Department of Biochemistry
Nobel Prize awards to erstwhile members of the department
Frederick Gowland Hopkins 1929: Physiology or Medicine. Coming to Cambridge in 1898, Hopkins founded the subject of biological chemistry and became the first Cambridge Professor of Biochemistry in 1914. He was awarded the prize for his discovery of the growth-stimulating vitamins, sharing it with Christiaan Eijkman who discovered the antineuritic vitamin. Hopkins, working with Sydney Cole, had been the first to isolate the amino acid tryptophan as a product of the hydrolysis of casein. Feeding mice with different proteins revealed that tryptophan was an essential dietary component. He went on to show that a basic diet of salts and a purified mixture of lard, starch and casein was insufficient for sustained growth of young rats and that a critical ingredient was provided by a small daily amount of milk, eventually shown to be due to its content of vitamins.
Albert Szent-Györgyi 1937: Physiology or Medicine. Born in Budapest in 1893, Szent-Györgyi, entered Budapest Medical School in 1911 but his studies were interrupted by the First World War in which he served as an army medic and was decorated for valour. Revolted by the war, he is said to have shot himself in the arm and he completed his MD in 1917 whilst the wound healed. After the war he worked in a number of European laboratories, his work on cellular metabolism bringing him to the attention of Gowland Hopkins who offered him a Rockefeller Fellowship. He received his PhD from Fitzwilliam House in 1927 for isolating an anti-oxidant from adrenal glands that he christened ‘hexuronic acid’ – now known as vitamin C or L-ascorbic acid in recognition of its activity against scurvy. Szent-Györgyi’s subsequent research on biological oxidation, particularly on the role of the dicarboxylic acids malate, succinate and fumarate laid the foundation for Hans Krebs to resolve the cyclic reactions that bear his name.
Ernst Boris Chain 1945: Physiology or Medicine. Chain was one of the first German scientists who, in the 1930s, sought refuge in England under the auspices of Gowland Hopkins. He arrived on 2nd April 1933 and became one of Hopkins’ graduate students, working on phospholipids. In 1935 he moved to a position as a lecturer in Pathology at Oxford and it was there that, in collaboration with Howard Florey, he resolved the mechanism of action of penicillin. They shared the Nobel Prize with Alexander Fleming.
Richard Laurence Millington Synge 1952: Chemistry. After taking Part II Biochemistry Synge became a research student in the department under the supervision of Norman (Bill) Pirie – who, in 1936 with Frederick Bawden, J.D. Bernal and Isidor Fankuchen had shown that a virus can be crystallized and obtained X-ray patterns of tobacco mosaic virus. After obtaining his Ph.D. Synge moved to the Wool Industries Research Association, Leeds where he collaborated with Archer Martin, developing partition chromatography, a technique used in the separation mixtures of similar chemicals, that revolutionized analytical chemistry. They shared the 1952 Nobel Prize. Synge went on to analyse the amino-acid composition of gramicidin, work later used by Frederick Sanger in determining the structure of insulin.
Hans Adolf Krebs 1953: Physiology or Medicine. Krebs was born in Hildesheim and by 1933 was working in Medical Clinic of the University of Freiburg, a post from which he was dismissed in April 1933. By that time, in collaboration with his research student Kurt Henseleit, he had published the details of the first cyclic metabolic pathway to be discovered – the ‘urea cycle’. Hopkins, who kept up with the German literature, had described this work to The Royal Society in the winter of 1932 and, following the events of January 1933, he wrote to Krebs offering him sanctuary in Cambridge. Krebs arrived in July 1933, becoming a Demonstrator in the department, a post he held until 1935 when he moved to Sheffield. It was there in collaboration with William Johnson that he resolved the sequence of reactions that they called the "citric acid cycle". They measured the decline in metabolic rate of a suspension of fresh, minced pigeon breast and found that adding a salt of citric acid extended the ‘life’ of the sample by three-fold. They were able to show that a cyclical pathway was involved that with each turn regenerates citric acid and releases ATP – the cell’s primary energy currency.
