Laboratory of Molecular Biology

The Laboratory of Molecular Biology (or LMB) is a research institute in Cambridge, England, which was at the forefront of the revolution in molecular biology which occurred in the 1950-60s. Since then it remains a major medical research laboratory with a much broader focus.

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Early beginnings: 1947-61

Max Perutz, following an undergraduate training in organic chemistry, left Austria in 1936 and came to Cambridge to study for a PhD, joining the X-ray crystallographic group led by JD Bernal. Here, in the Cavendish laboratory, he started his life-long 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 (MRC), under the guidance of its Secretary Harold Himsworth, 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. And the Queen was crowned and Everest scaled.

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 (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.

Opening of the LMB: 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 for chemistry in 1958 for the first protein sequence, that of insulin. The new laboratory was opened by Queen Elizabeth 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 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.

Molecular Biology: 1962-

During the next decade, 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. 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 (for which he received a second Nobel prize in chemistry in 1980). 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 (who received the Nobel prize for chemistry in 1982). The structure of the ATP synthase was solved by John Walker and Andrew Leslie, for which Walker shared the Nobel prize for chemistry in 1997. The structure of the ribosome was solved by Venki Ramakrishnan in 2006.

Diversification

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.

Development and C.elegans

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 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.

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

Cesar Milstein had over many years been working on antibody variation. He was joined in this by Georges Kohler 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 to make novel human antibodies and antibody fragments. Both monoclonal antibodies and their fragments are now of major medical importance.

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.

Neurobiology

A new division of Neurobiology was created in 1993 with a wide variety of topics. Unwin has further developed electron crystallography and solved the structure of the acetylcholine receptor, which activates many neurons. Michel Goedert has identified variant proteins associated with Alzheimer’s disease.

Instrumentation

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.

Famous alumni

Scientific staff of the LMB who have shared a Nobel prize are Sanger (twice), Kendrew, Perutz, Crick, Klug, Milstein, Walker, Brenner and Sulston. Visitors who have received a Nobel prize for work done, or initiated, at the LMB include Watson, Altman, Kohler, Horvitz, Kornberg and Andrew Fire. In addition, many alumni have gained great distinction which has been recognised by elections to learned bodies. A link to a list of past members of the LMB can be found below.

Administrative structure

The early success of the LMB was in no small way helped by the simple administrative environment. From outside the LMB, the parent MRC ensured that the triennial 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.

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, which made running the lab cheaper. It had state of the art equipment and was well financed by the MRC. Chemical reagents, glassware and other expendibles could be withdrawn from an extremely well-stocked store with no more than a signature. Key to the smooth functioning of the lab was Michael Fuller, who was responsible for its day-to-day running.

There was no overt hierarchy; everyone was on first-name terms. Most members of the lab met freely in the canteen, situated at the top of the building with a view across Cambridge, for mid-morning coffee, lunch and afternoon tea. This assisted inter-divisional communication and collaboration.

Today the LMB has around 340 scientists, of whom 130 are postdoctoral visitors and 90 students.