Basic Life Sciences
UCL SCHOOL OF LIFE AND MEDICAL SCIENCES
Creating knowledge, achieving impact
1
PREFACE
The UCL School of Life and Medical
Sciences is one of the world’s largest
and most prestigious aggregations
of academics in medical, brain, life
and population health sciences. Our
performance in the UK’s last Research
Assessment Exercise was outstanding.
We headed the UK’s performance table in
biomedicine and life sciences with more
than 200 researchers meriting the highest
rating of 4*, some 25 per cent ahead of
our closest rival. Moreover, when quality
and volume were combined in what the
Times Higher Education called ‘research
power’ the School again headed the
rankings, with a score some 24 per cent
ahead of its nearest competitor.
In part because of UCL’s size and
organisational complexity, the scale of
the School’s achievements is not always
apparent. This publication, one of five,
seeks to address this. Our reorganisation
in August 2011, with the creation of
four new Faculties, has been designed
to create a more coherent structure,
of which the Faculty of Life Sciences,
headed by the Dean, Professor Mary
Collins, is a clear example. But the
School’s restructuring has also placed
great emphasis on cross-Faculty
interactions and interdisciplinary research
– and indeed on interactions with UCL
departments outside the School. Such
interdisciplinary endeavour is promoted
through ‘Domains’, inclusive strategically
led fluid networks. This approach allows
us to connect all our activities related
to fundamental research, promoting
collaboration and the sharing of expertise,
platforms and resources. Professor
Michael Duchen and Dr Paola Oliveri are
chairs of the Basic Life Sciences Domain.
UCL is acutely aware that scientific
advance of real relevance to society
is not only aided by an interdisciplinary
approach but also through collaborative
strategic alliances with other researchintensive institutions with complementary
strengths. Our founding partner status
in the new Francis Crick Institute
engages us in what will be the
European powerhouse of biomedical
research expertise. Our links with our
London Academic Health Science
Centre partners also include our joint
engagement together with the
Medical Research Council in a new
imaging company, Imanova, and our
commitment to the London Life Sciences
Concordat. Our growing collaboration
with our Bloomsbury neighbours,
the London School of Hygiene and
Tropical Medicine, is fuelling exciting
developments in genetic epidemiology
and pathogen research.
The breadth and quality of our research
creates almost unique opportunities.
Our recent merger with the School of
Pharmacy, a stimulating addition to
the Faculty of Life Sciences, adds to
our capacity in drug development,
formulation and adoption. Our highly
productive links to the health service,
through UCL Partners, provides access
to unmatched clinical expertise and
large patient groups. We are fortunate
to be partners in three National Institute
for Health Research (NIHR) Biomedical
Research Centres and a new NIHR
Biomedical Research Unit in dementia.
The School’s academic environment is
one in which intellectual curiosity can
prosper, while a high priority is also given
to the practical application of knowledge
to improve health and quality of life.
This can take many forms, including
commercialisation of new products
as well as developing and informing
health and social policy, and engaging
with important stakeholders, including
the public.
This publication, one of five (see right),
showcases some of the outstanding
fundamental research being carried out
within the School and with collaborators
across UCL and our partners in
London, nationally and internationally.
It is impossible to be comprehensive,
but the stories give a flavour of the
breadth, quality and impact of the
School’s research in this area. Looking
forward, our aims are to enhance and
expand our research to ensure we remain
a global leader, and to see more people
benefit from the groundbreaking research
being carried out across the School.
Sir John Tooke
Vice-Provost (Health)
1
Basic Life Sciences:
‘Discovery’ research, from
molecules to ecosystems.
2
Translation and
Experimental Medicine:
Driving translation to
benefit patients’ health
and well-being.
3
Neuroscience and
Mental Health:
The science of the brain
and nervous system,
from synapse to social
interactions.
4
Population Health:
Protecting and improving
the health of populations,
UK and globally.
5
Education: Innovative
practice across the
educational life course.
CONTENTS
Overview: The roots of discovery
2
UCL supports groundbreaking curiosity-led research across
all biological scales.
Section 1: Molecular basis of life
4
Exploring the structure and function of molecules and molecular
complexes fundamental to life.
Feature: The great and the good: Nobel laureates and other key
figures in UCL’s life science history
10
Section 2: The cellular world
12
Understanding the processes that control a cell and contribute
to disease.
Feature: CoMPLEX: A model for interdisciplinary research
22
Section 3: Building tissues
24
Dissecting the mechanisms by which tissues and organs develop.
32
Section 4: All systems go
Systems-based approaches, from the cell to the brain –
and beyond.
Feature: Genes, culture and human behaviour
38
Section 5: Origins: Genes and evolution
40
Using genetics to understand evolutionary relationships and
human biology.
UCL institutes, support services, partners, funding and sponsors.
46
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
1
BASIC LIFE SCIENCE
UCL supports groundbreaking
curiosity-led research across
all biological scales.
Dorsal view of the zebrafish brain.
Research in the UCL School
of Life and Medical Sciences
has the potential to improve
human health and well-being.
There is an oft-cited danger
that, in an understandable
drive to translate research
into practical benefits, the
well-spring of discovery
is neglected. At UCL,
fundamental curiosity-led
research remains a high
priority and a core activity.
into the structure and
function of large multiprotein
complexes. Core structural
biological techniques – X-ray
crystallography, nuclear
magnetic resonance
(NMR) spectroscopy and
electron microscopy – are
being combined with other
biophysical techniques and
biochemical characterisation
to provide an integrated view
of molecular function.
There are many ways to
categorise such activities.
To avoid disciplinary
pigeonholing, in this
publication we have chosen
to focus on questions of
scale. Obviously, even this
approach is arbitrary – a
satisfactory understanding of
biological phenomena often
requires integration across
multiple biological scales.
The cell remains at the heart
of fundamental research.
As well as being the basic
building block of organisms,
abnormalities in cellular
function underlie numerous
disease processes. And
manipulating the activities
of cells is increasingly
offering new therapeutic
opportunities.
