Cicely Crewdson, an elegant lady in her late thirties, was on holiday with her father at their family holiday home in the small village of Syde in the Cotswolds. Her holiday was nearly spoiled because she needed urgent treatment for a septic finger. Sepsis was potentially life-threatening in those days before effective antibiotics, such as penicillin, were available. The local doctor was summoned and agreed to come over from the nearby village of Rendcomb to treat Cicely. The doctor’s name was Frederick Sanger and he was still a bachelor. Her treatment would have needed a number of visits by this doctor to see how the patient’s finger was improving. Cicely Crewdson and Frederick Sanger got to know one another and doctor and patient were married in 1916.

We can only guess what attracted Frederick and Cicely to one another but Frederick would have been a quite suitable match for Cicely. Educated at St John’s College, Cambridge, he qualified as a doctor and completed his MD in 1902. Soon after he travelled to China as a missionary where he worked as a hospital doctor and found time, energy and enthusiasm to set up a new school for poorer children who were generally denied the education available for the children of the mandarin or upper-class families. Returning to Devon, his parent’s family home – probably for health reasons in 1912, Frederick then moved with his widowed mother, Ann, to Gloucestershire where he practised as the local doctor. His mother died shortly after the move in 1913.

In the 1950s, biology was seen as such a soft science that it was not taught in the boys’ grammar school that I attended. Boys who wanted to study biology had to suffer the taunts of fellow pupils as they crossed the road for lessons at the high school for girls. That it is now a subject with a cutting edge (and fit for boys!) is due in large part to the scientific contributions of Fred Sanger. That such a modest, self-effacing man whose childhood nickname was ‘Mouse’ could have such a profound impact needed some explanation. In this biography, George Brownlee gives us that explanation.

When Fred Sanger joined the Laboratory of Molecular Biology (LMB) in Cambridge in 1962, he had already won a Nobel Prize for his work on the structure of insulin. This Nobel Prize was, appropriately, for chemistry, since he showed that proteins were proper chemicals, with a defined structure, and not some ill-defined mixture as thought by some. It was a discovery that opened up the chemistry of macromolecules, and created a new subject, distinct from the biochemistry of those days, that demanded a new name: molecular biology. In the LMB he turned his attention to the nucleic acids, no doubt influenced by the presence of Francis Crick’s Division of Molecular Genetics. While the molecular geneticists treated their central subject as a coding problem – how does the information in DNA end up as a sequence of amino acids – and used clever genetic tools to crack the problem, Sanger carried on with his chemist’s approach and developed powerful ways to sequence first RNA and then DNA. Along the way, as Brownlee describes, he made a number of important discoveries. And he introduced the notion that it was important to sequence entire genomes and then ask what the sequence told about the biology – an approach that is now called hypothesis-free discovery, carried out on a massive scale. But his work was not appreciated by all his colleagues. I once overheard Francis Crick remark: ‘The trouble with Fred is that he has developed all these powerful methods, but we can’t persuade him to do anything interesting with them.’

After Fred Sanger described his dideoxy sequencing method in 1977, the main technical innovation was the development of high-throughput automated methods that were not dependent on radioactivity. Autoradiography was replaced by the introduction of fluorescent ‘tags’ on short DNA ‘primers’ – one for each of the four dideoxy terminator reactions. The four dideoxy terminators – C, A, G and T – were distinguishable by the four different fluorescent tags on the primer used for the particular dideoxy terminator sequencing reaction. These tags were detected by lasers and a camera operating in real time monitoring the progress of the separation of the chain terminated reaction products during their separation by gel electrophoresis. The sequence was now recorded automatically. The raw sequence information was processed by suitable software programs on a computer and presented as a linear sequence. Thus Fred Sanger’s manual ‘read’ of radioactive bands on an autoradiograph of a gel was now replaced by an automated ‘read’ of fluorescent bands on the same type of gel.

Commercial machines using this technology soon became available and were first used by Craig Venter and colleagues in 1987. Subsequently there were further technical improvements to these machines optimising the matrix used for the electrophoretic separation of the chain terminated reaction products. Improvements were also made by positioning the fluorescent tag on the dideoxy terminating nucleotide. But these technical developments were still using the basic dideoxy sequencing method, the copying of a single-stranded template by primed synthesis with a DNA polymerase in the presence of dideoxy chain terminators, as devised by Fred Sanger in 1977.

At the suggestion of Cambridge University Press – after my manuscript was completed – I commissioned five short commentaries by distinguished molecular biologists who had read my biography. These complement the Foreword by Sir Edwin Southern.

The commentators are:

Fred Sanger retired in 1983 aged 65. Many people thought this was too early and that the Director then, Sydney Brenner, should perhaps have persuaded him to stay on at the laboratory. After all he was the most high-profile scientist at the lab. But Sanger himself felt it was the right time to retire. He had reached the pinnacle of his career. He had just won his second Nobel Prize. A third Nobel Prize was out of reach even for a man of Sanger’s determination, focus and energy. His work had paved the way for sequencing the human genome. Fred said his capacity for working at the bench and doing experiments was waning and space should be given to someone younger. Fred was to apply his remaining energy to his much larger garden when he and his wife, Joan, moved from Hills Road, Cambridge to ‘Far Leys’ (named in memory of his childhood home near Birmingham) in Swaffham Bulbeck outside Cambridge in the Fens. Here he was to grow roses, fruit trees, soft fruit, a vine cutting I gave him, along with his many other specimen flowers in his herbaceous borders. He also had time now to spend more time enjoying his hobby of sailing and watching his grandchildren, the children of his second son, Peter, grow up.

The overriding question, the central question in this biography, is why was Fred Sanger so successful as a scientist. What attributes allowed him to succeed twice on two different but fundamental problems and gain two Nobel Prizes? Was it his personal attributes? Was it the influence of his parents and education at school? Was it his own early career in the Department of Biochemistry in Cambridge where he started science? Was it his choice of the scientific problem or his choice of collaborators? Was it in his DNA? Was he perhaps just lucky to be awarded two Nobel Prizes?