MRC Laboratory of Molecular Biology

The new building of the LMB viewed from theCambridgeshire Guided Busway bridge in June 2013
Abbreviation	MRC LMB
Location	Cambridge, UK
Coordinates	52°10′35″N0°08′35″E / 52.1763°N 0.1430°E /52.1763; 0.1430
Fields	Molecular biology
Director	Jan Löwe
Parent organization	Medical Research Council
Website	www2.mrc-lmb.cam.ac.uk

TheMedical Research Council (MRC)Laboratory of Molecular Biology (LMB) is a research institute inCambridge,England, involved in the revolution inmolecular 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.^[1][2][3]

A new replacement building constructed close by to the original site on theCambridge Biomedical Campus was opened byQueen Elizabeth II in May 2013.^[4] The road outside the new building is namedFrancis Crick Avenue after the 1962 jointNobel Prize winner and LMB alumnus, who co-discovered the helical structure ofDNA in 1953.^[5]

Max Perutz, following undergraduate training in organic chemistry, leftAustria in 1936 and came to theUniversity of Cambridge to study for a PhD, joining theX-ray crystallographic group led byJ.D. Bernal. Here, in theCavendish laboratory, he started his lifelong work onhemoglobin. The death ofLord 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.^{[citation needed]}

AfterWorld 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, theMedical Research Council (MRC), under the guidance of its SecretaryEdward Mellanby,^[5] decided to form and support the "MRC Unit for the Study of the Molecular Structure of Biological Systems". The group, which by 1948 also includedHugh Huxley working on muscle, was joined in 1949 byFrancis Crick, who worked initially on protein crystallography. In 1951 they were joined byJames Watson.^{[citation needed]}

1953 was anannus mirabilis: Watson and Crick discovered the double-helical structure ofDNA, which revealed that biological information was encoded in a linear structure and how this information could be duplicated duringcell 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 thatmuscle contraction works by asliding filament mechanism.^{[citation needed]}

In 1957 the group's name was changed to the "MRC Unit for Molecular Biology". Also that year,Vernon Ingram discovered that the diseasesickle cell anaemia is caused by a single amino acid change in the hemoglobin molecule andSydney Brenner joined the Unit. In 1958, Crick's review "On Protein Synthesis" appeared: this laid out, for the first time, thecentral dogma of molecular biology, thesequence hypothesis and theadaptor hypothesis. In 1961 Brenner helped discovermessenger RNA and, in the same year, he and Crick established that thegenetic code was read in triplets.^{[citation needed]}

All this work was accomplished in a single-storey temporary building (The Hut), a few rooms in the Austin Wing, a room with a lean-to glass front (The Greenhouse) and a short sealed off corridor (The Gallery) within the Cavendish laboratory.^[6]

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 didAaron Klug from London. Sanger had invented methods for determining the sequence of amino acids in a protein: he was awarded theNobel Prize in Chemistry in 1958 for the first protein sequence, that ofinsulin. The new laboratory was opened byQueen Elizabeth II in 1962. Later that year, Kendrew and Perutz shared the Nobel Prize for Chemistry and Crick and Watson received a share of theNobel Prize for Physiology or Medicine. The LMB building was incorporated into the newAddenbrooke's Hospital complex as this was constructed in the 1970s.^[7]

The new LMB had Perutz as its chairman and contained 3 divisions:

• Structural Studies, headed by Kendrew.
• Molecular Genetics (Crick).
• Protein Chemistry (Sanger).

In all, there were about 40 scientists but this number rapidly increased, particularly with a large influx of post-doctoral visitors from the US.^[6]

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 includedmyoglobin,hemoglobin andchymotrypsin, the last byDavid Blow. The genetic code, from evidence around the world, was assembled by Crick. Punctuation signals in themessenger RNA — where to start translating the RNA into a protein sequence, and where to stop — were discovered by postdoctoral fellowJoan A. Steitz.^[8] Crick suggested how thetRNA molecules — his original adaptors — read the messenger in hiswobble hypothesis. Sanger devised new methods for sequencingRNA molecules and then later for DNA molecules (for which he received a second Nobel Prize in Chemistry in 1980). Much later, this line was extended to include determining the sequence of wholegenomes, in whichJohn Sulston played a key role. How tRNA precursor molecules are processed to give a functional tRNA was elucidated byJohn Smith andSid Altman, and this later led to the discovery ofribozymes. The atomic structure of the first tRNA molecule was solved andzinc fingers discovered by Klug (who received the Nobel Prize for Chemistry in 1982). The structure of theATP synthase was solved byJohn E. Walker and Andrew Leslie, for which Walker shared the Nobel Prize for Chemistry in 1997.^[6] In 1990,Kiyoshi Nagai began working on deciphering the structure of thespliceosome, first usingX-ray crystallography and later withcryogenic electron microscopy,^[9] and in 2016 his group published the first structure of the spliceosome captured in a fully active, substrate-bound state immediately following catalytic reaction.^[10] The structure of theribosome was solved byVenkatraman Ramakrishnan, for which he shared the Nobel Prize for Chemistry in 2009.^[11]