At the molecular level,
structural biology provides
important insight into
the function of biological
molecules. As technologies
improve, the size of structures
that can be studied
continues to increase, with
insight now being gained
2
While the basic function
of many cellular structures
have been determined, how
they are regulated is often
less clear. The dynamics of
cellular processes, and their
responses to external stimuli,
are therefore important areas
of study. Similarly, cellular
mechanisms of disease often
The cell remains at the heart of fundamental
research. As well as being the basic building
block of organisms, abnormalities in cellular
function underlie numerous disease processes.
remain poorly understood.
In recent years, for example,
it has become apparent that
mitochondrial abnormalities
play an important role in
Parkinson’s disease yet
details remain obscure.
Central to many questions
is how the fate of cells is
decided. Once the factors
controlling cell fate are
better understood, it will
be considerably easier to
intervene to alter cell fate for
therapeutic ends.
Genetic approaches,
particularly genome-wide
association studies, have
generated a long list of
genes potentially involved in
disease processes, but rarely
is much known about their
functional roles. Additional
work is normally needed
to explore their biological
function and how they might
be contributing to disease.
In particular, work in model
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
organisms is crucial if gene
function is to be understood
in the context of living
dynamic processes. As well
as laboratory mice, zebrafish
are an extremely valuable
tool, and UCL houses one of
the largest zebrafish facilities
in Europe.
Furthermore, cells do not
operate in isolation but as
part of integrated wholes.
Developmental biology
obviously depends on the
coordinated behaviour of
cells. In addition, many
physiological processes
can only be understood in
terms of the interactions
between multiple cells and
tissues. Biology is adopting
an increasingly systemsdriven, integrative approach
– at levels as varied as the
genetic programmes that
drive cell behaviour to the
physiological systems that
regulate eating.
Part of the bacterial type IV secretion system.
Scanning electron micrograph of the surface of a zebrafish embryo.
Frequently these integrative
approaches need to
embrace mathematic
and computational
methodologies. Much
biological research now
includes collaborations
across the mathematical
and computational sciences.
Neuroscience* is one
obvious area where such
approaches have gone hand
in hand with experimental
studies, but such crossdisciplinary interactions are
now increasingly common.
UCL established CoMPLEX
with the specific aim of
developing researchers able
to move fluidly between the
physical and life sciences.
Indeed, much UCL
life science research
crosses traditional
disciplinary barriers.
As well as mathematics
and computational input,
chemists have a critical role
to play in developing agents
to explore biological function,
while nanotechnology
provides a wealth of new
opportunities to explore
macromolecular and cellular
Fibres of secreted von Willebrand factor.
function. One of the most
important of areas, imaging,
draws all these areas
together, creating tools that
can provide unprecedented
views of living biological
processes (see right).
While discovery remains
at the heart of basic life
science research, it is
informed by dialogue with
clinicians and medical
scientists, and alert to
opportunities for translation.
The communication is
two-way, with medically
important genes or
processes providing an
intellectual challenge for
basic researchers, and the
insight generated through
fundamental studies
providing inspiration for
new therapies.
* Neuroscience makes an important
contribution to UCL’s basic life sciences
research. Given the extent of these
activities, they are covered in a
separate publication (Neuroscience
and Mental Health).
SEEING AND BELIEVING
The ability to understand biological processes is being
greatly enhanced by new imaging techniques.
Across different scales, imaging technologies are proving central
to the gathering of new information about biological processes.
At the molecular level, X-ray crystallography, NMR spectroscopy
and electron microscopy and tomography can provide atomic-level
detail of individual protein structures and multiprotein complexes.
Combined with advanced computer graphics, this insight can be
transformed into dynamic representations of biological processes.
Pinpointing the precise location of molecules and ions in living
cells can provide dazzling views of dynamic biological processes,
such as calcium currents. Biochemical reactions can also be
visualised, for example to explore mitochondrial function.
Many groups at UCL have developed great expertise in
microscopy techniques, and technical innovations continue to push
back the frontiers of visualisation. In neuroscience, two-photon
microscopy and other technologies are providing more information
about neural function in living tissue (see companion volume on
Neuroscience and Mental Health). With further developments such
as the brightness and stability of quantum dots, the specificity
of single-molecule tagging and super-resolution microscopy,
the ability grows to gather still more detailed information from
living cells and tissues.
At higher levels of organisation, a variety of non-invasive
techniques are providing unique insight into biological function
and disease mechanisms. UCL’s Centre for Advanced Biological
Imaging is a world-leading core centre of expertise in imaging
in living systems, supporting work across multiple departments.
With technologies such as magnetic resonance imaging and
nuclear imaging, ultrasound, bioluminescence and fluorescence
imaging, it has particular strengths in tissue- and organism-level
imaging in model organisms. Technical accomplishments such as
the remarkable analysis of living heart function after treatment to
promote heart muscle cell repair again illustrate the power of new
technologies to visualise dynamic biological processes. As well
as supporting basic discovery, the Centre also makes an important
contribution to early translational studies.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
3
SECTION 1
MOLECULAR
BASIS OF LIFE
Structural biology is providing insight
into ever-larger complexes, while
other techniques are shedding light
on key molecules inside the cell
and those signalling between them.
A bacterial transmembrane complex generating adhesive filaments (pili).
POPULATION HEALTH School of Life and Medical Sciences
4
Changes to the TRIMCyp restriction factor alter interactions at its virus-binding site.
Structural biology has
provided a view of
biomolecules way beyond
the resolution afforded
by light microscopy.
Increasingly, structural
techniques are being
applied to large protein
structures and, combined
with information from other
biophysical technologies
and sophisticated computer
graphics, provide a glimpse
of dynamic biological
processes at a molecular
level.
Visualising
nano-machines
Professor Gabriel Waksman
and colleagues at UCL
and Birkbeck College are
focusing on two bacterial
‘nano-machines’ that control
the movement of proteins
across the inner and outer
cell walls of Gram-negative
bacteria such as E. coli.
