.

Sanger, Frederick, and Margaret Dowding. Selected Papers of Frederick Sanger, with Commentaries. Singapore: World Scientific, 1996. Print. A huge and near-definitive collection of Sanger’s contributions to science, issued in a twentieth century biology series. It features typically modest autobiographical comments, which provide an invaluable context.

Silverstein, Alvin, and Virginia Silverstein. Frederick Sanger: The Man Who Mapped Out a Chemical of Life. New York: John Day, 1969. Print. A brief illustrated biography in the Great Men of Science series, which deals with Sanger’s determination of the structure of insulin.

Sobel, Dava. “Sketches of Nobel Laureates in Physics and Chemistry.” The New York Times 15 Oct. 1980. Print. One of several biographical sketches prompted by the award of the 1980 Nobel Prize in Chemistry. The article also discusses the work of Walter Gilbert and other prize winners from the same year.

Subramanian, Courtney. "Double Nobel Prize-Winning Biochemist Frederick Sanger Dies at 95." Time.com 21 Nov. 2013: 1. Business Source Complete. Web. 12 Dec. 2013.