If you don’t know about Fred Sanger, it’s not surprising. He was a quiet man, far more interested in his work than in recognition. In today’s world of media hypertrophy, that work generally gets a one-column, three-inch obituary, or about fifteen seconds of airtime.
Here’s a question. How many people have won more than one scientific Nobel Prize?
Three: Marie Curie (Physics, Chemistry), John Bardeen (Physics), and Fredrick Sanger (Chemistry)
I mention this because it is so rare and it indicates a contribution to science that is arguably more important to humanity than the contributions of all but a few political, military, cultural and sports figures. In the case of Fred Sanger, his work earned him the sobriquets (plural) among his peers as “The father of genomics,” and “The father of proteomics.” In other words, he did foundation work in the areas of genetics and proteins – the foundations of life. He was a great biochemist.
You could say that Sanger’s work (and life) was about getting things in order. His genius (and it was genius) was to look at something so complicated that it seemed either impenetrable or chaotic and find order – not only find it, but through painstaking laboratory techniques, many he developed himself, prove the existence of the order he saw (or suspected).
His first effort addressed the chemical configuration of proteins, which until that time were thought so complex as to be almost random. Sanger believed the amino acids, which make up proteins, were probably not chemically random but to unravel (and prove) their chemical structure was at the time beyond biochemical technique. So he invented techniques. He developed the “Sanger reagent” (fluorodinitrobenzene) to expose amino acid groups in the insulin protein of cows (the only pure protein commercially available at the time). He then isolated through partial hydrolisation smaller chains of amino acids (peptides). Using an ingenious “fingerprinting” technique (filter paper combined with electrophoresis and chromatography), he identified the amino acid composition of the peptides. Eventually, he was able to identify the entire sequence of amino acids in the protein insulin. Among other things, this led to the synthesis of insulin (vital for diabetics, of course), but more fundamentally he showed that proteins do indeed have a distinct structure – the foundation for the further study of proteins in the field of proteomics. For this, he won his first Nobel Prize in Chemistry (1958).
He then performed an encore of equal, if not greater, importance by sequencing RNA and DNA. Sequencing the amino acids in RNA involved techniques similar to those he used for the amino acids of insulin. The circumstances were different in that obtaining a ‘pure’ RNA sample to sequence was difficult and Sanger was in a kind of race for discovery with Robert Holley at Cornell. Holley sequenced the ribonucleotides of alanine tRNA in 1965. Sanger and colleagues followed with the sequence of ribosomal RNA in E. coli in 1967. Sanger then pushed on to DNA.
These days, DNA sequencing machines decode whole genomes in only a few hours. When Sanger started, circa 1970, approaches to even looking at a single sequence (much less a genome) were primitive and took days or weeks. Sanger, along with Alan Coulson and other colleagues, decided to study DNA polymerase, an enzyme involved in the process of DNA replication and see if it could be used to tease apart the DNA sequence of amino acids. Their first research resulted in the so-called “Plus and Minus” technique that broke DNA strands into short pieces (oligonucleotides). The short pieces were subjected to fractionation by electrophoresis and visualized through autoradiography. The technique worked, leading in 1975 to the first fully sequenced DNA genome.
While Plus and Minus was a major improvement over previous techniques, Sanger was not satisfied with the approach – too slow, too fragile to be useful for large genomes. He and his colleagues then worked to improve identification at the end of DNA sequences. By 1977, this led to a complex sequencing procedure now known as the “Sanger method.” It held sway for almost 25 years, and is still in use, although most modern sequencing machines use another approach (next generation). The Sanger method earned him his second Nobel Prize in Chemistry.
Scarcely five years after developing his signature method but on schedule in 1983 at the age of 65, Sanger retired to his home near Cambridge. In a way, he was like a Thomas Edison of biochemistry, an inspired tinker and inventor. As he put it, “I am just a chap who messed about in the lab.” He followed the Edison dictum about “genius” – 1 percent inspiration, 99 percent perspiration. His insight into the biochemical nature of proteins (including DNA and RNA) was subjected to endless experimentation in the lab and the development of new approaches and techniques that could make his insight “real.” His hands-on approach and devotion to work gave him an ethos that turned down an offer for knighthood (“too much distraction”). He was a perfect counter example about nice guys finishing last. He spent the final decades of his life tending his garden (pace Voltaire) and died in his sleep November 19, 2013 at the age of 95.
