November 20, 2013 | 2
British biochemist Fred Sanger died today at 95. He’s the only person to win two Nobel Prizes in chemistry, an achievement that is unlikely to be surpassed anytime soon. In his full but not overly long career – promptly ending with retirement at the mandatory retirement age in Britain – Sanger revolutionized both protein sequencing and DNA sequencing. Both the modern proteomics and genomics revolutions stand on his shoulders. And in a discipline whose major upheavals have traditionally been tool-driven rather than idea-driven, Sanger was among the very best of tool makers.
What was the secret to his success? In what is probably the only autobiographical article he ever wrote (Annu. Rev. Biochem., 1988, 57, 1) , Sanger provides a valuable clue:
“Of the three main activities involved in scientific research, thinking, talking and doing, I much prefer the last and am probably best at it. I am all right at the thinking, but not much good at the talking.”
It was this trait that made the technically brilliant and exceedingly soft-spoken and modest Sanger almost as unrecognized among the general public as he was recognized among his peers. Sanger’s lack of recognition is a ringing criticism of both the public’s adulation of people who talk more as well as the relative neglect of experimentalists who are adept at building things with their hands. In the 1950s when the very identity of proteins was unclear, Sanger came up with a simple chemical method for identifying individual amino acids in a protein or peptide by tagging them with a brightly colored chemical handle. The first protein whose sequence he unravelled – insulin – was both a revelation and a technical tour de force. Combined with Linus Pauling’s work on delineating the basic structure of proteins, Sanger essentially set protein science on a rational basis.
This achievement would have been enough to ensure him a place in history. Astonishingly enough, he followed up with a second act. In the 1970s when the details of genetics were being worked out and refined, Sanger created an even more elegant and ingenious method for sequencing the bases of DNA. The method hinged on the existence of “chain terminating” groups of bases that would essentially allow scientists to read the sequence of a stretch of DNA by tagging incremental fragments of the DNA with these terminating groups and then separating them with an electric field on a gel. The result was clear as day; by knowing the basic rules for complementary base pairing (A-T, G-C), you can literally read out the sequence of the DNA by looking at adjacent lanes on the gel. Using the method in 1977, Sanger read the 6000 base pair genome of the virus Phi X 174, a stupendous achievement for the time.
Sanger sequencing became the basis of every sequencing endeavor during the next 25 years including the Human Genome Project. Today it’s being surpassed by so-called “Next-Gen” methods but it’s quite clear that none of the early success could have come without Sanger’s advance (another method developed by Sanger’s fellow Nobel Prize winner Wally Gilbert is more tedious and was deprioritized). Sanger is as much the father of genomics as are Watson and Crick.
Along with his superior craftsmanship, it was Sanger’s unerringly quiet, modest and intensely dedicated personality – partly arising from his Quaker roots – that undoubtedly contributed to his great success. His parents died when he was an undergraduate, an event that must surely have contributed to his serious pursuit of scientific truth. In a way Sanger was the Paul Dirac of chemistry; technically brilliant, wedded to his work, reserved to a fault, averse to teaching and administration, a scientist’s scientist in every way. Unlike most scientists who are content with directing the careers of their students after a certain point in their own career, Sanger personally worked with his hands at the bench every single day. Just like Enrico Fermi he did not shun any kind of work, no matter how creative or mundane. In addition he eschewed honors, turning down a knighthood for fear that it might interfere with his work.
It helped that he worked at the best molecular biology laboratory in the world – the MRC Laboratory of Molecular Biology which has produced eight Nobel Laureates. A future Nobel Laureate had vivid memories of Sanger when he was a postdoc at the institute. The postdoc once dropped a large flask of a chemical liquid; as he panicked and looked around for personnel who might clean up the spill, he was startled to come back and see Sanger gently wiping it up with a washcloth. Sanger may have been reserved in the extreme, but he was also extremely helpful and friendly to the brilliant young people populating the institute. Cycling to work every morning come rain or shine, he inspired them through his actions rather than words. The Sanger Institute which was named after him became a pioneer in gene sequencing and contributed to the early draft of the human genome; the institute’s title was a tribute to the man who had made it possible rather any invitation to administrative duties on his part.
Curiously enough, his rules about retirement were as well-defined as his rules about research. After wrapping up his last experiment on the day that he was supposed to retire, Sanger did not again work in the lab and spent the rest of his life gardening. Diligently working at the bench every day of his career, winning two Nobel Prizes, revolutionizing molecular biology and genomics in the process and lovingly looking after his roses; for Fred Sanger it was all in a day’s work. It is now time for us to follow his example, to do more and to talk less.