Both of Fred Sanger’s parents died of cancer at relatively young ages, his father, Frederick, aged 60 in 1937 from an operation to remove a stomach cancer. His mother, Cicely, aged 58, died a year later from cancer of the colon. Fred Sanger was a young man of 20 then – still studying at Cambridge for his first degree. At that young age, he could not have imagined that later in his life it would be his research that would make the dream of sequencing the human genome a reality. In 1938 it would have been a leap of faith to predict that by the beginning of the twenty-first century, the entire human genome would have been sequenced.

Fred rarely allowed himself the luxury of predicting future results of research. ‘I don’t want to look into the future very much. I’m a scientist not an astrologer! I don’t like to predict things you can’t be too sure about.’ He believed in evidence, not in theories of what might be possible and how long it might take to solve a problem. But we know that Fred hoped that his research might lead to medical advances even though he rarely spoke about this in public. In 1992, in an interview with a journalist, he said: ‘If we know the complete sequence of the human genome and understand how it works, and how tumours are formed, then we can begin to understand how to deal with tumours better.’ The knowledge that cancer had caused the early death of both his parents may have been in the back of Fred’s mind when he made this remark.

Fred Sanger started his research in arguably the best-known biochemistry department in Britain in 1940 under the leadership of Frederick Gowland Hopkins. Hopkins, affectionately known as ‘Hoppy’, held the first Chair of Biochemistry in Cambridge from 1914 and had modernised biochemistry in the UK. Biochemistry had lagged behind advances in this subject in Europe, and particularly in Germany, in the previous century. The subject had evolved from physiological chemistry and was originally a branch of physiology with a chemical bias. But Hopkins, as the first Professor of Biochemistry in Cambridge – although not the first in the UK which was in Liverpool University in 1902 – established a vibrant British school of biochemistry even though he had an unconventional training as an analytical chemist and medic and had never formally studied biochemistry himself. ‘In Hopkins two things were significantly combined: the training and tastes of an organic chemist, and the imagination of a biologist and physician.’ A careful and committed experimentalist, he had brought Cambridge fame through his discovery of vitamins as accessory food substances needed in minute quantities, for which he was awarded the Nobel Prize in 1929. But his engaging, friendly and benign personality meant that ‘Hoppy’ headed an open and enquiring department, where no subject, including politics, was off-limits. He was popular and approachable with the advanced Part II students. He had appointed talented and sometimes controversial scientists, such as J. B. S. Haldane, Joseph Needham, Malcolm Dixon, Bill Pirie, Ernest Baldwin and Robin Hill. Among his appointments were the women scientists Dorothy Moyle (later Needham) and Marjorie Stephenson who became eminent in their fields. Hans Krebs and Ernst Chain – fleeing persecution from Nazi Germany and both to become future Nobel prize winners – were made welcome by Hopkins in the 1930s. In fact the department was affectionately known by some as the ‘Hopkins Matrimonial Agency’ because of the number of marriages between research workers and ‘Little Moscow’ because of the left-wing tendency of the Needhams, Pirie and others.

The lean years

Fred described 1955–64 as his ‘lean years’ as he published relatively little then. In fact, this was a transitional period in which Fred was exploring completely new ideas for sequencing proteins. His idea was to radioactively label proteins. After radioactively labelling a protein and then isolating a radioactive peptide, he would work out the sequence around the labelled amino acid, indirectly. For example, he would use various modifications of the peptide, e.g. removal of the N-terminal amino acid, and monitor changes in the mobility of the peptide on paper chromatography or paper electrophoresis. He was using the position of the peptide as a way of sequencing.

This new way of thinking would, in principle, have many advantages. It would not require as much protein as his classical procedures worked out on insulin, since radioactively labelled peptides would be easily and quickly detected on paper by the then relatively new and sensitive method of autoradiography – using an X-ray film. The protein would not necessarily have to be pure, as long as it was radiochemically pure. For example in 1958 Fred incubated an isolated oviduct from a hen with 1 mCi 32P-labelled inorganic phosphate. He successfully isolated 32P-labelled ovalbumin, which was known then to contain two serine phosphates. Fred correctly deduced the presence of one phosphate-containing dipeptide, as serine phosphate-alanine, an observation confirmed ten years later by classical methods of peptide sequencing. Twenty years later on in 1978, in a very different era of DNA sequencing, my colleagues and I showed the exact position of this dipeptide in ovalbumin, as deduced from the nucleotide sequence of a cDNA clone of ovalbumin mRNA.

Fred Sanger (FS) and I (GB) are seated in a recording studio at Imperial College, London. This is a slightly edited transcript of the final interview.