One of these complexes
generates the long sticky
filaments, pili, that bacteria
use to attach to host cells
(see page 7). The second
is one of a range of
mechanisms bacteria use
to secrete materials or
Increasingly, structural techniques are being
applied to large protein structures and, combined
with information from other biophysical
technologies and sophisticated computer
graphics, provide a glimpse of dynamic biological
processes at a molecular level.
transfer them to target cells.
This type IV secretion system
is of particular medical
interest, as one of its roles
is to transfer plasmids
containing antibiotic
resistance genes.
As a model, Professor
Waksman’s group has used
the type IV system of E. coli –
a huge multiprotein complex
that stretches methods of
structure determination to
the limit. A combination of
cryo-electron microscopy of
the core of the complex1 and
X-ray crystallography of the
outer membrane region2 has
revealed two layers forming
pores in the inner and outer
membrane. Unexpectedly,
one of the proteins in the
complex spans both layers
– the only protein known to
span both inner and outer
bacterial membranes.
The structures provide
clues to how the system
may operate. Moreover,
by identifying key points of
interaction between protein
subunits, they also reveal a
host of regions that could be
targeted by small chemicals,
to inhibit the structure’s
function. Professor Waksman
has worked with groups
in Sweden and the USA
on agents that block pilus
formation3,4 and a similar
strategy could be applied
to the type IV secretion
apparatus.
1 Fronzes R et al. Structure of a type IV
secretion system core complex. Science.
2009;323(5911):266–8.
2 Chandran V et al. Structure of
the outer membrane complex of a
type IV secretion system. Nature.
2009;462(7276):1011–5.
3 Chorell E et al. Design and
synthesis of C-2 substituted thiazolo
and dihydrothiazolo ring-fused
2-pyridones: pilicides with increased
antivirulence activity. J Med Chem.
2010;53(15):5690–5.
4 Pinkner JS et al. Rationally designed
small compounds inhibit pilus biogenesis
in uropathogenic bacteria. Proc Natl
Acad Sci USA. 2006;103(47):17897–902.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
5
Structure of the core complex of the bacterial type IV secretion apparatus.
All living organisms can
be categorised into three
domains – eukaryotes,
bacteria and archaea.
The latter may superficially
look like bacteria, but their
genetics and biochemistry
align them more closely with
eukaryotes. Professor Finn
Werner has taken advantage
of archaeal peculiarities
to gain insight into the
molecular mechanisms
of RNA polymerase (see
page 8). The findings also
shed intriguing light on the
possible evolutionary origins
of this most fundamental
of living processes.
All living things need to
read (transcribe) sequence
information from DNA into
RNA, a task accomplished
by RNA polymerases.
Indeed, the core proteins
involved in this process are
conserved in eukaryotes,
bacteria and archaea.
But there are also significant
differences between the
three groups, raising
questions about how the
forerunner of all living
organisms – the ‘last
universal common ancestor’,
or LUCA – transcribed
its RNA.
6
Notably, points out Professor
Werner, alongside RNA
polymerase, only one other
critical protein (known as
Spt5, SPT5 and NusG) is
conserved across the three
groups, and hence is likely
to have been present in
LUCA. Surprisingly, Spt5
is involved not in initiation –
binding of RNA polymerase
to DNA – but in locomotion
of the enzyme along the
DNA template. The proteins
responsible for initiation
are related in archaea and
eukaryotes, but completely
different in bacteria. The
simplest explanation is
that LUCA lacked initiation
factors, which evolved
independently in bacteria
and in the lineage that
later split to give rise to the
archaea and eukaryotes5.
If this is true, it implies
that initiation was initially
a passive process, and
regulation was to begin
with based on control of
elongation steps. Possibly,
RNA polymerase originally
bound to AT-rich regions
of DNA, where strands of
DNA are naturally easier to
separate (notably, bacterial
and eukaryotic initiation
Present in the membranes of most if not all cells,
ion channels are critical to numerous cellular
functions and are also important targets for many
therapeutic agents.
sites, although dissimilar,
are both AT-rich). Spt5 may
have had a general role
during elongation, helping
RNA polymerase through
DNA sequences that slowed
its progress. Indeed, Spt5
may have allowed RNA
polymerases to transcribe
longer genes, ultimately
leading to larger genomes.
No open and shut case
Among the most widely
studied macromoleular
structures are ion channels.
Present in the membranes
of most if not all cells, ion
channels are critical to
numerous cellular functions
and are also important
targets for many therapeutic
agents. Professor Annette
Dolphin has studied
the mode of action and
properties of calcium
channels which, among other
things, are the targets of the
gabapentin class of painkilling drugs (see page 7).
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Surprisingly, detailed work
on their mechanism of
action suggests that these
drugs interfere not with
channel activity directly
but with trafficking to the
plasma membrane. A similar
regulatory process has been
seen by Dr Josef Kittler in
his work on GABA receptors
(see page 18).
Channel function – and their
role in numerous disease
states – is a core area of
neuroscience research
(see companion volume
on Neuroscience and
Mental Health).
Defence molecules
To coordinate cellular
responses, the body
produces countless
signalling molecules. Again,
these are common targets
for chemical interventions.
5 Werner F, Grohmann D. Evolution
of multisubunit RNA polymerases in
the three domains of life. Nature Rev
Microbiol. 2011;9(2):85–98.
A multi-subunit complex generates filamentous pili.
Elevated levels of 2 1 (green) in rat spinal cord.
BUILDING REGULATIONS
BACK TO THE SURFACE
Stunning structures of multiprotein complexes have
revealed how E. coli synthesises its adhesion-promoting pili.
Drugs used to treat pain associated with nerve damage
have a highly unusual mode of action.
Bacteria such as E. coli attach to host cells through long sticky
filaments known as pili. The pili of E. coli that infect the urinary
system consist of an adhesive tip composed of three types of pilin
protein attached to a long filament made up of a polymeric chain
of a fourth filament protein. Using X-ray crystallography, Professor
Gabriel Waksman and colleagues at UCL and Birkbeck College
have generated a remarkable view of the pilus being synthesised
and threaded through the bacterial cell wall.