On submitting their findings to Nature they were famously informed that the journal had enough material for the next ‘seven or eight weeks’: their paper appeared in the Dutch journal Enzymologia.
Krebs shared the Nobel Prize with Fritz Lipmann who had discovered co-enzyme A. Subsequently, working with Hans Kornberg, who was the Sir William Dunn Professor here from 1975 to 1995, he discovered the glyoxylate cycle, a variation of the citric acid cycle occurring in plants, bacteria, protists and fungi.
Frederick Sanger 1958 and 1980: Chemistry. Like Richard Synge before him, Sanger took Part II Biochemistry before starting a PhD in 1940 under the supervision of Bill Pirie. However, Pirie shortly moved to the Rothamsted Experimental Station in Harpenden to pursue his interest in viruses and Albert Neuberger became Sanger’s supervisor for a project on the metabolism of the amino acid lysine. After obtaining his PhD in 1943 Sanger worked with the newly appointed Head of Department, Charles Chibnall, whose previous work on bovine insulin lead to Sanger determining the complete amino acid sequence of its two polypeptide chains. To this end he used fluorodinitrobenzene (now known as the ‘Sanger Reagent’) to label N-terminal amino group acids and refined the methods of Synge and Martin to fractionate mixtures of peptides in two dimensions (first by electrophoresis and then by chromatography) to generate what Sanger called ‘fingerprints’. The finding that the two polypeptides of insulin had distinct amino acid sequences carried the implication that every protein had a unique sequence. For this work he received his first Nobel prize in Chemistry in 1958.
When the Medical Research Councilopened the Laboratory of Molecular Biology in 1962 Sanger moved from the Biochemistry Department to the new building opposite Addenbrooke’s Hospital. He developed ways of sequencing RNA before turning to DNA and by 1975 he and Alan Coulson had come up with a way of generating short oligonucleotides with defined 3' termini that could be fractionated on a polyacrylamide gel. This lead to the first complete sequence of a DNA genome – of the bacteriophage φX174.
By 1977 Sanger and colleagues had developed the ‘dideoxy’ chain-termination method for sequencing that permitted rapid and accurate sequencing of long stretches of DNA. For this he shared the 1980 Nobel prize in Chemistry in 1980 with Walter Gilbert and Paul Berg.
This ‘Sanger Method’ was used to sequence human mitochondrial DNA (16,569 base pairs), bacteriophage λ (48,502 bps) and the worm genome ~100 million bps) before it was eventually used to sequence the entire human genome, a project that was completed in 2003.
Sanger is one of only two people to have won two Nobel Prizes in the same category.
Rodney Robert Porter 1972: Physiology or Medicine. After graduating from the University of Liverpool Rodney Porter moved to Cambridge to become Fred Sanger's first Ph.D. student. His career was interrupted by the war in which he served with the Royal Army Service Corps, rising to the rank of Major. He was with the First Army in 1942 in the invasion of Algeria and with the 8th Army during the invasion of Silicy and then Italy. He eventually gained his Ph.D. in 1948 and went on to work at the National Institute for Medical Research, Mill Hill and St. Mary’s Hospital Medical School before following in the footsteps of Rudolf Peters as Whitley Professor of Biochemistry at Oxford. At Mill Hill he worked on methods of protein fractionation in collaboration with Archer Martin who shared the 1952 Nobel Prize with Richard Synge.
Porter went on to show that papain splits the immunoglobulin molecule into three pieces of equal size, two of which are identical and are able to bind antigen – the Fab (Fragment antigen binding) pieces. The American Gerald Edelman had shown that peptide chains within IgG molecules were linked by both inter- and intra-chain disulphide bridges and Porter found there were four chains in each antibody molecule, two identical larger chains, the heavy chains, and two identical smaller, light chains.
