MRC Laboratory of Molecular Biology
Index 2
Director's introduction
4 Research
4 Structural Studies
5 Tackling difficult long-term problems
6 PNAC
7 Addressing basic biology questions with implications for health
8 Cell Biology
9 Supporting young researchers and innovative research
10 Neurobiology
11 Tackling human disease by unraveling the basic underlying science
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New building – new future
16 Delivering flexibility for the future
18 Encouraging collaboration and technology transfer
Pioneering techniques for research 18 20
Attracting and training outstanding scientists
20 Providing freedom and flexibility
20 Building on success
20 Working with supporters
21 Attracting talented scientists from the UK and overseas
22 Building an international science community
24
Supporting and encouraging translation
24 Taking the long view
24 Nurturing new discoveries
25 Heptares Therapeutics
26
Research groups
31
Maps and contact details
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LMB timeline MRC LMB
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Director's introduction The LMB is a research institute founded by the Medical Research Council over 50 years ago, in the long-sighted belief that molecular biology would one day be of medical benefit. Its founders were an exceptional group of scientists who established a tradition of interdisciplinary work focused on major long-term scientific questions, often requiring the development of new techniques. This basic scientific approach has indeed allowed the LMB to make profound contributions to medicine, notably through the pioneering development of X-ray crystallography to determine protein structures, now used for structure-based drug design, the revolutionary development of DNA sequencing and the exploitation of monoclonal antibodies for therapeutic use. The aim of the Laboratory today remains that of understanding biological processes at the molecular level. We seek to understand not just the structures of molecules and molecular machines, but also their fates and functions within cells, and how these contribute to the workings of complex systems such as the immune system and the brain, and to problems of human health and disease. New approaches in chemical and synthetic biology and biotechnology provide the tools for future discoveries and applications. We continue actively to promote the application of our research findings, both by collaboration with existing companies and by the founding of new ones.
"The Laboratory provides an unsurpassed environment for both young and established researchers."
The combination of ambitious goals, a shared budget and stable long-term support has generated a collaborative LMB culture that values boldness and originality. It has resulted in ten Nobel Prizes awarded for work carried out by LMB scientists, and may also account, in part, for the equal number of Nobel Prizes awarded to alumni for work done elsewhere. Our move to a brand new building in 2013 has provided much improved facilities and many new opportunities, but in the planning of the building we have sought above all to preserve the culture that is the hallmark of the LMB. The LMB provides an unsurpassed environment for both young and established researchers. Our scientists are drawn from all over the world, creating a lively international community for the exchange of ideas and technical innovation. Many are inspired by the knowledge that discoveries made at the LMB have made a difference to the world, and will continue to do so. Hugh Pelham 2
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Research Science in the LMB is organised in four research Divisions, each with its own strengths and goals. While the science covers a broad range, the common theme is the emphasis on understanding biological processes at the molecular level. In all of the Divisions fundamental studies that offer opportunities for medical applications or technical innovation are supported and encouraged.
Structural Studies The Structural Studies Division is working to understand the structure, function and interactions of biologically important molecules, using techniques such as X-ray crystallography, electron microscopy and NMR. The Division’s focus is on long-term challenging problems that go hand-in-hand with advancing the methods used to study them. Therefore, efforts to improve data analysis in crystallography or electron microscopy are accompanied by the study of major biological questions such as replication, splicing and mRNA control, translation, cellular transport and signalling.
Many of these areas are also important for understanding and developing cures for various diseases. The research groups within the Division are also dedicated to developing computational methods for the analysis, interpretation and use of the wealth of data rapidly accruing from the structures of molecules as well as from sequencing of whole genomes. This work is likely to lead to a better understanding of the large-scale networks that are involved in the regulation of genes and the interactions of proteins in the cell. Left to right: Model of a designed object made of compact DNA helices | Schematic lattice of DNA helices (grey circles) | Electron microscopy density of a eukaryotic ribosome
Tackling difficult long‐term problems The information in our genes is used to make the thousands of proteins that carry out diverse functions in each cell. This essential process of translating the genetic code into protein, which is carried out by the ribosome (a large macromolecular complex present in all cells), has been studied at the LMB since its inception. Virtually every molecule in the cell is either made by the ribosome or by protein enzymes that are themselves made by the ribosome. However, because of its size and complexity, understanding how the ribosome works is a difficult and long-term problem. A major breakthrough was achieved in 2000-01 when Venki Ramakrishnan’s group described the atomic structure of the small subunit. Over the next decade, they obtained snapshots of the whole ribosome in many different stages of the process – increasing our understanding of how the ribosome helps to read the genetic code, how it moves along the mRNA and how it terminates the process. Venki shared the 2009 Nobel Prize in Chemistry for his work on the ribosome. The group’s work also provided insights into how antibiotics bind to specific pockets in the ribosome structure. This could help in the design of antibiotics to treat people who are infected with a bacterium that has developed antibiotic resistance, for example some of the strains of bacteria that cause tuberculosis.
