MRC Laboratory of Molecular Biology
The Medical Research Council 'Laboratory of Molecular Biology' is a research institute in Cambridge, England, involved in the revolution in molecular biology which occurred in the 1950–60s. Since then it has remained a major medical research laboratory at the forefront of scientific discovery, dedicated to improving the understanding of key biological processes at atomic, molecular and cellular levels using multidisciplinary methods, with a focus on using this knowledge to address key issues in human health.
A new replacement building constructed close by to the original site on the Cambridge Biomedical Campus was opened by Queen Elizabeth II in May 2013. The road outside the new building is named Francis Crick Avenue after the 1962 joint Nobel Prize winner and LMB alumnus, who co-discovered the helical structure of DNA in 1953.
History
Origins: 1947-61
, following undergraduate training in organic chemistry, left Austria in 1936 and came to the University of Cambridge to study for a PhD, joining the X-ray crystallographic group led by J.D. Bernal. Here, in the Cavendish laboratory, he started his lifelong work on hemoglobin. The death of Lord Rutherford led to his successor, Lawrence Bragg, a pioneer in X-ray crystallography, becoming the new Cavendish professor of physics in 1938. Bragg became a major supporter of Perutz and his group in those early days.After World War II, many scientists from the physical side of science turned to biology, bringing with them a new way of thinking and expertise. John Kendrew joined Perutz's group to study a protein closely related to hemoglobin — myoglobin — in 1946. In 1947, the Medical Research Council, under the guidance of its Secretary Edward Mellanby, decided to form and support the "MRC Unit for the Study of the Molecular Structure of Biological Systems". The group, which by 1948 also included Hugh Huxley working on muscle, was joined in 1949 by Francis Crick, who worked initially on protein crystallography. In 1951 they were joined by James Watson.
1953 was an annus mirabilis: Watson and Crick discovered the double-helical structure of DNA, which revealed that biological information was encoded in a linear structure and how this information could be duplicated during cell division. Perutz discovered that the detailed three-dimensional structures of proteins, such as myoglobin and hemoglobin could, in principle, be solved by X-ray analysis using a heavy metal atom labeling technique. Hugh Huxley discovered that muscle contraction works by a sliding filament mechanism.
In 1957 the group's name was changed to the "MRC Unit for Molecular Biology". Also that year, Vernon Ingram discovered that the disease sickle cell anaemia is caused by a single amino acid change in the hemoglobin molecule and Sydney Brenner joined the Unit. In 1958, Crick's review "On Protein Synthesis" appeared: this laid out, for the first time, the central dogma of molecular biology, the sequence hypothesis and the adaptor hypothesis. In 1961 Brenner helped discover messenger RNA and, in the same year, he and Crick established that the genetic code was read in triplets.
All this work was accomplished in a single-storey temporary building, a few rooms in the Austin Wing, a room with a lean-to glass front and a short sealed off corridor within the Cavendish laboratory.
Opening of the LMB in 1962
The MRC built a new Laboratory on the outskirts of Cambridge — the LMB — into which the Unit from the Cavendish moved in early 1962. Additionally, Fred Sanger's Unit which had been housed in the university's Biochemistry department joined them, as did Aaron Klug from London. Sanger had invented methods for determining the sequence of amino acids in a protein: he was awarded the Nobel Prize in Chemistry in 1958 for the first protein sequence, that of insulin. The new laboratory was opened by Queen Elizabeth II in 1962. Later that year, Kendrew and Perutz shared the Nobel Prize for Chemistry and Crick and Watson received a share of the Nobel Prize for Physiology or Medicine. The LMB building was incorporated into the new Addenbrooke's Hospital complex as this was constructed in the 1970s.The new LMB had Perutz as its chairman and contained 3 divisions:
- Structural Studies, headed by Kendrew.
- Molecular Genetics.
- Protein Chemistry.