Move to the new lab

1. GB At this time, in 1962, you moved to a new lab in Cambridge.

2. FS Yes, that’s right. This was to the Laboratory of Molecular Biology (Figure 44).

3. There were two groups in Cambridge, really, my own group working in Biochemistry and we had nothing to do with the teaching, so we were the poor relations. We were supported by the Medical Research Council (MRC). Then there was Perutz’s group in the Cavendish – working in the hut in front of the Cavendish. Both of us were looking for possibilities of new labs and expansion – particularly them. The MRC decided to build a new lab for us – the new Laboratory of Molecular Biology which was completed in 1961.

4. GB You took with you your own extended group.

5. FSYes, the new laboratory had three groups at that time. There was the Structural Studies group headed by Perutz, who was also head of the lab. John Kendrew, Aaron Klug and Hugh Huxley were there. And there was Francis Crick’s group, called Molecular Genetics, later Cell Biology. Sydney Brenner was in that group (Figure 45). There was my group (Figure 46) on the top floor, called Protein Chemistry. No mention of nucleic acids at that time. I was joined by various people, who had worked with me in Biochemistry – Leslie Smith who had been on the insulin work (Figure 41), Ieuan Harris (Figure 46) and Brian Hartley (Figure 46). Brian had worked on the important project of sequencing chymotrypsin. He completed that in the Molecular Biology Lab.

Fred Sanger (FS) and I (GB) are seated in a recording studio at Imperial College, London. This is a slightly edited transcript of the continuing interview.

Postgraduate research at Cambridge, 1940–1943

1. GBI’ve read, Fred, that at this stage you had still not quite decided to go into research.

2. FSWell, the thing is, I had not really decided that I was that good. I hadn’t been getting first classes in my Part I exams, and so I really didn’t have the confidence that I could do research. Usually you had to get a first to go into research. In this Part II Biochemistry there were all these brainy people who had got firsts in their Part I. They all seemed very clever compared to me. So at the end of the year I took the exams and I sort of went off and didn’t think too much about what I was going to do. In fact, I was thinking I would probably do some war work of some sort. War had broken out. But then, to my surprise, someone had seen in the paper that I had got a first. Actually, I was staying with my cousin. He was in the Air Force and he had been to the mess and he had just had a look at the Cambridge results in The Times and he’d seen I had got a first. And I said that’s ridiculous, it couldn’t be, but it was so. I had got a first. There were just two of us who had got firsts in this exam. So that changed my mind. So there was the possibility of doing research.

3. GBBut before you actually started research you had actually preplanned some training in Devon, I understand.

4. FSYes, that’s right, I went to a place called Spison (now Spiceland), a Quaker Relief Training Centre, which was a training place for conscientious objectors, where I was learning various things they could do to help save lives, instead of taking lives. We learned agriculture and a bit about building, and after I had done that course I went to work in a hospital, cleaning the floors and that sort of thing – just as an orderly. I started work there. That was the first job I had. I got 10 shillings (50p) a week for that.

Fred Sanger asked me to interview him for the Biochemical Society archives in October 1992. He never told me why he chose me as an interviewer rather than one of his many colleagues and friends in Cambridge. I had worked with Fred in Cambridge from 1963 to 1980 but by 1992 had moved to the Sir William Dunn School of Pathology at the University of Oxford. Naturally I was honoured and accepted. In that interview Fred Sanger gave a full and frank account of his life and provided some insight into what qualities he thought were needed to be a successful scientist. This biography is, in part, based on that interview.

Fred had an unusual upbringing and it may surprise many readers to learn that he was not initially committed to research. As a young man he had a strict Quaker upbringing. He was ambivalent about studying medicine, changing his mind to study biochemistry rather than medical subjects at Cambridge because his father, a doctor in general practice, was always rushing around attending to patients and ‘could not really concentrate on anything’. Both his parents died when he was an undergraduate, leaving him vulnerable. He doubted he was good enough to do research and applied at the last minute to study for a higher degree, a PhD, in biochemistry at Cambridge only after he learnt he had been awarded, to his surprise, a first class degree. Sanger was a conscientious objector in the Second World War. He learned to do research rather than killing the enemy.

In spite of this uncertain beginning to his career, he quickly showed aptitude for research. He seemed to have the ability to succeed in solving ‘impossible research problems’ where others had feared to tread. He was a ‘hands-on’ researcher doing research himself with the help of a trusted technical assistant right up to the end of his career. Many of his critical research findings were the result of his own findings carried out personally. This did not mean he was not a good leader. In fact he was a consummate team leader and early on attracted others to his research team because of his achievements and the great personal effort he made. This personal commitment to research inspired confidence in his many collaborators, including me. He was also unusual in stressing the contribution of the whole of his research team.

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.

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?