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Better targeting of the bacterial ribosome should also help to avoid negative effects on human cells, helping to reduce the side effects of taking antibiotics. Venki comments: “I came to the LMB because it offers an ideal and stable environment that allows long-term research on fundamental problems. Our work is an example of how such research can lead to medically important applications. Currently, we are trying to understand how the much larger (one and a half times) ribosomes in animals and plants start the process of making proteins and how viruses hijack this process.” “In a factory you know what you're going to make. Here, we plant things that grow and mature. It takes a long time.” Aaron Klug
Above: The ribosome from bacteria, showing the large subunit that makes the protein chain in blue and the small subunit that reads the code in yellow
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Research PNAC Research groups within the Protein and Nucleic Acid Chemistry Division are working to gain insights into human biology and disease to help develop strategies for diagnosis and treatment. The Division’s research focuses on the biological processes leading to immunity and cancer, and uses molecular, cellular and transgenic approaches, as well as chemical and biophysical analyses of molecules central to biology. The Division’s current work focuses on two broad areas. One addresses fundamental questions concerning the molecular evolution of life, with approaches ranging from organic chemistry to the in vitro engineering of synthetic biological polymers. Work in this area aims to discover the chemical origins of RNA and DNA building blocks and of the primitive genetic code. It is complemented by attempts to evolve novel types of nucleic acids in the test tube and to create an orthogonal synthetic protein translation system in prokaryotic cells. Ultimately, this work will provide new tools for fundamental biological research and could lead to novel molecular scaffolds for therapeutic applications. The Division’s second area of research focuses on the cellular pathways that guard against infection and cancer – from the mutational processes that underpin genomic changes in cancer and immune diversification to 6
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the molecular mechanisms preserving the genomes of stem and proliferating cells from such damage. Much effort is devoted to the molecules and signalling pathways that protect organisms from infection as well as those that maintain tissue homeostasis and which are often aberrantly activated in cancer.
Above: Crystal structure of Parkin, with Parkinson’s disease mutations in red Left: Superresolution image of Salmonella Typhimurium in the cytosol of a human cell, attacked by Galectin-8 (green) and NDP52 (blue)
The Division also hosts a Centre for Chemical and Synthetic Biology (CCSB), developed in 2012. Within the CCSB, molecular and cellular biologists work closely with innovative organic chemists to apply chemical biology and molecular engineering of biological systems to solving fundamental questions in biology.
Addressing basic biology questions with implications for health Andrew McKenzie's research looks at the basic mechanisms that regulate and coordinate the body's defence against pathogens, in particular the role of soluble molecules, known as interleukins, such as IL-25. This work is providing crucial insights into many diseases where the normal regulation of the immune system goes awry, such as autoimmunity and asthma.
As Andrew explains: “By studying the cytokine IL-13, which induces mucus secretion and contraction in the airways, we discovered a previously unappreciated immune cell type, the ‘nuocyte’. Nuocytes respond to the cytokines IL-25 and IL-33 by proliferating and producing high levels of IL-13, orchestrating the initiation of allergic asthma.”
Asthma is a common chronic inflammatory disorder characterised by inflammation and hyperreactivity of the airways, which afflicts around 300 million people worldwide. The disease has a complex pathophysiology and poorly understood aetiology. Although the majority of asthma sufferers respond to medication with steroids, such treatment can be associated with a number of side-effects and a proportion of sufferers (5-20%) develop a form of severe asthma that is not controlled by standard treatments. The discovery of a new immune cell, that is induced by IL-25, has caused a paradigm shift in the understanding of allergic diseases and led the group to work on generating inhibitory monoclonal antibodies to human IL-25, which have been shown to prevent many of the symptoms of asthma in models of human disease. These antibodies have been ‘humanised’ using a method pioneered at the LMB and are undergoing further development following external licensing to Janssen in the US.
Above: Influx of T cells (red) and IL-13-producing nuocytes (green) in the lung during an inflammatory response MRC LMB
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Research Cell Biology The bodies of complex animals such as humans are made up of billions of individual cells. Whilst our cells share many features, they also have specialist roles to allow the different parts of our bodies to perform different functions. The Cell Biology Division aims to understand the fundamental principles of cellular organisation and how these are modified in cell types that perform important specialised tasks. The Division’s work has a strong focus on the investigation of membrane-bound compartments and of the cytoskeleton. These are studied in a diverse range of model organisms, including yeast, flies, nematodes, and mice, as well as using cell culture and in vitro techniques, but there is a shared interest in understanding underlying principles that apply both to model systems and to humans.
Within the Division, the research groups also share an interest in methods – including advanced microscopy, genetic methods and protein biochemistry – that can link biology and pathology to the underlying molecular mechanisms. In addition to examining the mechanisms that underlie processes shared by most, if not all cells, the Division also investigates how these mechanisms are varied to allow specialised cells of particular biological and clinical importance to perform their unique roles. These include investigating how oocytes specify our genetic make up, how neurons sense our environment, how epithelial cells form our organs, and how motile cells migrate to heal wounds and fight infection.
Left to right: Sensory neurons in a Drosophila larva | Birth of organ-forming glands in a Drosophila embryo | Microtubule organising centres (and chromosomes) in an oocyte
upporting young S researchers and innovative research Melina Schuh joined the LMB as a group leader straight after completing her PhD at EMBL. Since joining the Laboratory she has been elected into the EMBO Young Investigator Programme starting in 2013 and was awarded the Biochemical Society’s Early Career Research Award (2014). Melina’s group is researching how aneuploidy (abnormal number of chromosomes) arises in mammalian oocytes, the female germ cells involved in reproduction. Miscarriages and genetic disorders, such as Down's syndrome, are most commonly caused by errors during meiotic maturation, the process by which an oocyte develops into a fertilisable egg. Work being carried out by the group may help to advance understanding of mammalian oocyte maturation and the causes of miscarriages, genetic disorders and infertility. As Melina explains: “My group is investigating novel functions of actin in oocytes. Actin forms microfilaments that can be organised into dynamic networks and bundles. These actin assemblies are required for many essential steps of oocyte maturation, including the elimination of half of the chromosomes into a polar body before fertilisation.