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.^{[citation needed]}

Sydney Brenner started working on the genetics of the nematodeC. elegans in 1965. This group expanded, especially with many foreign visitors who today form the core ofC. elegans research. Sulston determined the cell lineage of this small worm andJohn 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 inC. 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.^{[citation needed]}

Peter Lawrence came to study pattern formation, helping discover how compartments inDrosophila determine the fly's body plan. Under his influence, Crick also became interested in morphogenetic gradients and how they may help specify biological patterns.^{[citation needed]}

César Milstein had over many years been working on antibody variation. He was joined in this byGeorges Köhler and, together, they discovered how to producemonoclonal antibodies. For this they shared the Nobel Prize for Physiology or Medicine in 1984. This area was extended byGreg Winter^[12] who pioneered antibody engineering usingphage display to make novel human antibodies and antibody fragments, for which he shared the Nobel Prize in Chemistry in 2018.^[13] Both monoclonal antibodies and their fragments are now of major medical importance.^{[citation needed]}

Michael Neuberger discovered the mechanism by which antibody diversification occurs byActivation-induced (cytidine) 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 ofkataegis in breast cancer. Sadly, Michael Neuberger died from myeloma – the irony of which was not lost on him.^{[citation needed]}

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 thehuman erythrocyte membrane and itsphospholipid asymmetry.Richard Henderson andNigel Unwin developedelectron crystallography to determine the structure of two-dimensional arrays, applying this to the bacterial purple protein,bacteriorhodopsin.Barbara Pearse discovered the major components ofclathrin-coated vesicles, structures formed duringendocytosis, 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 theendoplasmic reticulum,Golgi apparatus or theplasma membrane — and the role of this in cell polarity, have been elucidated by Bretscher,Hugh Pelham^[14] andSean Munro. Thespindle 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.^[15]

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, thenucleosome, and continues with the focus on understanding the higher orders of folding DNA.^{[citation needed]}

A new division of Neurobiology was created in 1993 with a wide variety of topics.Nigel Unwin has further developed electron crystallography and solved the structure of theacetylcholine receptor, which activates many neurons.Michel Goedert has identified variant proteins associated withAlzheimer's disease.^{[citation needed]}

Scientific advances often depend on technological advances: the LMB has been at the forefront of many of these. Some major examples include nucleic acid sequencing, protein and antibody engineering, construction of new X-ray equipment and the invention of the scanning confocal microscope.^[6]

The LMB has a deliberately simple administrative environment.^[16] From outside the LMB, the parent MRC ensured that the quinquennial assessment had a light touch: only a brief explanation of past achievements and an indication of where future plans lay were required by the external committee. Their recommendations were simply advisory, leaving the division leaders a free hand as to how to run their affairs: they were assumed to know best.^{[citation needed]}

Within the LMB, Perutz's criterion of how to arrange things was that the act of doing science should be facilitated at all levels. The LMB had a single budget: there were no personal budgets or equipment — everything was communal. It had state-of-the-art equipment and was well financed by the MRC.^{[citation needed]} Chemical reagents, glassware and other expendables could be withdrawn from a single store with only a signature required. Key to the smooth functioning of the lab was Michael Fuller, who was responsible for its day-to-day running.^[17]

There was no overt hierarchy; everyone was on first-name terms. Most members of the lab met freely in the canteen, which was said to assist inter-divisional communication and collaboration.^[6] Today the LMB has around 450 scientists, of whom 130 arepostdoctoral researchers and 110 students. The new building (situated on theCambridge Biomedical Campus) was opened in 2013^[4] and has four seminar rooms named after LMB scientists:Sydney Brenner,Aaron Klug,César Milstein andFrederick Sanger, as well as a lecture theatre named after the lateMax Perutz.

As of 2024^[update] there are around fifty group leaders^[12][18] Groups are part of one of the four divisions of the LMB:Cell Biology,Neurobiology,Protein andNucleic Acid Chemistry andStructural Studies. Group leaders include the following people:

The LMB is also home to a number ofEmeritus Scientists, pursuing their research interests in the Laboratory after their formal retirement^[18] including:

Scientific staff of the LMB who have been awarded individually or have shared Nobel Prizes^[32][33][34] are:

Visitors who received a Nobel Prize for work done, or initiated at the LMB and alumni include:

^[50]

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