Molecular Biology: after 1962
During the 1960s, molecular biology the world over flourished, the outline bones of the 1950s now having flesh put on them. The detailed 3-D atomic structures of a series of proteins, and how they function, were deduced. These included myoglobin, hemoglobin and chymotrypsin, the last by David Blow. The genetic code, from evidence around the world, was assembled by Crick. Punctuation signals in the messenger RNA — where to start translating the RNA into a protein sequence, and where to stop — were discovered by postdoctoral fellow Joan A. Steitz. Crick suggested how the tRNA molecules — his original adaptors — read the messenger in his wobble hypothesis. Sanger devised new methods for sequencing RNA molecules and then later for DNA molecules. Much later, this line was extended to include determining the sequence of whole genomes, in which John Sulston played a key role. How tRNA precursor molecules are processed to give a functional tRNA was elucidated by John Smith and Sid Altman, and this later led to the discovery of ribozymes. The atomic structure of the first tRNA molecule was solved and zinc fingers discovered by Klug. The structure of the ATP synthase was solved by John E. Walker and Andrew Leslie, for which Walker shared the Nobel Prize for Chemistry in 1997. In 1990, Kiyoshi Nagai began working on deciphering the structure of the spliceosome, first using X-ray crystallography and later with cryogenic electron microscopy, and in 2016 his group published the first structure of the spliceosome captured in a fully active, substrate-bound state immediately following catalytic reaction. The structure of the ribosome was solved by Venkatraman Ramakrishnan, for which he shared the Nobel Prize for Chemistry in 2009.1960s: Development and ''C. elegans''
Towards the end of the 1960s decade, it seemed that new problems in biology could be solved using the approaches which proved so successful in molecular biology.Sydney Brenner started working on the genetics of the nematode C. elegans in 1965. This group expanded, especially with many foreign visitors who today form the core of C. elegans research. Sulston determined the cell lineage of this small worm and John Graham White the entire wiring diagram of its nervous system. Robert Horvitz, who helped in the cell lineage, was to share the Nobel Prize for Physiology or Medicine with Brenner and Sulston in 2002. Jonathan Hodgkin established the genetic pathway in C. elegans which controls sex determination. John Gurdon developed the use of the frog oocyte to translate mRNAs, sharing the 2012 Nobel Prize for Physiology or Medicine for his earlier work showing that genetic information remains intact during development.
Peter Lawrence came to study pattern formation, helping discover how compartments in Drosophila determine the fly's body plan. Under his influence, Crick also became interested in morphogenetic gradients and how they may help specify biological patterns.
Immunology
had over many years been working on antibody variation. He was joined in this by Georges Köhler and, together, they discovered how to produce monoclonal antibodies. For this they shared the Nobel Prize for Physiology or Medicine in 1984. This area was extended by Greg Winter who pioneered antibody engineering using phage display to make novel human antibodies and antibody fragments, for which he shared the Nobel Prize in Chemistry in 2018. Both monoclonal antibodies and their fragments are now of major medical importance.Michael Neuberger discovered the mechanism by which antibody diversification occurs by Activation-induced deaminase. This fundamental discovery is the keystone to understanding the molecular mechanism by which organisms can produce a diverse repertoire of antibodies to recognise new pathogens. This is of wider importance in understanding the role of directed mutagenesis and DNA repair in physiology. Finally, the molecular mechanisms elucidated by Neuberger may be of great importance in understanding the mutational pattern of kataegis in breast cancer. Sadly, Michael Neuberger died from myeloma – the irony of which was not lost on him.
Cell biology
The emphasis on classical molecular biology shifted towards cell biology and development, so that the Molecular Genetics division was renamed Cell Biology. Mark Bretscher discovered the topological way proteins are arranged in the human erythrocyte membrane and its phospholipid asymmetry. Richard Henderson and Nigel Unwin developed electron crystallography to determine the structure of two-dimensional arrays, applying this to the bacterial purple protein, bacteriorhodopsin. Barbara Pearse discovered the major components of clathrin-coated vesicles, structures formed during endocytosis, and a low resolution structure of the cage-like lattice around them was determined. How proteins become localised to different parts of the cell — such as to the endoplasmic reticulum, Golgi apparatus or the plasma membrane — and the role of this in cell polarity, have been elucidated by Bretscher, Hugh Pelham and Sean Munro. The spindle pole bodies — the large structures in yeast cells which act as the foci to which chromosomes are moved during mitosis — have been purified and a low resolution structure of them deduced by John Kilmartin.A continuing interest has been the structure of chromosomes. This was initiated by a visitor, Roger Kornberg, who discovered the first level of condensation of DNA, the nucleosome, and continues with the focus on understanding the higher orders of folding DNA.