Frederick Sanger (1918–2013)

As a researcher in biochemistry, Frederick Sanger studied the structure of proteins, RNA, and DNA during the mid-twentieth century in Cambridge, England. He was the first person to determine the amino acid sequence of a protein, the hormone insulin, which regulates blood sugar levels. Later, he developed an efficient method for sequencing the nucleotide bases in DNA, an organism’s hereditary material. Named Sanger sequencing in his honor, the method was a staple of molecular biology techniques for over forty years. It formed the backbone of methods used for the Human Genome Project, the international effort to sequence the DNA in a human genome, and foreshadowed the development of more modern DNA sequencing techniques. Sanger is one of only a handful of individuals to receive two Nobel Prizes. Through his work elucidating the structure of biological molecules and devising methods to sequence them, Sanger fundamentally shaped the course of biology in the twentieth century.

Early Life and Education

Sanger was born on 13 August 1918 in the village of Rendcomb in Gloucestershire, England. He was the second child of Cicely Crewdson, daughter of an affluent cotton manufacturer, and Frederick Sanger, a general medical practitioner. Sanger’s father had worked as an Anglican medical missionary in China after obtaining his medical degree in 1905. However, due to poor health, he had to leave China to return to England in 1912. Sanger had two siblings: an older brother, Theodore, and a younger sister, Mary. Sanger’s father converted to Quakerism after reading some Quaker books belonging to his father-in-law. However, his mother never converted. Sanger and his brother Theodore spent their childhoods exploring the natural environment around their home, which, according to Sanger, sparked his interest in science.

When Sanger was five, his family moved to Tamworth-in-Arden, a village in Warwickshire, England. There, a Quaker governess, or private tutor, gave him instruction and taught his siblings and other local children as well. When he turned nine, he went to Downs Preparatory School in Colwall, a civil parish in Herefordshire, England. The school ran on Quaker principles that promoted practical learning alongside academic study.

At age fourteen, Sanger went to the newly established Bryanston School in Dorset, England. The school promoted innovation combined with tradition, represented in its motto et nova et vetera (new and old). Sanger frequently participated in expeditions for biology projects and making laboratory slides. He spent most of his senior year running his first research project, which involved growing colored crystals under the supervision of his chemistry instructor, Henry Geoffrey Ordish. Ordish had studied at the University of Cambridge in Cambridge, England, where he was a researcher in the Cavendish Laboratory, the name for the university’s department of physics. The Cavendish Laboratory was founded in 1874 under the direction of James Clerk Maxwell, who developed electromagnetic theory. The department had produced several Nobel Prize-winning contributions to physics, including Joseph John Thomson’s discovery of the electron, the first subatomic particle found. Sanger qualified to leave school a year early. His award of seven credits is the highest of anyone in the school’s history, and guaranteed him admission into Cambridge.

In 1936, Sanger began his bachelor’s degree at the same institution his father had attended, St John’s College in the University of Cambridge, applying to study science. He pursued an interdisciplinary program called the Natural Sciences Tripos, completing the first phase in three years with physiology, physics, and mathematics courses. For the second phase, he focused on biochemistry, a relatively new department founded in 1914 by Frederick Gowland Hopkins, who had received the 1929 Nobel Prize in Physiology or Medicine for the discovery of essential substances in natural foods, now commonly known as vitamins. Sanger completed his Bachelor of Arts in natural science in 1939 and was among the two biochemistry students awarded a first-class honors degree.

While completing the final phase of his bachelor’s degree and writing an article on the economic impact of spending money on military weapons for a Cambridge Scientists’ Anti-War Group, Sanger met his future wife, Margaret Joan Howe. She was an economics student at Newnham College for women at the University of Cambridge. They married in 1940 and later had two sons, Robin and Peter, and a daughter, Sally Joan. Although Howe was not a scientist, Sanger called her the most important contributor to his research by providing him with a peaceful and happy home.

World War II began in 1939, the same year Sanger completed his undergraduate education, but he was exempted from military service as a registered conscientious objector. Instead, Sanger attended the Quaker Relief Training Center in Devon, England, where he acquired medical training, and worked at Winford Hospital in the village of Winford, near Bristol, England. The hospital treated people injured in the war, and Sanger worked as an orderly, or an assistant to the medical staff.