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Our long term goal is to understand how oocytes eliminate half of their chromosomes before fertilisation and to identify new causes of aneuploidy in mammalian oocyte maturation.”
Elimination of chromosomes into a polar body before fertilisation
Different actin assemblies in a mouse oocyte
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Research Neurobiology One of the biggest challenges facing the biological sciences is to understand how brains can give rise to minds. The nervous system is a complex machine but at its simplest level it consists of the interactions between its basic units, the nerve cells. The Neurobiology Division aims to understand the properties of nerve cells and how they behave, both in health and disease, in order to explain how these networks of nerve cells give rise to cognition and behaviour. Current areas of research are centred on synaptic function, the processing of information by neuronal circuits and the molecular mechanisms underlying common neurodegenerative diseases. Scientists in the Division are exploring how neurons communicate with each other. Using a combination of biochemistry, structural biology, imaging and electrophysiology they aim to build up a detailed picture of how synaptic vesicles release and recycle neurotransmitters, how ion channels are trafficked to the cell surface and, once there, how neurotransmitters trigger the opening of the channels. To understand how the properties of nerve cells determine the processing of information within circuits and how this translates into behaviour, the Division is researching the basis of synaptic integration, the processing of olfactory information in the brain, as well as the 10
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organisation and function of neuronal networks controlling movement, motivation and circadian rhythms. Scientists in the Division are also trying to unravel the molecular and cellular mechanisms by which the abnormal aggregation of a small number of proteins causes common human neurodegenerative diseases. To achieve this, instead of adopting a narrow disease focus they are looking into general mechanisms of aggregation and the cell responses to aggregates, with the aim of identifying novel therapeutic approaches. Top to bottom: A fruit fly brain - the size of a poppy seed contains 100,000 neurons (1 million times fewer than a human brain) | Two neurons filled with dye during in vivo electrical recording | 3D map of sex pheromone circuits in the fly brain
Tackling human disease by unraveling the basic underlying science Degenerative diseases of the brain affect 5-10% of the population over the age of 65 and 20-30% over the age of 80. Alzheimer’s disease and Parkinson’s disease are the most common neurodegenerative diseases, affecting more than 30 million people worldwide.
Michel comments: “Our work is aimed at understanding the mechanisms by which the normally soluble tau and alpha-synuclein proteins assemble into abnormal filaments. To this effect, we are developing experimental models of tau and alpha-synuclein aggregation.
Existing therapies focus, at best, on the symptoms of these diseases rather than on their underlying mechanisms. The symptoms of Alzheimer’s disease (a dementing disorder) and Parkinson’s disease (primarily a movement disorder) result from the dysfunction and degeneration of specific types of nerve cells in particular brain regions. These diseases are characterised by the presence of abnormal filamentous inclusions within some cells. Similar inclusions are found in related disorders, including Pick’s disease, progressive supranuclear palsy, dementia with Lewy bodies and multiple system atrophy.
In due course, this work may lead to the development of mechanism-based therapies for these diseases.”
Work carried out by Michel Goedert’s group was instrumental in establishing that the filamentous inclusions characteristic of these diseases are made of either the microtubule-associated protein tau or the protein alpha-synuclein and that their formation and subsequent spreading cause neurodegeneration and disease. In the human brain tau and alpha-synuclein inclusions are believed to form in a small number of cells, from where they spread in a 'prion-like' manner over time.
Staining of the hippocampal CA3 region from a mouse transgenic for wildtype human tau with anti-tau antibody AT8 (top), Gallyas-Braak silver (middle) and anti-tau antibody AT100 (bottom) 15 months after the injection with brain extract from a mouse transgenic for human mutant P301S tau. The injection of brain extract induced the formation of filamentous inclusions of wild-type tau
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New building – new future
Moving in to the new MRC Laboratory of Molecular Biology building on Francis Crick Avenue MRC-LMB 2013-14 12
MRC-LMB 2013-14 13
New building – new future “Discoveries in basic science lead often, in unpredictable ways, to medical advancements.” César Milstein
The MRC’s Centenary year (2013) coincided with a major development for the LMB – the move to a brand new, purpose-built laboratory, replacing the LMB’s old home built in the 1960s. The new building allows the LMB to respond to the pace of progress, the growth of new techniques and approaches, changing expectations and increasing competition from other world-class laboratories. Located on the edge of the Addenbrooke’s hospital site and adjacent to the London-Cambridge railway line, the building is at the hub of the expanding Cambridge Biomedical Campus, which aims to provide one of the largest and most internationally competitive concentrations of healthcare-related talent and enterprise in Europe.