Previous work had identified the core components of this
extrusion system. At its heart lies an ‘usher’ protein, FimD, a large
barrel-shaped protein spanning the bacterium’s outer membrane.
Also critical is a ‘chaperone’, FimC, which sits in the space between
the outer and inner membranes, picks up new subunits posted
through the inner membrane and delivers them to the FimD usher.
Professor Waksman’s latest study solved the structure of the
FimD usher bound to the terminal pilin subunit, FimH, and its
associated chaperone, FimC. On its own, access to the inside of the
FimD usher is blocked by a molecular ‘plug’. When FimC and FimH
dock, however, this plug hinges open, enabling FimH to enter the
core of the FimD barrel.
Furthermore, FimH is positioned in such a way to promote
binding and attachment of the next pilus subunit (FimG), delivered
by the FimC chaperone. This arrangement depends on a second,
previously unsuspected FimC-binding site on the FimD usher.
Although not directly visualised, binding of a new chaperonebound pilin subunit is presumed to position it for attachment to
the base of the growing pilus. It is then translocated to the other
chaperone-binding site, freeing up the first binding site for another
chaperone-bound subunit. In this way, the pilus is extended from its
base in a stepwise fashion, subunit by subunit.
As well as revealing a likely mode of action for a remarkable
bacterial ‘nano-machine’, the study may also have practical spinoffs.
The structures highlight the key areas that could be targeted to
disrupt pilus formation and prevention attachment to cells lining the
urinary system, thereby preventing infection by E. coli.
Ion channels control the flux of ions across cell membranes, playing
important roles in numerous physiological processes, not least nerve
function. They are a popular target for drug development, the goal
generally being to modulate ion flows in ways that are therapeutically
beneficial. However, Professor Annette Dolphin has found that
one class of agents, gabapentin and its relatives, act in an entirely
different way.
Professor Dolphin has worked extensively on calcium channels,
which are critical to nerve function and many other cellular
processes. As their name suggests, voltage-gated calcium
channels open and close in response to changes in voltage across
the cell membrane. They consist of an 1 subunit, which forms the
actual pore, an intracellular subunit and a membrane-bound but
predominantly extracellular 2 subunit.
Gabapentin was originally developed as an analogue of the
neurotransmitter GABA (gamma-aminobutyric acid) but it soon
became clear that it did not bind to GABA receptors. In fact,
evidence began to accumulate that its effects were mediated
through interactions with the 2 subunit of calcium channels.
Colleagues at Pfizer, in collaboration with Professor Dolphin,
provided the first convincing evidence in animal models that this
was indeed the case.
Even so, gabapentin’s mode of action remained unclear, with
conflicting reports of its effects on ion currents. However, the drug
takes several days to have an effect and does not inhibit acute pain,
leading Professor Dolphin to suggest that it might work by affecting
ion channel numbers at the cell surface rather than by directly
modulating channel function.
Indeed, gabapentin’s site of action was found to be within the
cell, and it reduced the number of ion channels at the cell surface.
More detailed analysis revealed that the critical step was not the
production and delivery of new ion channels but the recycling of
existing calcium channels through endosomal pathways.
The studies therefore highlight an entirely novel way in which
agents can influence the action of ion channels involved in pain.
Remaut H et al. Fiber formation across the bacterial outer membrane
by the chaperone/usher pathway. Cell. 2008;133(4):640–52.
Field MJ et al. Identification of the alpha2-delta-1 subunit of voltagedependent calcium channels as a molecular target for pain mediating
the analgesic actions of pregabalin. Proc Natl Acad Sci USA.
2006;103(46):17537–42.
Phan G et al. Crystal structure of the FimD usher bound to its cognate
FimC-FimH substrate. Nature. 2011;474(7349):49–53.
Hendrich J et al. Pharmacological disruption of calcium channel
trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci USA.
2008;105(9):3628–33.
Bauer CS et al. The increased trafficking of the calcium channel subunit
alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by
the alpha2delta ligand pregabalin. J Neurosci. 2009;29(13):4076–88.
Tran-Van-Minh A, Dolphin AC. The alpha2delta ligand gabapentin
inhibits the Rab11-dependent recycling of the calcium channel subunit
alpha2delta-2. J Neurosci. 2010;30(38):12856–67.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
7
Different forms of TRIMCyp differ in their affinity for HIV.
NEAT AND TRIM
Retroviruses and the cells they prey upon are locked in a
constant evolutionary battle.
Lentiviruses, the family of retroviruses that include HIV, are extremely
fussy in the species they infect. Species specificity depends on
components of the innate immune response known as restriction factors,
particularly the TRIM family of proteins. As Professor Greg Towers and
colleagues have discovered, TRIM proteins and lentiviruses have been
waging an ongoing evolutionary battle lasting millions of years.
Professor Towers has focused on the TRIM5 restriction factor.
The tip of TRIM5 includes a domain that binds the surface coat of
lentiviruses, intercepting invading viruses and targeting them for
destruction. The specificity of TRIM5 binding to viral coat proteins
dictates which viruses can and cannot establish infections.
Remarkably, in a new world monkey, the owl monkey, the virusbinding domain of TRIM5 has been replaced by a host protein,
cyclophilin. The protein is still functional, and now targets cyclophilinbinding viruses. Even more remarkably, Professor Towers and
colleagues subsequently found that old world monkeys, Rhesus
macaques, also have a ‘TRIMCyp’ fusion – but it differs significantly
from the owl monkey version. Hence the two seem to have evolved
entirely independently.
The sequence of the TRIMCyp gene differs across the macaque
genus, and Professor Towers has enlisted the help of structural
biologists at the University of Cambridge to investigate the
consequences of these differences. Sequence variants influencing
binding specificity typically affect amino acid residues that make
contact with the virus. In TRIMCyp, however, key changes lie some
distance from virus-binding sites – but the changes affect a charged
residue and trigger a cascade of conformational shifts, ultimately
altering the virus-binding site.