In 1940, Sanger began graduate studies at the University of Cambridge, working in the laboratory of Albert Neuberger, a professor of biochemistry. Though Neuberger did not give Sanger instruction during his undergraduate study, he took Sanger as his PhD student when Sanger’s first doctoral supervisor suddenly left. According to Neuberger’s son Michael S. Neuberger, Deputy Director of the Medical Research Council Laboratory of Molecular Biology, or MRC Laboratory, in Cambridge, England, the war had increased concerns about the nutritional value of domestically produced food. In response, his father started government-funded research project on the nitrogen content of potatoes, and Sanger joined him in that work in 1940.

Sanger’s thesis ultimately focused on animal metabolism of the amino acid lysine. Amino acids are the building blocks of proteins, and there are twenty different types of amino acids. Although it would take researchers another thirty years to work out the metabolism of lysine, Sanger credited Neuberger with being the person who taught him how to conduct research in biochemistry. According to Sanger, his thesis laid the foundation for his future work by giving him a strong understanding of amino acid chemistry.

Professional Career

Sanger completed his doctoral degree in 1943 and began working on a new area of research, in part because Neuberger moved to the National Institute for Medical Research in London, England. That same year, Sanger began work in Albert Charles Chibnall’s biochemistry laboratory at the University of Cambridge, and in 1944 Sanger obtained a Beit Memorial Fellowship for Medical Research to study the amino acid composition of different proteins.

Chibnall’s research focused on plant biochemistry, and Chibnall encouraged Sanger to focus on the amino acid analysis of insulin, a protein hormone that regulates blood sugar levels. The advantages of conducting research with insulin were its small size and being one of the few pure proteins available in large quantities. Chibnall secured funding from two pharmaceutical companies, Eli Lilly and Company in Indianapolis, Indiana, and Imperial Chemical Industries in London, England. To learn more about the structure of insulin, Sanger used acid hydrolysis, a chemical process involving concentrated acid, which caused the insulin to break down into smaller pieces. By 1953, after almost ten years of analysis, Sanger and his collaborators had determined the sequence of all 51 amino acids in insulin, the first known primary structure of a protein.

In 1962, Sanger joined the MRC Laboratory as the Head of the Protein Chemistry Division. There, Sanger joined Francis Crick, one of the scientists responsible for identifying the structure of DNA, and Sydney Brenner, known for his work on the genetic code, who were researching nucleic acids, including DNA and RNA. At MRC, Sanger primarily worked on determining RNA sequences.

In the 1970s, Sanger shifted the focus of his research from RNA to DNA. In 1975, Sanger developed a simple yet accurate technique to determine nucleotide sequences in DNA, which he called the plus and minus method. Using that method, in 1977, Sanger’s team successfully sequenced the entire DNA sequence of a bacteriophage, the first complete DNA genome ever sequenced.

Sanger introduced further developments to the plus and minus method, which led to the chain-termination or dideoxy method, later called Sanger sequencing. That method works using modified DNA nucleotides that halt copying when added to a growing DNA chain. The method also creates fragments that, when sorted by size, reveal the exact order of the nucleotide bases.

Impacts

Sanger’s chain-terminating method contributed to the sequencing of many genomes, including the influenza virus, commonly called the flu, and the Epstein-Barr virus and cytomegalovirus, which are herpesviruses transmitted via bodily fluids. The Human Genome Project, a $3 billion international program that lasted from 1990 to 2003 and sequenced 92 percent of the human genome, fundamentally depended on Sanger’s chain-terminating method. Sanger won his first Nobel Prize in Chemistry in 1958 for determining the amino acid sequence of insulin and his second in 1980 for developing a method for sequencing nucleic acids.

Apart from the two Nobel Prizes, Sanger also won several other awards for his scientific work. The Royal Society of Chemistry awarded Sanger the Corday-Morgan Medal and Prize in 1951, and the British Royal Society awarded him the Royal Medal in 1969. Queen Elizabeth II made Sanger a Commander of the Most Excellent Order of the British Empire, an appointment in recognition of service to the United Kingdom or the Commonwealth of Nations, in 1963, and he declined the higher appointment of knighthood in 1981. In 2000 the Republic of Palau issued a stamp featuring Sanger.

Sanger retired in 1983, and in 1992, the Wellcome Trust and the Medical Research Center created the Sanger Centre, called the Wellcome Trust Sanger Institute as of 2001, to study genomes. Although newer sequencing methods, known as Next-Generation Sequencing, or NGS, provide cost and speed advantages in sequencing genomes, Sanger sequencing provided the necessary foundation for those advances.

Sanger died on 19 November 2013 at the age of ninety-five in Cambridge, England. 

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