New building – new future “There have been very good research institutions that have tried to capture the flavour and spirit but they haven't got it.” Joan Steitz, discoverer of snRNPs, on the LMB
Delivering flexibility for the future In keeping with other world-class laboratories, the design provides the flexibility to rearrange the workspace to allow for future changes in the proportion of instrument rooms to wet space to dry space. The building is also fully air-conditioned and air-filtered to provide the right environment for staff and for delicate equipment. A lot of the floor space is devoted to central facilities, including a containment suite, computing, media preparation, chemistry labs, NMR and X-ray facilities, electron and optical microscopy, mass spectrometry, fermentation, stores and maintenance. The building also includes state-of-the-art mechanical, electrical and computing workshops, and sufficient ‘free’ space to accommodate future equipment and facilities needs. Heavy plant servicing for the building is housed either in a separate energy centre, or in the four stainless steel-clad towers linked to the building. This removes weight and sources of vibration from the main building, allowing a more lightweight construction. Within the main building, full height Interstitial Service Voids (ISVs) between each floor house all the ductwork, pipes and services. This key element of the design means that maintenance and modifications can take place without entering the laboratory spaces – so changes can be made rapidly and with minimal disruption. 16
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The new building was designed by RMJM architects, and built by BAM Construction, at a total cost of £212 million – covered by the royalties derived from antibody-related work at the LMB. Preliminary work began in summer 2008, BAM handed over the building to the LMB in November 2012 and the move was completed in March 2013. The LMB’s new home is approximately twice the size of its previous building, with around 32,000 sq m of workspace, on three main
floors. In overall shape the building consists of two kinked laboratory blocks joined by a central atrium, in a shape reminiscent of a chromosome. Although physically very different from the original building, the layout has been designed to help the LMB preserve its distinctive culture – encouraging close interaction within groups, and an open, collaborative and dynamic way of working. The main laboratories are in 1,000 sq m modules, each
housing 40 benchworkers, and including separate write-up spaces, offices and local equipment rooms. The location of the offices, next to the laboratories, encourages hands-on involvement of the group leaders, whilst providing quiet, clean workspaces. Equipment rooms are separated from the laboratories by a main corridor, to ensure they are accessible to everyone and to encourage interactions between scientists. MRC LMB
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New building – new future The structure of the new building is designed to provide maximum flexibility for the future, and to provide space for specialist equipment and facilities as they are developed. The building is easy to navigate and its open, airy walkways, spacious rooftop restaurant, fully equipped lecture theatre and library and comfortable coffee and breakout rooms on each floor all encourage interaction and communication. Encouraging collaboration and technology transfer The new building houses over 600 scientists and support staff. To help encourage the exchange of ideas and technical innovation, around 50 scientists from the University of Cambridge Clinical School will be working alongside LMB staff. In addition, a further 40 workspaces have been set aside for temporary projects such as initiatives to support technology transfer.
Electron Microscopy
Pioneering techniques for research The LMB is noted for its development of new techniques and technologies to help advance research. The move to the new building ensures that the LMB’s researchers have easy access to some of the world’s highest quality scientific technologies on site and provides the right environment to foster innovation. Since the mid 1980s, the LMB has helped to pioneer electron cryo-microscopy (cryo-EM) techniques to help study the three-dimensional structure of macromolecules without the need to crystallise the samples first.
Mass Spectrometry
Robotics
A solution of the chosen biomolecule is frozen in a thin layer of ice, and this layer is imaged in an electron microscope. Many thousands of images, from different orientations, are needed to determine the structure of each biomolecule. These are then computationally assembled into a three-dimensional image to give the structure of the macromolecule. Work by Sjors Scheres group at the LMB has combined data from a new type of direct-electron detector developed by Richard Henderson and Wasi Faruqi with new methods of image processing that results in structures of greatly increased resolution. Sjors comments: “The recording of movies allows tracking the movement of individual complexes while the sample is exposed to the electron beam. As a result, my group has been able to determine the ribosome structure to near-atomic resolution from cryo-EM images.” Left: Average cryo-EM images of 80S ribosome particles
“Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” Sydney Brenner
Electrophysiology
Attracting and training outstanding scientists More than 600 scientists and support staff work in the LMB, with around 400 directly carrying out research in more than 50 groups (see chart below for exact breakdown). The LMB attracts some of the best people from around the world – at all stages of their careers. Over 40 nationalities are represented, with around half of the Laboratory’s PhD students, two thirds of postdoctoral scientists and around 40% of group leaders originating from outside the UK.
Providing freedom and flexibility The LMB’s intellectual base and unique culture – developed over the last 50 years – remains important in attracting and retaining key scientists. Many groups in the Laboratory are small, consisting of eight or fewer people under the leadership of a senior researcher. These small groups help to maintain the dynamism and flexibility of research at the LMB, and encourage close interactions both within groups and throughout the Laboratory. This interaction is further fostered by an idiosyncratic antipathy towards rigid hierarchy, by a wealth of freely-shared services and resources and by generous central funding.
Building on success Although it can claim to be the birthplace of modern molecular biology, the LMB is now one of many laboratories carrying out outstanding research and competing to recruit the world’s best scientists. The LMB’s new building provides a huge step forward – giving existing researchers stateof-the-art laboratory space, equipment and facilities and helping the Laboratory to compete for new talent from around the globe. Supporting scientists and sustaining a robust and flourishing environment for world-class research will be a key element in the LMB’s continuing success.
Working with supporters The LMB is grateful to the many members of its scientific alumni who are helping to make a difference to the current generation of students and scientists. Of particular note is the Max Perutz Fund, which includes donations in honour of Max Perutz, Fred Sanger and César Milstein and attracts support from a number of donors. The Fund provides studentships for talented young scientists and honours the achievements of PhD students with the annual Max Perutz Student Prizes as well as supporting travel, short visits and the initiation of new research projects.