Mapping TRIMCyp sequences onto the macaque family tree
suggested that a single amino acid change appeared in the cyclophilin
domain early in evolution, probably providing protection against
multiple lentiviruses. Later, other amino acid changes enhanced
recognition of specific viruses, but narrowed the range of viruses that
could be recognised. Oddly though, present-day macaques are not
known to harbour lentiviruses. Possibly, the relevant macaque virus has
not yet been identified, or antiviral responses were so effective that the
virus was vanquished.
A further evolutionary conundrum is the independent appearance
of two TRIMCyp fusions. Their existence hints at the importance of
cyclophilin to lentivirus infection. Cyclophilin is part of a complex at the
nuclear pore that appears to control traffic into the nucleus, which HIV
may hijack. In its absence, HIV shows markedly different patterns of
integration into the host genome.
Wilson SJ et al. Independent evolution of an antiviral TRIMCyp in rhesus
macaques. Proc Natl Acad Sci USA. 2008;105(9):3557-62.
Price AJ et al. Active site remodeling switches HIV specificity of antiretroviral
TRIMCyp. Nat Struct Mol Biol. 2009;16(10):1036–42.
Ylinen LM et al. Conformational adaptation of Asian macaque TRIMCyp directs
lineage specific antiviral activity. PLoS Pathog. 2010;6(8):e1001062.
Ocwieja KE et al. HIV integration targeting: a pathway involving Transportin-3
and the nuclear pore protein RanBP2. PLoS Pathog. 2011;7(3):e1001313.
8
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Factors compete for binding to RNA polymerase.
EXTREME ANSWERS
Work on enzymes found only at hydrothermal vents has
revealed an elegant mechanism controlling a key event
in transcription.
RNA polymerases, enzymes that read DNA sequence
information into RNA, are huge multisubunit complexes with
many associated factors regulating their behaviour. Because of
their size and complexity, their detailed mechanisms of action
have been difficult to study. By developing a novel in vitro
system based on heat-resistant archaeal proteins, Professor
Finn Werner has been able to gain unparalleled insights into
a critical step in transcription.
Archaea are the third kingdom of life, alongside bacteria and
eukaryotes. Although single-celled and superficially similar
to bacteria, their genetics and biochemistry hint at a closer
relationship to eukaryotes. Archaea include many exotic forms of
life, including the ‘extremophiles’ – organisms that thrive in some
of the most challenging environments on Earth.
Using an archaeal strain living around ‘black smoker’
hydrothermal vents, Professor Werner has been able to generate
recombinant proteins that reconstituted a functioning in vitro
system – something that has so far proven impossible with
eukaryotic RNA polymerases. The crucial factor seems to be
adaptation of the archaeal enzymes to high temperature – they
form highly stable structures and refold efficiently in the test tube.
With this system, Professor Werner has been able to engineer
fluorescent tags into the archaeal proteins, and then explore
interactions between different regulatory proteins and RNA
polymerase during its initial binding to DNA and as it begins to
move along the DNA template.
Of particular interest was a critical transcription factor, TFE,
which helps to separate DNA strands during the initiation of
transcription. TFE appeared to bind to a previously identified
‘clamp’ region on RNA polymerase, but so too did a second
factor, Spt4/5. Indeed, the two factors appeared to compete for
binding to the clamp. At initiation, TFE wins the battle, promoting
binding of RNA polymerase to the promoter of the DNA template
and separation of DNA strands. Then, however, conformational
changes in the complex subtly alter binding affinities, enabling
Spt4/5 to get the upper hand. This lifts the handbrake imposed
by TFE, enabling the enzyme to travel along the DNA template
more efficiently.
Transcription machineries are highly conserved across all
living systems. Homologues of the archaeal proteins are also
found in eukaryotes. Hence the mechanisms discovered in
archaea are likely to be relevant to eukaryotes, and the unique
in vitro system developed by Professor Werner should continue to
provide general insights into this fundamental biological process.
Grohmann D et al. The initiation factor TFE and the elongation factor
Spt4/5 compete for the RNAP clamp during transcription initiation and
elongation. Mol Cell. 2011;43(2):263–74.
Professor Derek Gilroy has
explored responses to one
of the most commonly used
agents, aspirin, revealing
individual variation in
responses that could have
significant implications for
inflammatory and defence
responses (see right).
Studies of the human
genome are revealing sites
where human evolution has
been shaped by contact
with pathogens. Across
the animal world more
generally, evidence can be
found of an ongoing battle
between viruses and their
hosts. The constant vying
for supremacy, suggests
Professor Greg Towers,
is an example of the Red
Queen hypothesis – the
evolutionary theory named
after the Alice Through the
Looking Glass character who
declared, “It takes all the
running you can do, to keep
in the same place.”
Professor Towers’ interest
was sparked by the
observation that particular
lentiviruses (the class of
retroviruses that includes
HIV) can only infect cells
from certain species. The
answer lies in ‘restriction
factors’ – components of
the host’s innate immune
system that prevent viruses
becoming established in
a cell.
Classic restriction factors
include TRIM5 proteins,
which bind to viral coat
proteins and target both
themselves and their
attachments for digestion
within the cell. Professor
Towers has gathered
considerable evidence of
the evolutionary interplay
between lentiviruses and
their host cells. Suggestive
evidence comes from signs
of ‘positive selection’ in the
genome – genetic changes
that appear to have been
actively selected for in
evolution. The importance
of such changes can be
confirmed by functional
studies, which compare
the effects of different
sequences – in viral or host
proteins – on the efficiency
of infection. Sure enough,
even minute changes at sites
in TRIM5 can dramatically
affect the specificity of
infection. Furthermore,
structural studies can provide
mechanistic explanations
for the changes seen (see
page 8).
To date, no chemical agent
has managed to eradicate
HIV from the body – small
reservoirs always survive.
The only exception is a
single patient who was being
treated for a blood cancer
and received a bone marrow
transplant. Fortunately, a
matched donor was available
who carried a genetic variant
in a co-receptor required
for HIV infection, rendering
his cells essentially resistant
to HIV. Encouragingly, the
recipient’s blood cells are
not being infected by HIV.