Porter and Edelman shared the 1972 Nobel Prize for resolving the structure and mode of action of antibodies.
In the early 1980s Porter turned to the identification of the genes involved in the classical and the alternate pathways for complement activation but his participation in these studies was cut short but his tragic death in a road accident in September 1985.
Peter Dennis Mitchell 1978: Chemistry. Born in Mitcham, Surrey, Peter Mitchell came up to Cambridge in 1939 to read Natural Sciences and, after taking Part II Biochemistry, completed a Ph.D. in 1951 on the mode of action of penicillin. He held the post of Demonstrator at the Department of Biochemistry from 1950 to 1955 when he moved to Edinburgh University to set up the Chemical Biology Unit in the Department of Zoology. Illness led to his resignation in 1963 after which he supervised the restoration of Glynn House near Bodmin, Cornwall, in part as a research laboratory.
By the 1960s it had been established that ATP was the universal 'energy currency' of living cells but the mechanism by which electron transfer is coupled to ATP synthesis in oxidative phosphorylation and in photophosphorylation remained unknown. In 1961 Mitchell proposed a completely novel explanation based on an indirect interaction between oxidizing and phosphorylating enzymes. He suggested that the flow of electrons through the enzymes of the respiratory or photosynthetic electron-transfer chains drives positively charged hydrogen ions (protons) across the membranes of mitochondria, chloroplasts and bacterial cells, generating a trans-membrane electrochemical proton gradient. The gradient consists of two components: a difference in hydrogen ion concentration (pH) and a difference in electric potential (p). The two together form what Mitchell called the 'protonmotive force'. The synthesis of ATP is driven by a reverse flow of protons down the gradient.
Initially received with much scepticism, Mitchell's revolutionary 'chemiosmotic theory' has shaped our understanding of the mechanisms of biological energy conservation. He received the 1978 Nobel Prize in Chemistry ‘for his contribution to the understanding of biological energy transfer through the formulation of the chemiosmotic theory.’
César Milstein 1984: Physiology or Medicine. Milstein was born in Bahía Blanca, Argentina and studied at the university of Buenos Aires, completing a Ph.D. on the enzyme aldehyde dehydrogenase. This led him to Cambridge to work on phosphoglucomutase with Malcolm Dixon in the Department of Biochemistry. During this period he collaborated with Fred Sanger and, having obtained a Cambridge Ph.D., he moved to Sanger's group in the Department. In 1961 he returned to Argentina but in 1963 he re-joined Sanger's group, by now located in the newly-formed Laboratory of Molecular Biology at Addenbrooke’s Hospital. It was at Fred’s suggestion that he turned his attention from enzymology to immunology. He focused on antibodies, the proteins produced by mature B lymphocytes (plasma cells) as part of the immune response. He used myeloma cells – cancerous forms of plasma cells that multiply indefinitely – to study somatic hypermutation and the mechanism by which antibody diversity is generated. In 1975 Milstein and Georges Köhler developed the hybridoma technique for the production of monoclonal antibodies, for which they shared the Nobel Prize in Physiology or Medicine in 1984 with Niels Kaj Jerne.
This discovery led to an enormous expansion in the exploitation of antibodies in science and medicine.
Richard Timothy Hunt 2001: Physiology or Medicine. Tim Hunt read Natural Sciences at Cambridge and became a research student in the Department in 1964 under the direction of Asher Korner. He spent a few months in the New York laboratory of Irving London, whence he returned after completing his Ph.D. in 1968 to work on protein synthesis in the rabbit reticulocyte system. He continued this interest when he came back to work with Tony Hunter and Richard Jackson in the Department,where he remained until 1990 when he moved to what is now the Cancer Research UK London Research Institute.
