The first sequence. Fred Sanger and insulin.

FRED Sanger is an amazingly modest man, and his into the Laboratory of Molecular Biology), took me on as a research student. Vernon had just shown that sickleown retrospective, written after he retired, a delightful prefatory chapter for the Annual Reviews of cell hemoglobin differed from normal hemoglobin by a single amino acid substitution, the first characterizaBiochemistry, is called “Sequences, sequences, and sequences” (Sanger 1988). In it he describes the paths tion of the molecular consequences of mutation on proteins (Ingram 1956, 1957); earlier Neel (1949) had that led to the successful methods he developed for the sequencing of proteins, then RNA, and then DNA. What shown that sickle-cell anemia is inherited as a Mendelian character, and Pauling et al. (1949) showed that sicklea career! Especially now, with the human genome largely fincell hemoglobin differed electrophoretically from normal hemoglobin and coined the term “molecular disished, it is almost impossible to imagine a world without sequences of proteins and of nucleic acids. The fact that ease.” I had been trained as a chemist and knew nothing about proteins: I had heard Alex Todd’s exciting lecit has been only 50 years since Sanger showed that there was such a thing as the unique amino acid sequence of tures to chemistry students on the organic chemistry of natural products that included vitamins, steroids, and a protein seems amazing from where we now stand— sequences are such a dominant part of the world we nucleic acids, but not a word about proteins! To work on hemoglobin in Vernon’s laboratory, I was going to work in today. Amazing, but perhaps not surprising, when we think of, say, the change in the power of comhave to learn to become a protein chemist, and Francis Crick urged me to go and see Fred Sanger, who was at puters that has occurred over just about the same time period. (I would love to be around, marbles intact, 50 that time in the Biochemistry Department. In preparation for this, I read Fred’s 1952 review in Advances in years from now, to find out how the brain really works.) Before Fred’s work, it was already known that differProtein Chemistry entitled “The arrangement of amino acids in proteins” (Sanger 1952). I had also read a ent proteins had different amino acid compositions, different biological activities, and different physical preprint of Francis’s own review, “On protein synthesis” (Crick 1958). Each review was completely stunning, but properties and that genes had an important role in controlling them. But in a world of biochemistry domiin very different ways. Francis’s article was full of elegant theory, with great leaps of speculation (at the time the nated by the role of enzymes in intermediary metabolism, it was not at all clear how molecules as large as existence of messenger RNA and transfer RNA was not known), but conveying a sense of joy that was as thrilling proteins could be synthesized; the idea that proteins were stochastic molecules, with a sort of “center of gravas that emerging from the Origin of Species. Fred’s was full of technique, and his review was scholarly, with ity” of structure but with appreciable microheterogeneity, was taken seriously. This is the paradigm that Fred’s major emphasis on experiments. Both of them made a huge impression on me, but I was particularly struck by results shifted. This essay is a celebration of his first triumph: the Fred’s emphasis on the importance of developing new techniques. Today, when “hypothesis-driven research” first complete amino acid sequence determination of a protein, the B chain of insulin, published just over 50 has somehow become a gold standard, in many areas one must be very brave to admit to working on techyears ago. Although I was not involved in the work in any way, I was scientifically aware enough to feel its niques, at least in the biological sciences. I think it may be different in chemistry—at least that is what my recent contemporary impact. In 1957, Vernon Ingram, who at the time was working in the MRC Unit for the Study of contacts with mass spectrometry suggest. Bill Dove has noted that Al Hershey (Nobel Prize winner in 1969), the Molecular Structure of Biological Systems in the Cavendish Laboratory at Cambridge (later this morphed another temperamentally modest scientist who made