MRC Laboratory of Molecular Biology
Index
2
Director's introduction
4Research
4 Structural Studies
5 Tackling difficult long-term problems
6PNAC
7 Addressing basic biology questions with implications for health
8 Cell Biology
9 Supporting young researchers and innovative research
10Neurobiology
11 Tackling human disease by unraveling the basic underlying science
12
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
32
LMB timeline
MRC LMB
1
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
MRC LMB
MRC LMB
3
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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MRC LMB
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
MRC LMB
5
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
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MRC LMB
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
7
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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MRC LMB
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
MRC LMB
9
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
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MRC LMB
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
MRC LMB
11
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
MRC LMB
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
17
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
20
Group
leaders
Postdoctoral
scientists
Support
scientists
PhD
students
Technical support,
admin and services
Total
54
194
72
95
205
620
MRC LMB
MRC LMB
21
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
MRC LMB
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
MRC LMB
23
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
24
MRC LMB
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
25
Research Groups
DIVISION:
M. Madan Babu
madanm@mrc-lmb.cam.ac.uk
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
aberto@mrc-lmb.cam.ac.uk
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
mb2@mrc-lmb.cam.ac.uk
betz@mrc-lmb.cam.ac.uk
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
tbranco@mrc-lmb.cam.ac.uk
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
vanbreug@mrc-lmb.cam.ac.uk
sbullock@mrc-lmb.cam.ac.uk
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 chin@mrc-lmb.cam.ac.uk
Mario de Bono
cartera@mrc-lmb.cam.ac.uk
debono@mrc-lmb.cam.ac.uk
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
dbarford@mrc-lmb.cam.ac.uk
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.
26
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
alan@mrc-lmb.cam.ac.uk
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
pauladf@mrc-lmb.cam.ac.uk
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
mg@mrc-lmb.cam.ac.uk
PNAC
STRUCTURAL STUDIES
Michael Gait
mgait@mrc-lmb.cam.ac.uk
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
ig@mrc-lmb.cam.ac.uk
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
mha@mrc-lmb.cam.ac.uk
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
rhegde@mrc-lmb.cam.ac.uk
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
ph1@mrc-lmb.cam.ac.uk
Gregory Jefferis
jefferis@mrc-lmb.cam.ac.uk
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
dk@mrc-lmb.cam.ac.uk
rh15@mrc-lmb.cam.ac.uk
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
lcj@mrc-lmb.cam.ac.uk
rrk@mrc-lmb.cam.ac.uk
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
mlamers@mrc-lmb.cam.ac.uk
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
jyl@mrc-lmb.cam.ac.uk
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
hmm@mrc-lmb.cam.ac.uk
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
garib@mrc-lmb.cam.ac.uk
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
kn@mrc-lmb.cam.ac.uk
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
ben@mrc-lmb.cam.ac.uk
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
andrew@mrc-lmb.cam.ac.uk
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
anm@mrc-lmb.cam.ac.uk
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
sean@mrc-lmb.cam.ac.uk
Lori Passmore
passmore@mrc-lmb.cam.ac.uk
Hugh Pelham
hp@mrc-lmb.cam.ac.uk
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
ramak@mrc-lmb.cam.ac.uk
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
agm@mrc-lmb.cam.ac.uk
rhodes@mrc-lmb.cam.ac.uk
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
dn@mrc-lmb.cam.ac.uk
jes@mrc-lmb.cam.ac.uk
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
oneillj@mrc-lmb.cam.ac.uk
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.
scheres@mrc-lmb.cam.ac.uk
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
kjp@mrc-lmb.cam.ac.uk
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
car@mrc-lmb.cam.ac.uk
Felix Randow
randow@mrc-lmb.cam.ac.uk
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
kroeper@mrc-lmb.cam.ac.uk
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
wschafer@mrc-lmb.cam.ac.uk
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
mschuh@mrc-lmb.cam.ac.uk
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
RO
City centre (2.5 miles)
Train station (1.5 miles)
AD
W
AY
NG
Goods
In
Car
Park
Reception
B
GUIDED
BUSW
Flats
DD
IC
OM
Car
Park
Deliveries
BE
W
U
E
Car
Park
Sports
Centre
Flats
AY
Public
NCP Car
Park
Car
Park
rlw@mrc-lmb.cam.ac.uk
Addenbrooke’s Hospital
WAY
OA D
N
AM R
NS
O
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
mtripodi@mrc-lmb.cam.ac.uk
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
ON
Marco Tripodi
cgt@mrc-lmb.cam.ac.uk
13
NS
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
johns@mrc-lmb.cam.ac.uk
RO
John Sutherland
AV
ms@mrc-lmb.cam.ac.uk
PNAC
CK
Murray Stewart
NEUROBIOLOGY
S C
RI
CELL BIOLOGY
FRA
DIVISION:
+44 (0) 1223 267000
+44 (0) 1223 268300
enquiries@mrc-lmb.cam.ac.uk
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