Attracting talented scientists from the UK and overseas John Sutherland, winner of the Origin of Life Challenge and the Max Tischler Prize Lectureship joined the LMB in 2010 from the University of Manchester. John succeeded in solving a major problem concerning the origin of life: how the building blocks of RNA, called nucleotides, could have spontaneously assembled themselves in the conditions of primitive Earth. This discovery helped lead to further discoveries about life's origin and, in future, may help scientists to develop a plausible explanation for how information-carrying biological molecules could have emerged through natural processes from chemicals on early Earth. At the LMB John Sutherland's group is attempting to recreate the chemistry that seeded the emergence of complex molecules from basic chemical components, in particular the precursors of RNA and DNA, in the hope that it will lead to a better understanding of the basic principles that are common to all living organisms. As John explains: “I came to the LMB because it offered an ideal, distraction-free, research environment in which to pursue my curiosity driven research into the chemical origins of biology. Knowing how chemistry spawned extant biology will be fundamental to the development of synthetic biologies with all the attendant medical - and economic - benefits they will bring in the future.”
Ramanujan Hegde earned his MD and PhD from the University of California, San Francisco and became an independent researcher at the National Cancer Institute as an NCI Scholar. He later joined the Cell Biology and Metabolism Program at the National Institutes of Health as head of its Unit on Protein Biogenesis. He received the R. R. Bensely Award in Cell Biology, issued by the American Association of Anatomists, in 2008 and joined the LMB in 2011. Manu's group is interested in the cross talk between the biosynthesis of proteins and the rest of the cellular machinery. The aim is to unravel the mechanisms that cells use to control the quality of their building blocks and of the molecules that carry out their functions. Manu comments: “The LMB brings together a diverse range of scientists exploring nearly every cellular process in considerable depth. Scientists here have the luxury of allowing their curiosity to drive their research. The combination of scientific breadth, mechanistic depth, and complete freedom is rare; that it can be accomplished in a cosy environment with daily interactions with all your colleagues is unique. I spent a day visiting the LMB and the infectious enthusiasm hooked me immediately...”
Staff numbers 2013
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Group leaders
Postdoctoral scientists
Support scientists
PhD students
Technical support, admin and services
Total
54
194
72
95
205
620
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Attracting and training outstanding scientists Building an international science community LMB scientific alumni: known locations 2013
Recent students - their next destination...
Country
No.
China
9
Hong Kong
5
Malta
1
Serbia
1
The Netherlands
26
Argentina
5
Cyprus
1
Hungary
5
Mexico
3
Singapore
14
Tunisia
1
Australia
67
Czech Republic
6
India
14
New Zealand
19
Slovak Republic
1
UK
698
Austria
12
Denmark
25
Ireland
3
Norway
6
South Africa
1
USA
568
Belarus
1
Finland
4
Israel
23
Peru
1
South Korea
1
Taiwan
4
Belgium
13
France
101
Italy
71
Poland
7
Spain
70
Thailand
3
Brazil
2
Germany
151
Japan
59
Portugal
5
Sri Lanka
1
Venezuela
2
Canada
53
Greece
7
Luxembourg
3
Puerto Rico
2
Sweden
43
Chile
2
Grenada (W.I.)
1
Malaysia
5
Russia
14
Switzerland
63
Academia
Science related
Non-scientific
Further training
83
14
13
7
“The LMB provides a wonderful environment for students... although attached to a research group, the whole lab is, in essence, their playground meaning they can approach anyone in the building who can help them with their project...” Julian Sale (Director of Graduate Studies, LMB)
North America 627
Asia
Europe excluding UK
153
625
UK 698
Recent postdoctoral scientists - their next destination…
South America 12
22
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Research
Science related
Other/unknown
Totals
UK
54
9
1
64
Europe
63
6
4
73
World
50
2
0
52
167
17
5
189
Africa 2
Oceania 86
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Supporting and encouraging translation The LMB has an enviable record in promoting the application of its research findings. Researchers at the LMB benefit from the Laboratory’s long experience in this field, and expert advice is available on how best to exploit their discoveries – whether by the licensing of patents, collaborations with existing companies or by founding new spin-off companies. The MRC has also benefited, by receiving significant sums to invest in future scientific research. For example, in the years from 2005-10 the MRC earned over £330 million from royalties, share sales and licences based on LMB discoveries, mostly from antibody-related patents. Taking the long view Inevitably, the Laboratory’s focus on curiositydriven and long-term basic research means that there is often a long gap between initiating a project and reaching the point where it is suitable for exploitation. Nevertheless, there have been spectacular successes, notably the development, over 30 years, of humanised monoclonal and synthetic antibodies – which now make up a third of all new drug treatments for a variety of diseases, including cancer, arthritis and asthma. When intelligently exploited, this type of research pays handsome dividends for both human health and UK industry.
For example, LMB’s work on human antibodies was exploited via local start-up company Cambridge Antibody Technology, and led to the development of Humira®, a key drug in the treatment of rheumatoid arthritis. More recently, 20 years of effort to determine the structure of G-protein-coupled receptors culminated in a general method for analysing these drug targets, which formed the basis of another spin-out company, Heptares. Other notable contributions include the development of laser-scanning confocal microscopes and the more recent exploitation of custom-designed zinc finger proteins for gene therapy and genome engineering. Nurturing new discoveries Promising new areas for technology transfer include ground breaking work in synthetic biology – producing unnatural proteins and nucleic acids which could ultimately produce novel macromolecular therapeutics. Other key areas include research into the biology of the cytokine IL-25, which may lead to new treatments for allergic asthma, and work on intracellular defences against infection, which could pave the way to a new generation of antiviral drugs.
