EVERY DAY, ACROSS THE GLOBE, labs perform testing using Sanger sequencing and other fundamental techniques of proteomics and genomics pioneered and developed by Frederick Sanger, who died last month at the age of 95.
Sanger is considered one of the giants in biochemistry. He was one of only three people awarded two Nobel prizes in science. Both of his Nobel prizes were for chemistry, in 1958 and 1980. The other dual awardees were Marie Curie (physics and chemistry) and John Bardeen (twice in physics). Linus Pauling’s two Nobel prizes were for chemistry and peace.
In the 1950s, working at the University of Cambridge in the United Kingdom, Sanger was the first to unravel the structure of a protein. That was insulin. Among other things, Sanger proved that the ordering of amino acids was crucial to the actual function of a protein. His work led to the laboratory synthesis of insulin and major advances in treating the disease.
Developed Sanger’s Reagent
To accomplish this feat, Sanger developed a technique that used a marking agent—now called Sanger’s reagent—that took long chains of amino acids in protein molecules and broke them down into short fragments. Over a ten-year period, in his study of insulin, he analyzed these short fragments to understand their composition.
By 1953, Sanger was able to accurately specify the exact sequence of amino acids for bovine insulin. He also demonstrated that precise and very small differences existed among the insulins from various types of mammals. For these accomplishments, Sanger was awarded the 1958 Nobel Prize for chemistry.
In the early 1960s, Sanger became part of a new molecular laboratory at Cambridge. This lab was led by Max Perutz. Other members of the team included James Watson and Francis Crick, who had identified the structure of DNA just a few years earlier.
Informed by the insight that a single, precise sequence of amino acids was essential to the function of the protein, Sanger next set out to understand how the information contained within DNA is used to make the proteins that do the work inside living cells. As described by The Guardian newspaper:
Once Crick and Watson had produced an explanation for how the genetic code was inherited through DNA, it was inevitable that Sanger should apply his flair in amino acid sequencing to deciphering the detailed construction of individual genes. Sanger said in his Nobel lecture in 1980 that it was the coded amino acid sequences within specific sections of the strands of DNA that conveyed the genetic information. Those sequences were as much the stuff of genes as the DNA helix.
In Sanger’s group at this time were Bart Barrell, Alan Coulson, and George Brownlee. Together, they worked to develop methods to sequence both DNA and RNA. Their work produced techniques such as chain terminators, very thin gel systems, and cloning methods to produce strands of DNA.
First To Map A Genome
The breakthrough achieved by Sanger and his team was to be first in the world to map the entire genome of a living organism. This was accomplished in 1977 and their target was the virus Phi X 174, which consisted of 5,400 base pairs of DNA. Next, the team sequenced the DNA of a human mitochondrian, which is the structure that generates energy in human cells.
The 1980 Nobel Prize was awarded to three individuals. Sanger shared the prize with Walter Gilbert of Harvard University and Paul Berg at Stanford University. Sanger and Berg were recognized for their work in determining the base sequences of nucleic acids. Berg was recognized for demonstrating a method to recombine segments of DNA in ways that made genetic engineering possible.
Frederick Sanger was recognized as a modest man by those who knew him. He was born in 1918 and attended St. John’s College in Cambridge on a scholarship. One influence on Sanger during this time was Frederick Gowland Hopkins, a Nobel Laureate who had discovered vitamins.
Interest in Proteomics
Upon graduation in 1939, Sanger pursued his Ph.D. in protein metabolism. As a Quaker, he was a conscientious objector during World War II. During this time, he was close to the work of British biochemists Archer Marting and Richard Synge. These two scientists had initiated a scientists to separate and purify very large molecules, including proteins and nucleic acids. Sanger’s first grant supported his research into the structure of proteins, with insulin being the primary subject.
Sanger retired in 1983. In The Guardian’s obituary covering his life, Sanger was characterized as “almost absurdly self-effacing, describing himself as someone who had merely ‘messed about in his lab.’”
One anecdote about his life confirms this trait. He declined to accept a knighthood, saying that he preferred not to be called “sir.”
Sanger was made a fellow in the Royal Society in 1954 and a Commander of the Order of the British Empire in 1963. In 1986, he earned the Order of Merit.
UK’s Sanger Institute
In recognition of his lifetime of accomplishments in proteomics and genomics, the National Health Service named its molecular and genomics research organization the Sanger Institute.
Today, Sanger sequencing is still the most widely-used technique for genetic sequencing. It is considered the gold standard for most clinical gene sequencing applications.
Independently, biotech companies and other research teams are developing different techniques for sequencing DNA. But even these research and development efforts are building upon the body of work left by Frederick Sanger.
Sanger’s passing at the age of 95 might be seen as one more door closing on the first era of proteomic and genomic research. At the same time, Frederick Sanger will be long-remembered as an essential pioneer in proteomics and genomics who brought the science to a point where humankind was able to benefit from this knowledge.