Inspired by this case, in
collaboration with Professor
Waseem Qasim, Professor
Towers is pursuing the idea
of gene therapy for HIV
patients. The idea is that T
cells would be collected from
patients and engineered so
that they would be resistant
to HIV infection, before
being returned to the patient.
This novel approach holds
particular promise for young
people infected with HIV,
who otherwise face the
prospect of a lifetime on
powerful antiretroviral drugs.
Professor Derek Gilroy.
RESOLVE TO DO BETTER
People differ markedly in their response to inflammation.
The classic signs of inflammation – redness, swelling and so
on – usually disappear of their own accord fairly quickly. It
used to be thought that this was a passive process in which
inflammatory processes gradually faded away, but it is now clear
that inflammatory responses are more actively curtailed. And
Professor Derek Gilroy and colleagues have found that people
differ markedly in their ability to terminate inflammatory reactions.
The discovery arose out of Professor Gilroy’s interest in lowdose aspirin’s effects on inflammation. High-dose aspirin has
well-known anti-inflammatory properties, while much lower doses
protect against cardiovascular disease. Although low-dose aspirin
was known to trigger production of lipids with inflammationresolving powers, it was unclear whether it was anti-inflammatory
in practice.
To answer this question, Professor Gilroy turned to an unusual
model – skin blistering cause by a toxic extract of the Spanish fly
(confusingly, a type of beetle). Cantharidin, historically used as an
aphrodisiac (albeit a potentially lethal one), and more recently to
treat warts, generates fluid-filled blisters when applied to the skin.
The blisters show all the hallmarks of classic inflammation. And
low-dose aspirin did indeed turn out to have anti-inflammatory
properties (though through a different mechanism from high-dose
treatment).
Curiously, though, only about 60 per cent of people responded
to low-dose aspirin. Indeed, people fell into two clear classes –
‘early resolvers’, in whom inflammation cleared within a few days,
and ‘delayed resolvers’ whose blisters persisted much longer.
A key difference between the two groups was a lipid-like
mediator, 15-epi-LxA4. In early resolvers, 15-epi-LxA4 levels
started low and rose as inflammation cleared, while in delayed
resolvers it started high but then fell away. Low-dose aspirin
triggered 15-epi-LxA4 production, but only in early resolvers.
As for mechanisms, 15-epi-LxA4 is generated by the enzyme
COX-2 after it has been chemically modified (acetylated) by
aspirin. COX-2 levels increase during inflammation so, in the
presence of aspirin, more acetylated enzyme is generated, levels
of 15-epi-LxA4 rise, and inflammation is brought under control.
Recently, small amounts of 15-epi-LxA4 have been identified
even in the absence of aspirin, but it remains unclear where they
come from.
The results suggest that natural variation affecting 15-epi-LxA4
pathways could influence responses to infections and inflammatory
responses. They also highlight a potentially important pathway that
needs to be considered in the design of anti-inflammatory agents.
Morris T et al. Effects of low-dose aspirin on acute inflammatory responses
in humans. J Immunol. 2009;183(3):2089–96.
Morris T et al. Dichotomy in duration and severity of acute inflammatory
responses in humans arising from differentially expressed proresolution
pathways. Proc Natl Acad Sci USA. 2010;107(19):8842–7.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
9
UCL has housed some of the UK’s most pre-eminent life
science and medical researchers, who set a benchmark
against which current research must be judged.
Below left: Bernard Katz.
Below right: Archibald Vivian Hill.
THE GREAT AND
THE GOOD
Neuroscience is a
particularly strong discipline
at UCL, and it is building
on notable foundations.
A pivotal figure was Sir
Bernard Katz, noted for
his pioneering work on the
synapse.
The rise of Nazism in the
1930s saw a stream of
talented Jewish researchers
from Germany and other
European countries seek
refuge in the UK. Among
them was a young medic,
Bernard Katz, who arrived at
UCL in 1935 to study under
Archibald Vivian Hill – Hill
co-founded the Academic
Assistance Council,
which helped hundreds of
academics escape Nazi
persecution. Following a
period in Australia, Katz
returned to UCL after the
war, remaining until his
retirement.
Katz was interested in events
at the synapse, particularly
acetylcholine signalling at the
neuromuscular junction. His
key discovery was that the
release of neurotransmitter
was ‘quantal’ – it always
increased in discrete steps.
Now known to be due to the
release of neurotransmitters
from uniform secretory
vesicles, the discovery
earned Katz a Nobel Prize in
1970. One of Katz’s students
10
was Bert Sakmann, who
with Erwin Neher went on
to win a Nobel Prize for
the development of patch
clamping.
Katz’s mentor, Archibald
Vivian Hill, had himself
been awarded a Nobel
Prize, in 1922 for his work
on the biophysics of muscle
contraction. He joined UCL
in 1923, taking up a position
of Professor of Physiology
from yet another giant of
research – Ernest Starling,
perhaps best known for his
eponymous ‘law of the heart’.
Starling also showed that
secretin stimulates secretion
from the pancreas, and
was the first to use the term
‘hormone’.
Among Katz’s many
collaborations was with
Andrew Huxley, who
joined UCL in 1960. With
Alan Hodgkin, Huxley was
responsible for one of the
most outstanding scientific
discoveries of the past
century. Working primarily
with the squid giant axon,
and combining experimental
studies with theoretical work,
they not only recorded action
potentials but also generated
computational models to
explain their origins. Their
studies led them to propose
the existence of ion channels,
years before they were
actually isolated. As well
as receiving a Nobel Prize
in 1963 (with Hodgkin and
John Carew Eccles), Huxley
served as President of the
Royal Society and received
many other plaudits.
Huxley and Hodgkin’s
seminal contributions owed
a sizeable debt to John
Zachary (J Z) Young, who
discovered and pioneered
work on the squid giant
axon. Although he never
received the Nobel Prize,
he was awarded the Linnean
Society’s Gold Medal and
delivered the BBC’s 1950
Reith lectures (on ‘doubt
and certainty in science’).