“Innovation is driven by the curiosity to answer fundamental questions.” Michael Neuberger
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In 2007 the LMB’s Richard Henderson and Chris Tate cofounded Heptares Therapeutics to exploit pioneering new technology to stabilise G-protein-coupled receptors (GPCRs). Because they play a crucial role in many diseases, GPCRs are the targets of 25-30% of all modern drugs. As Chris comments: “GPCRs are an important family of proteins found in cell membranes, which are responsible for triggering responses inside cells to external factors such as hormones, neurotransmitters and sensory stimuli. Commonly prescribed drugs, such as beta-blockers and anti-migraine drugs, specifically interact with these receptors. Understanding the structure of GPCRs at a molecular level is important in designing new and more effective drugs to combat many human illnesses. Heptares’ StaR (Stabilised Receptor) technology platform allows us to apply contemporary drug discovery approaches to stabilised GPCRs – improving the chances of finding drugs to previously intractable targets and enabling the development of safer and more selective therapeutic agents.” Heptares is using this technology to work on its own and with partners to discover new medicines to target key diseases such as Alzheimer’s, schizophrenia, type 2 diabetes, cancers and HIV. To date the company has raised more than £40 million from leading life science venture investors and signed drug discovery collaborations with Astra Zeneca, Shire, Takeda and Novartis.
Structure of the adenosine A2A receptor. Top: view of the receptor in the membrane showing how the agonist adenosine binds (inset). Bottom: structure of the receptor bound to a preclinical candidate developed by Heptares Therapeutics for the treatment of Parkinson’s disease. [PDB codes 2YDO and 3UZC, respectively]. MRC LMB
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Research Groups
DIVISION:
M. Madan Babu
[email protected]
Systems biology. We are interested in understanding how the regulation of biological systems is achieved at different scales of complexity (from genomes to molecules to organisms) and how biological systems influence the evolution of the genome.
Molecular mechanisms of the anaphasepromoting complex and the mitotic checkpoint. We study how the anaphase-promoting complex (APC/C) recognises and ubiquitinates proteins during the cell cycle, and the basis for its regulation by the spindle assembly checkpoint.
Anne Bertolotti
[email protected]
Alexander G. Betz
Protein misfolding in neurodegenerative diseases. Our aim is to understand the misfolding of disease-causing proteins and the mechanisms that cells use to prevent the accumulation of misfolded proteins.
Mariann Bienz
[email protected]
[email protected]
Initiation of immune responses. Our aim is to understand how the immune system decides whether or not to start an immune response – attacking pathogens whilst sparing the cells in its own body.
Tiago Branco
[email protected]
Synaptic integration in circuits controlling innate behaviour. Our goal is to understand the biophysical processes underlying the computations in the mouse brain that convert sensory signals into innate behaviours, such as feeding or fighting.
Mark van Breugel
Simon Bullock
[email protected]
[email protected]
Structure and assembly mechanisms of centrioles. We aim to understand the assembly mechanisms and molecular architecture of centrioles, essential cell organelles with key roles in cell division, sensing and movement.
Mechanisms and functions of cytoskeletal transport. Our goal is to shed light on how cellular components are sorted and dispersed by microtubule-based motor complexes, and how these transport processes contribute to the functions of cells within organisms.
Andrew Carter
Jason W. Chin
[email protected]
Mario de Bono
[email protected]
[email protected]
Dissecting how nervous systems work. We combine genetics, genomics, cell biology, neural imaging and optogenetics to elucidate how neurons and neural circuits work to generate behaviour in animals. MRC LMB
[email protected]
Wnt signalling and cancer. We aim to understand how Wnt signals and protein degradation control β-catenin activity, and to develop the potential of β-catenin and its co-factors as inhibitory targets in colorectal cancer.
The structure and mechanism of dynein. We use structural biology approaches and single molecule microscopy to understand how the microtubule motor dynein transports cargos.
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David Barford
Evolution and synthesis of new function. We aim to create new technologies by developing alternative and novel methods of engineering biological systems in combination with innovative chemistry.
Alan Fersht
[email protected]
Tumour suppressor p53 structure and drug discovery. Our aims are to solve the structures of the tumour suppressor p53 in complex with its partner proteins and to design novel drugs that restore the function of p53 mutants as anticancer therapies.
CELL BIOLOGY
NEUROBIOLOGY
Paula da Fonseca
[email protected]
Structure and function of cell regulatory protein complexes. Our work focuses on determining the structure and function of lowsymmetry cell regulatory protein complexes by electron cryo-microscopy and image analysis based methods.
Michel Goedert
[email protected]
PNAC
STRUCTURAL STUDIES Michael Gait
[email protected]
Therapeutic applications of oligonucleotide analogues and peptide conjugates. Our work focuses on chemical synthesis of modified oligonucleotides and their peptide conjugates for treatment of neuromuscular diseases by targeting intracellular RNA.
Ingo Greger
[email protected]
Molecular mechanisms of neurodegeneration. We are unraveling the mechanisms that cause the abnormal aggregation of tau protein and alpha-synuclein and how this process results in nerve cell degeneration and human diseases.of sleep and metabolism.
Biology of AMPA-type glutamate receptors. Our work aims to understand the molecular basis of higher order cognitive process by understanding the principles of fast excitatory iGlu mediated neurotransmission.
Michael Hastings
Ramanujan Hegde
[email protected]
Neurons and biological timing. Our aim is to unravel the molecular, genetic and neurobiological mechanisms by which the brain defines circadian (24 hour) time and how this internal clockwork controls our daily rhythms of sleep and metabolism.
Richard Henderson
[email protected]
Membrane protein biosynthesis and quality control. We seek to understand how secreted and membrane proteins are assembled, how cells handle mistakes in these pathways, and the diseases that arise from their failure.
