‘It’s in my DNA’ is an expression we hear often nowadays. Nucleic acids were discovered by the chemist Friedrich Miescher in 1869, but the secrets of DNA were largely hidden until the DNA of the human genome, which comprises about 3.0 × 109 base pairs, was sequenced 132 years later, in 2001. Now, DNA sequencing is routine and underpins many biological research programmes, including those aimed at understanding human evolution, development and disease.

Fred Sanger (1918–2013) was the man who made this possible. In 1975, he described an elegant method — the plus and minus method — of sequencing DNA based on the position of DNA molecules copied by a DNA polymerase from the DNA of a simple bacteriophage under conditions of limiting different dNTPs. In this method, not only did Sanger introduce the idea of separating individual DNA molecules that differed by only a single residue according to their length on polyacrylamide gels, he also found a way of defining the 3′ end of each molecule, thereby deciphering the DNA sequence. Before publication of this method, DNA sequencing was extremely laborious and only short lengths of DNA had been sequenced, usually by degradative methods.

I judge his 1977 paper to be even more important, because it was the basis of all the early genome sequencing projects

In 1977, Sanger improved and simplified his method by using the DNA-chain terminators, 2′,3′ -dideoxynucleoside triphosphates (ddNTPs), three of which — ddATP, ddGTP and ddCTP — had never been synthesized before. Sanger described his 1975 paper as his ‘most important paper’, but I judge his 1977 paper to be even more important, because it was the basis of all the early genome sequencing projects — the human, nematode, yeast and Escherichia coli projects. Even now, one of the popular high-throughput genome sequencing methods uses chain terminators, although modified to be reversible. Thus, Sanger developed a method that still has great impact today.