One of J Z Young’s early
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
collaborators was a young
Peter Medawar, who spent
most of the 1950s at UCL
before becoming Director
of the National Institute for
Medical Research at Mill
Hill in 1962. Another Nobel
Prize winner (in 1960),
Medawar is perhaps as well
known for the exceptional
quality of his writing as for
his landmark studies in
immunological tolerance
and transplantation.
In Darwin’s footsteps
One of the most colourful
figures in 20th-century
science, J B S Haldane,
spent the bulk of his career
at UCL. With R A Fisher
(who was also at UCL for
almost a decade from 1933)
and the American Sewall
Wright, Haldane established
the discipline of population
genetics and played a
central role in the ‘modern
synthesis’, which reconciled
the principles of Darwinian
evolution and natural
selection with the genetics
of Mendel.
Fisher had the insight to
realise that continuous
variation could be seen as
the result of many individual
genes of small effect, and
was therefore compatible
with Mendelian inheritance.
Natural selection could
change the frequency of
alleles of these genes,
leading to evolution. Haldane
developed mathematical
models of this process.
He also analysed reallife examples of natural
selection, including the
famous example of industrial
melanism in peppered moths
in the North of England.
Both figures fall within a
broader historical context,
in which the figure of
Francis Galton casts a long
shadow. Galton, half-cousin
to Charles Darwin, was an
old-fashioned polymath. He
is perhaps best known for
inventing the term ‘eugenics’
(as well ‘nature versus
nurture’) and brought his
considerable statistical
expertise to bear in studies
of heredity.
On his death, he bequeathed
funds to set up the Galton
Laboratory and a Chair of
Eugenics, a position first
held by his protégé Karl
Pearson. Another committed
eugenicist, Pearson made
AN INORDINATE FONDNESS FOR BEETLES
J B S Haldane is almost as well known for his colourful turn of phrase as his landmark scientific studies.
Among his most notable aphorisms concerned unconventional ideas in science: “Theories have four
stages of acceptance. (1) This is worthless nonsense; (2) this is an interesting, but perverse, point of
view; (3) this is true, but quite unimportant; (4) I always said so.”
He also had a habit of conducting experiments on himself, ending up with crushed vertebrae and
perforated eardrums, to which he responded: “The drum generally heals up; and if a hole remains in it,
although one is somewhat deaf, one can blow tobacco smoke out of the ear in question, which is a social
accomplishment.”
It is disputed whether Haldane coined the immortal line, “An inordinate fondness for beetles” when
asked what studies of evolution had told him about God. But it is often attributed to him and he frequently
used the phrase and variants of it.
enormous contributions
to statistical methodology,
and many of the tools used
in science today have
their roots in his work,
from P-values to principal
component analysis. He also
pioneered mathematical
approaches to the study
of evolution, leading the
‘biometric’ school from which
arose the statistical analyses
underpinning the modern
synthesis.
Pearson was succeeded
by R A Fisher, who in turn
passed the baton on to
Lionel Penrose. Penrose,
a humane and enlightened
researcher, was among the
first to study the biological
and genetic basis of mental
retardation. He received a
Lasker Award in 1960.
A UCL contemporary of
Karl Pearson’s was Charles
Spearman (though the two
did not get on), another who
left a lasting impression on
statistics. As well as his work
on correlation, he is known
for his work on general
intelligence (or ‘g’).
Figures like Haldane,
Pearson and Penrose
pioneered the application
of genetics to human
traits, including medical
conditions. More generally,
Haldane and Fisher were
both important influences
on the evolutionary theories
developed by W D Hamilton.
A knotty issue in evolution
has always been how natural
selection can lead to the
appearance of altruistic
behaviours that impose a
cost on an individual but
benefit others. Hamilton
proposed that the key
issue was relatedness, as
helping kin would indirectly
promote the propagation of
genes. This line of thinking
contributed significantly to
the growth of ‘socio-biology’
as well as gene-centric
ways of viewing evolution
– popularised in Richard
Dawkin’s landmark book
The Selfish Gene.
Hamilton was also an
influence on John Maynard
Smith. A student of Haldane,
Maynard Smith converted
from aeronautical engineer
to evolutionary theorist.
He made wide-ranging
contributions, including
influential early work on
lifespan and ageing, the
evolution of sex, and the
application of game theory
to evolution. His notion of the
‘evolutionarily stable strategy’
is a central pillar of modern
thinking about animal
behaviour.
Below left: Karl Pearson.
Below right: A demonstration
by Professor Sir William Bayliss,
with Professor Earnest Starling
and Sir Henry Dale to the left.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
11
SECTION 2
THE CELLULAR WORLD
Cells are the building blocks of life, and understanding
the fundamental principles of cell biology will help to
pinpoint key changes that lead to disease.
Neurons obtained from embryonic stem cells.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
12
Developing vasculature in the retina.
The structures of the cell,
and much of its biochemistry,
have been well described
and fill many textbooks.
Yet how they act together
to guide the fate of the cell
often remains mysterious.
Visualising
mitochondrial activity
Mitochondria generate most
of the energy on which
cellular life depends. Given
this critical role, it is not
surprising that abnormalities
in mitochondrial function
have been implicated in
numerous conditions, from
diabetes to Parkinson’s and
Alzheimer’s disease.
As befits this central role in
cell biology, mitochondria
specialist Professor Michael
Duchen collaborates
extensively across UCL,
investigating mitochondrial
function in numerous
disease states. A variety
of imaging techniques
reveal dynamic changes in
the concentrations of key
metabolites and calcium
signals that regulate
mitochondrial function.
A variety of imaging techniques reveal
dynamic changes in the concentrations of key
metabolites and calcium signals that regulate
mitochondrial function.
Recent years have seen
a growing realisation that
mitochondrial dysfunction
is central to Parkinson’s
disease, where several
genes influencing the
risk of the disease affect
mitochondria-related
proteins6. In Alzheimer’s
disease, Professor Duchen
has generated intriguing
findings on the possible role
of -amyloid in the death
of neurons (see page 14).