Philipp Holliger
[email protected]
Gregory Jefferis
[email protected]
Intracellular Immunity. We are investigating how cells defend themselves against infection by intracellular pathogens.
Neural circuit basis of olfactory perception in Drosophila. We study how neural circuits process sensory information and transform this into behaviour, especially processing of sex pheromones and general odours by the fly olfactory system.
Rob Kay
David Komander
[email protected]
[email protected]
High resolution 3D structures by electron cryo-microscopy. We aim to determine the structure of interesting or important membrane proteins or membrane protein complexes using cryo-EM.
Leo James
[email protected]
[email protected]
Cellular chemotaxis in Dictyostelium. We want to know how cells read chemical landscapes and how they move towards chemotactic signals.
Synthetic genetics. Our aims are the generation of synthetic genetic polymers and their evolution for applications in medicine, nanotechnology and material science.
Specificity in the ubiquitin system. We aim to define cellular roles of the diverse forms of ubiquitination, by identifying the proteins that assemble, bind and hydrolyse specific links of ubiquitin chains. MRC LMB
27
DIVISION:
CELL BIOLOGY
NEUROBIOLOGY
Meindert H. Lamers
[email protected]
Structural features of DNA replication and repair. We study the structural features of DNA replication and DNA repair, with a special emphasis in the switching of the replicative and repair DNA polymerases at a site of a DNA lesion.
Jan Löwe
[email protected]
The bacterial cytoskeleton. We investigate biological systems involving prokaryotic filamentous proteins that are involved in mechanical processes such as constriction and DNA segregation during cell division.
Harvey McMahon
[email protected]
Membrane curvature. Our work is elucidating the mechanisms of membrane bending and their role in membrane fission and fusion to understand and identify known and novel pathways of receptor trafficking.
Garib Murshudov
[email protected]
Computational crystallography. We develop computational, statistical and structural bioinformatic tools for the analysis of macromolecular crystal structures, in particular dealing with limited and noisy data.
Kiyoshi Nagai
[email protected]
Crystallographic and functional studies of the spliceosome. Our aim is to understand the molecular mechanism of pre-mRNA splicing and provide insights into the evolutionary origin of the spliceosome.
Ben Nichols
[email protected]
Endocytic pathways in mammalian cells. We employ live cell imaging, electron microscopy and biochemical techniques to understand how mammalian cells transfer membrane and proteins from the surface to the inside of the cell.
28
MRC LMB
PNAC
STRUCTURAL STUDIES Andrew Leslie
[email protected]
Structures of macromolecular assemblies. We use X-ray diffraction to look at the structures of macromolecular complexes and membrane proteins like G protein-coupled receptors, while developing software to analyse diffraction data.
Andrew McKenzie
[email protected]
Transgenic models of immune and haematopoietic disorders. We focus on understanding the molecular regulation of the immune responses underlying allergy and asthma, with the aim of identifying novel pathways for therapeutic intervention.
Sean Munro
[email protected]
Lori Passmore
[email protected]
Hugh Pelham
[email protected]
Macromolecular machines in mRNA polyadenylation. We investigate the mechanisms that control mRNA polyA tail formation using structural, biochemical and genetic techniques in order to understand the regulation of gene expression. Membrane protein sorting. We study how proteins are sorted within cells and in particular how, if they are damaged or unwanted, they are marked by ubiquitination for subsequent destruction.
Venki Ramakrishnan
[email protected]
The organisation of membrane traffic by G proteins. We investigate how each organelle acquires a unique set of active G proteins, and how these then control the structure of organelles and direct the traffic between them.
Structure of the translational apparatus. We are interested in the mechanism and regulation of translation in both bacteria and eukaryotes and understanding how agents such as antibiotics or viruses interfere with translation.
Alexey Murzin
Daniela Rhodes
[email protected]
[email protected]
Structural classification of proteins. We investigate the relationships between protein families and their structural and genomic features in order to extract new general principles governing protein folding and evolution.
Chromatin and telomere structure. Our goal is to understand how the structure of chromatin is involved in transcriptional regulation and how the tips of chromosomes, the telomeres, are involved in preserving chromosome integrity.
David Neuhaus
Julian Sale
[email protected]
[email protected]
Solution structure by NMR spectroscopy. We study the structure and the interactions of biological macromolecules and their complexes in solution employing modern NMR and isotope labelling techniques.
Vertebrate mutagenesis. We aim to understand how impediments to DNA replication lead to mutation and to changes in the epigenetic signals that control gene expression.
John O'Neill
Sjors Scheres
[email protected]
Cellular rhythms, signalling and metabolic regulation. We explore the biochemical basis of circadian timekeeping and how biological rhythms integrate with other cellular systems to orchestrate temporal control of metabolism.
[email protected]
Visualising molecular machines in action. We develop data collection and processing methods for cryo-EM structure determination, and use these to understand how macromolecular machines work.
KJ Patel
[email protected]
Chromosome instability and stem cell biology. We aim to understand the molecular basis of inherited genomic instability and the role it plays in the biology of stem cells.
Cristina Rada
[email protected]
Felix Randow
[email protected]
Immunity and DNA deamination. We investigate the contribution of targeted deamination of cytosine in DNA by AID/APOBEC enzymes to antibody gene diversification, viral restriction and genome mutation in cancer.
Cell-autonomous and innate immunity. We study innate immunity on a single cell level to understand how cells defend themselves against pathogens.
Katja Röper
[email protected]
The cytoskeleton in tissue morphogenesis. We investigate how the formation of epithelial tissues is driven by cellular and molecular changes, with a particular focus on the role of the cytoskeleton and its regulators during these processes.
