‘Just a chap who messed about in the lab’: Fred Sanger and DNA sequencing
Lara Marks |
When Fred Sanger, twice Nobel Prize winner, was born nearly a century ago on 13 August 1918, little was known about DNA (deoxyribonucleic acid). By the time he died, in 2013, there had been a revolution in knowledge about DNA and its role in health and disease. Much of this was due to the time-consuming and patient work of Sanger and the techniques he developed for deciphering the structure of proteins and then DNA. It was on the basis of this work that he was awarded the Nobel Prize in 1958 and in 1980. In today's hypercharged academic scientific environment it is interesting to reflect on how much of Sanger's scientific breakthroughs could not have been achieved without him having the time and space to think and experiment.
Despite his major contributions, Sanger, in his typically self-effacing manner, saw himself as 'just a chap who messed about in the laboratory' and 'one of the backroom boys'. His modesty is captured by an article he wrote in 1988:
Unlike most of my scientific colleagues, I was not academically brilliant. I never won scholarships and would probably not have been able to attend Cambridge University if my parents had not been fairly rich; however, when it came to research where experiments were of paramount importance and early narrow specialization was helpful, I managed to hold my own even with the most academically outstanding.
What helped him was the fact that early on in his career he managed to secure permanent research appointments, funded by the UK Medical Research Council, firstly in the Department of Biochemistry at Cambridge University and then in the Laboratory of Molecular Biology. This meant he was not under pressure to apply for lots of grants and produce lots of papers.
Another advantage was that he had very little competition from other researchers when in 1944 he began working on the building blocks, known as amino acids, that make up insulin, a small protein secreted by the pancreas that helps regulate sugar levels in the blood. Indeed, as he recalled:
It seemed strange to me that hardly anyone else felt it sufficiently important to be working on.
In part this reflected the fact that many scientists in this period believed that proteins, such as insulin, were just a random mixture of material suspended in fluid and not pure chemical entities with a specific molecular pattern. Most of his scientist friends, by contrast, complained about competing with others to make new discoveries in their respective fields. Not having many others to compete against suited Sanger’s personality. As he put it:
I like the idea of doing something that nobody else is doing rather than racing to be the first to complete a project.
It took Sanger 11 years to complete the insulin project. His work demonstrated conclusively for the first time to scientists that proteins were real chemicals with a defined sequence and opened up the possibility of synthesising insulin, which from 1902 began to be used to treat diabetes. Reaching this point had been a painstaking and time-consuming process which involved breaking up insulin into small fragments and then reconstituting its chains of amino acids by identifying where they overlapped. Sanger described the process like piecing together a jigsaw.
On the back of his insulin work Sanger was awarded his first Nobel Prize, in 1958. Winning the prize aged 40 meant that he was able to work without any pressure to prove himself for the rest of his career. It also released him from having to take on the time-consuming process of running a university department and the responsibility of teaching students. As he said, he 'could afford to attack problems that were more "way out" and longer term'. In fact, because few could adopt this approach he felt 'some obligation to do so'. Such freedom, Sanger recognised, was a major contributor to his development of DNA sequencing.
DNA - deoxyribonucleic acid - had been discovered in the late nineteenth century, yet it remained little studied for many decades. In part this was because proteins, rather than DNA, were considered to hold the genetic blueprint for organisms. Indeed, when Sanger began his research in the 1940s DNA was considered an inert substance. As he put it, the notion that DNA contained 'all the information for making a complete organism would have been thought of as science fiction.'
Attitutes to DNA began to change in the wake of some experiments reported in 1944 which showed that purified DNA could change one strain of bacteria into another type. This demonstrated for the first time that DNA could transform the properties of cells. Until then most scientists had believed genetic information was carried by proteins. Knowledge was increased further by James Watson and Francis Crick's publication of the double-helix model of DNA in 1953.
Initially, Sanger was not interested in sequencing DNA. By the late 1950s, however, he had begun some experiments to sequence nucleic acids, the building blocks that make up DNA. This was partly stimulated by discussions he began to have with Crick and his colleagues. In many ways such sequencing was a natural extension of his work on insulin. Yet, it was a much more formidable challenge. Some of the key obstacles were the difficulties in securing a suitable starting material on which to experiment and the large size of the DNA molecule which would be difficult to break down into manageable fragments for analysing. It was not until 1975, after laborious methodical work, that Sanger and his team managed to crack the problem, for which he won his second Nobel Prize in 1980.
In today's academic environment when scientists’ time in the laboratory is increasingly squeezed by competing demands, the story of how Sanger developed DNA sequencing underlines the value of research councils providing enough funding and resources to scientists so that they have enough free time to think and experiment without the constant pressure to produce papers, grant applications, and the duties of administration and teaching Now that DNA sequencing is carried out by automated machines it is easy to forget how time-consuming and laborious the process was when Sanger started his work. Yet it was his ability to devote himself to the methodical and repetitive laboratory work that laid the basis for DNA sequencing - one of the most important tools in medicine today and the basis for the genomic revolution which is already providing a meanss to combat the rise of antimicrobial resistance and the development of drugs to treat diseases like cancer.Please note: Views expressed are those of the author.