It became Tim’s habit to spend summers at the Marine Biological Laboratory at Woods Hole, Massachusetts where the ready supply of surf clams and sea urchins was much appreciated by those interested in protein synthesis in embryogenesis and mitosis. In the summer of 1982, having added [35S] methionine to a suspension of fertilized sea urchin eggs and removed samples at intervals for gel electrophoresis, Hunt noticed that the autoradiogram ‘showed something very odd and unexpected’, namely that, although most of the protein bands got stronger and stronger as time went by, one band did not show this expected behaviour. It was prominent at the beginning but at a certain point it faded away. He concluded that this protein underwent specific proteolysis at some point in the early development of the fertilized egg.
Thus were the cyclins discovered and Hunt went on to show that cyclins begin to be synthesised after egg fertilization, increase in levels during interphase and decline very quickly in the middle of mitosis in each cell division. Cyclins are present in vertebrate cells and Hunt and others showed that they bind and activate a family of protein kinases, now called the cyclin-dependent kinases, one of which had been identified as a crucial cell cycle regulator by Paul Nurse. Beginning in 1976, Nurse had identified the gene cdc2 in fission yeast (Schizosaccharomyces pombe) as controlling the progression of the cell cycle from G1 phase to S phase and the transition from G2 phase to mitosis. In 1987, Nurse identified the homologous human gene, CDK1, a cyclin dependent kinase. Also working in yeast, Leland H. Hartwell identified the fundamental role of checkpoints in cell cycle control and in particular of genes such as cdc28, which controls the start of the cycle – the progression through G1.
Roger Yonchien Tsien 2008: Chemistry. Roger Tsien is a New Yorker who studied at Harvard before completing a Ph.D. in 1977 as a member of the Physiological Laboratory in Cambridge where he remained as a Research Fellow until moving to the University of California, Berkeley and then to the University of California, San Diego. His Ph.D. supervisor was Jeremy Sanders in the Department of Chemistry and the subject was ‘The Design and Use of Organic Chemical Tools in Cellular Physiology’ which represented Tsien’s early steps as a pioneer of the development of fluorescent dyes that are sensitive to the presence of particular ions such as calcium. The prototype, Quin-2, was first demonstrated in experiments carried out in this department. Another calcium imaging dye, Fura-2, has been widely used to track the movement of calcium within cells. Indo-1, another popular calcium indicator, emerged from Tsien's group in 1985 and he has also developed fluorescent indicators for other bio-relevant ions.
Complementary to the quantification of cellular cation fluxes has been the realization of methods to visualize proteins in cells and thus to be able to track their movement and measure their levels as cells respond to signals. The first step in this extraordinary achievement happened in 1962 when Osamu Shimomura, Frank Johnson, and Yo Saiga isolated a photoprotein – a protein that can emit light – from luminescent jellyfish that they called aequorin. They also found another protein that gave off a greenish fluorescence and helpfully called it green fluorescent protein (GFP). It transpired that when calcium binds to aequorin it glows blue but some of this blue light is absorbed by its companion GFP and re-emitted as green light (lower energy). In due course, other creatures were also found to make GFPs (Obelia, a sort of jellyfish and Renilla, a sea pansy).
After the GFP gene had been tracked down, Martin Chalfie engineered DNA that could be taken up by an animal of choice, which then made GFP. Chalfie had worked as a postdoc on worm development with Sydney Brenner and John Sulston at the Laboratory of Molecular Biology in Cambridge. With this background the choice of model animal was obvious and, GFP-coding DNA with a regulatory sequence that would be switched on only in one type of worm cell having been constructed, the world first saw the use of GFP as a marker for gene expression in the form of a “glow worm” with green fluorescent spots in the few neurons where GFP was made. In 1995 Roger Tsien made the first mutant of GFP with enhanced fluorescence (brighter light). Tsien’s “molecular engineering” of GFP led to the generation of a number of other mutants with different spectral properties—giving, for example, blue, cyan, red, or yellow fluorescence.
These achievements have completely transformed the world of cell biology and for making it all possible, Osamu Shimomura, Martin Chalfie and Roger Tsien shared the 2008 Nobel Prize in Chemistry.