William Schafer
[email protected]
Cellular and molecular mechanisms of behaviour. We try to elucidate the mechanisms by which nervous systems process information and generate behaviour, and the cellular and molecular basis of sensory transduction and neuromodulation.
Melina Schuh
[email protected]
Meiosis in mammalian oocytes. Our aim is to understand how diploid oocytes mature into haploid, fertilisable eggs and to analyse the causes of aneuploidy in mammalian oocytes. MRC LMB
29
STRUCTURAL STUDIES
LO
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City centre (2.5 miles) Train station (1.5 miles)
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Goods In
Car Park
Reception
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GUIDED
BUSW
Flats DD
IC
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Car Park
Deliveries
BE
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Car Park
Sports Centre
Flats
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Public NCP Car Park
Car Park
[email protected]
Addenbrooke’s Hospital
WAY
OA D
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A130
Trumpington Park & Ride, A603, M11 (London, Stansted Airport) & A14 (West)
Bus Station
RAH
ROBI
Haverhill, M11 (London, Stansted Airport)
“Discoveries cannot be planned. They pop up, like Puck, in unexpected corners.” Max Perutz
7
Structural studies of phosphoinositide signaling. We investigate and modulate phosphoinositide signaling and autophagy in health, ageing and disease using a variety of structural and functional approaches.
BAB
Roger Williams
MRC Laboratory of Molecular Biology Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0QH, UK Tel: Fax: email: Web:
AY
EN
Neural circuits for motor control. We study the neural circuits responsible for the emergence of motor behaviour, focusing on the genetics of their assembly and their function during voluntary and automatic movements.
PU
CR UK
MRC LM
[email protected]
NCI
Structural biology of integral membrane proteins. We are determining the structures of medically-relevant membrane receptors and transporters to understand their mechanism of action and for facilitating drug development.
4
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Marco Tripodi
[email protected]
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Chris Tate
A1
HI LLS R OAD
Chemical origins of molecular biology. We are interested in uncovering prebiotically plausible syntheses of the informational, catalytic and compartment–forming molecules necessary for the emergence of life.
oad Long R rm Sixth Foge Colle
Integrating mRNA export into the gene expression pathway. My lab is determining the structures of gene expression pathway components involved in mRNA nuclear export and in linking this function to preceding steps in the gene expression pathway.
Trumpington Park & Ride, A10, A603, M11 & A14 (West)
BI
[email protected]
RO
John Sutherland
AV
[email protected]
PNAC
CK
Murray Stewart
NEUROBIOLOGY
S C RI
CELL BIOLOGY
FRA
DIVISION:
+44 (0) 1223 267000 +44 (0) 1223 268300
[email protected] www2.mrc-lmb.cam.ac.uk
LMB timeline 1947
1980s
1990s
1947
1962
1962
1962
1977
1980
MRC ‘Unit for Research on the Molecular Structure of Biological Systems’ established
MRC Laboratory of Molecular Biology opened
Nobel Prize for Physiology or Medicine: Francis Crick and Jim Watson
Nobel Prize for Chemistry: John Kendrew and Max Perutz
Method for sequencing DNA developed
Nobel Prize for Nobel Prize for Chemistry: Fred Sanger Chemistry: Aaron Klug
1989
1994
1997
2013
First LMB spin-out company, Cambridge Antibody Technology, formed
Structure of F1 subunit of mitochondrial ATPase revealed
Nobel Prize for Chemistry: John Walker
Nobel Prize for Chemistry: Michael Levitt
1950s
1960s
1953
1961
1967
1975
1983
Double-helical structure of DNA elucidated
Demonstration of the triplet nature of the genetic code
First mutant of C. elegans (nematode worm) produced
First 3D structure of a membrane protein, bacteriorhodopsin
Embryonic cell lineage of C. elegans unraveled
1988
1997
2013
First patient treated with humanised antibody, Campath-1
Major component of filamentous lesions found in Parkinson’s disease identified
New MRC Laboratory of Molecular Biology building opens
1953
1959
1968
1975
Sliding filament model for muscle contraction proposed
Structure of haemoglobin determined
3D reconstruction of structure from electron micrographs introduced
Monoclonal antibody methodology invented
1984
1987
1998
2009
Nobel Prize for Physiology or Medicine: César Milstein and Georges Köhler
Commercial production of MRC confocal microscope
Genome of nematode worm completed
Nobel Prize for Chemistry: Venki Ramakrishnan
1982
1970s
2000s
1957
1958
1959
1971
1972
1972
1985
Single amino acid change causes sickle cell anaemia
Nobel Prize for Chemistry: Fred Sanger
First atomic resolution map of a protein, myoglobin
Precursor tRNA molecules found and discovery of catalytic RNA
Asymmetric lipid bilayer structure for biological membranes proposed
Signal peptide sequence which directs protein secretion discovered
Zinc-finger DNA First humanised binding motif proposed antibody produced
1986
1986
2000
2002
Structure of the nervous system of C. elegans produced
Structure of the 30S ribosomal subunit and its complexes with antibiotics
Nobel Prize for β-adrenergic receptor Physiology or Medicine: structure Sydney Brenner, Bob determined Horvitz, John Sulston
2008
Editors Valerie McBurney Cristina Rada Liz Pryke Design | Photography LMB Visual Aids CELL BIOLOGY
NEUROBIOLOGY
PNAC
STRUCTURAL STUDIES
Reprinted June 2014