In other collaborations,
Professor Duchen has
worked with cardiovascular
researchers Professor Derek
Yellon, Dr Derek Hausenloy
and Dr Sean Davidson on
the response of mitochondria
to impaired oxygen supply
(ischaemia and reperfusion).
Much of this work focuses
on the ‘mitochondrial
permeability transition pore’.
High levels of calcium in
the mitochondrion trigger
opening of this pore, leading
to an outflow of ATP and
ultimately death of the cell.
Inhibiting pore opening limits
the impact of reperfusion
injury after ischaemia.
It has been implicated
in the mechanisms of
preconditioning7 – restricting
oxygen supply briefly to
protect the heart from later
ischaemia (see companion
volume on Translation and
Experimental Medicine).
Mitochondria have also
been implicated in kidney
conditions. Interestingly, the
imaging work of PhD student
and nephrologist Andrew
Hall has revealed that
mitochondrial activity varies
6 Gandhi S et al. PINK1-associated
Parkinson’s disease is caused by
neuronal vulnerability to calcium-induced
cell death. Mol Cell. 2009;33(5):627–38.
7 Hausenloy D, Wynne A, Duchen M,
Yellon D. Transient mitochondrial
permeability transition pore
opening mediates preconditioninginduced protection. Circulation.
2004;109(14):1714–7.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
13
The fission yeast, Schizosaccharomyces pombe.
Imaging of NADH in a cochlea explant culture.
WHO’S BINDING WHO?
DEATH OF A NEURON
Precisely timed protein degradation is vital to cell division,
but how does the critical protein-degrading complex
know what to digest and when?
Death of neurons in Alzheimer’s disease may result from
loss of essential support from neighbouring cells.
The anaphase-promoting complex (APC) plays a fundamental
role in cell division. By attaching multiple ubiquitin tags, it marks
key proteins such as cyclins for destruction at specific points
in the cell cycle. Regulation of APC is thus crucial. As well as
timing, regulation also has to address substrate specificity: how
does APC know what to digest? Professor Hiro Yamano and
colleagues have recently shed important light on these questions.
To operate, APC relies on additional accessory proteins
– Cdc20/Fizzy at early stages of cell division and Cdh1/Fizzyrelated at later stages. It was originally thought that these
accessory proteins were required to activate APC, but their ability
to bind APC substrates led to the idea that they were recruitment
factors, delivering proteins to APC for ubiquitin tagging and then
degradation.
This view took a hit in 2006, when Professor Yamano and
Professor Andrew Fry at the University of Leicester found that one
APC substrate, Nek2A, could bind directly to APC even in the
absence of Cdc20/Fizzy. This direct binding depended on a short
sequence motif in the C-terminal tail of Nek2A.
Crucially, this independent binding also enabled Professor
Yamano to look separately at recruitment and ubiquitin tagging.
Surprisingly, the results revealed that Cdc20/Fizzy was an APC
activator after all. In the absence of Cdc20/Fizzy, Nek2A can bind
to APC but it is not tagged with ubiquitin unless an N-terminal
fragment of Cdc20/Fizzy is also present. Notably, though, this
region of Cdc20/Fizzy is not the one required for it to bind and
recruit other substrates. Hence there is a previously unsuspected
interaction between Cdc20 and APC, crucial for ubiquitin
addition, that requires specific sequences in the N-terminal
region of Cdc20.
As well as the insight into a process at the heart of cell
division, the work may also open up a route to new therapeutic
interventions. It may be possible to target this new point of
interaction between Cdc20 and APC and specifically arrest the
division of dividing cancer cells. Professor Yamano is now aiming
to pinpoint the site on APC binding to the N-terminal region of
Cdc20, with a view to screening for small-molecule inhibitors
that could block the interaction.
Hayes MJ et al. Early mitotic degradation of Nek2A depends on Cdc20independent interaction with the APC/C. Nat Cell Biol. 2006;8(6):607–14.
Kimata Y, Baxter JE, Fry AM, Yamano H. A role for the Fizzy/Cdc20 family
of proteins in activation of the APC/C distinct from substrate recruitment.
Mol Cell. 2008;32(4):576–83.
Alzheimer’s disease is characterised by the presence in the brain
of protein tangles and plaques, the latter composed of fragments
of -amyloid protein. Although its role in disease is controversial,
-amyloid is toxic to neurons in culture. Yet, suggests the research of
Professor Michael Duchen and colleagues, its impact on neurons may
be an indirect consequence of its effects on glia, the cells that provide
neurons with essential metabolic support.
Professor Duchen’s research focuses primarily on mitochondria,
damage to which can trigger cell death. But how might -amyloid
affect the function of mitochondria? Over the past decade, the
research of Professor Duchen and Dr Andrey Abramov has revealed
a possible route – which, although complex, offers the enticing
prospect of novel remedies.
Professor Duchen’s principal tool has been co-culture systems of
neurons and astrocytes (glial cells). If -amyloid is added to these
cultures, neurons die. However, close examination revealed a curious
phenomenon. In the first few hours after addition of -amyloid, it was
astrocytes that showed a response rather than neurons. Perhaps then
the primary problem was in astrocytes, which were prevented from
providing essential support to neurons.
Delving deeper, Professor Duchen identified a long slow loss of
mitochondrial membrane potential in astrocytes as a key mediator of
-amyloid’s effects. The picture emerging from several years’ work
is that oxidative stress activates a DNA repair enzyme, PARP, which
exhausts the supply of a key metabolite required for glycolysis. The
failure of glycolysis depletes the substrates required by mitochondria,
which fail – starving in the midst of plenty.
Other factors also influence cell death through this pathway.
For example, there is some evidence that the cholesterol content
of the plasma membrane determines -amyloid’s toxicity. Indeed,
Professor Duchen found that membrane cholesterol levels are
significantly higher in astrocytes than neurons. Cholesterol enhances
the ability of -amyloid to form pores in the plasma membrane,
enhancing calcium influx that eventually cripples mitochondria.
The identification of this pathway has revealed a new set of
targets for intervention. Remarkably, in cultured cells, adding
substrate for mitochondrial respiration protects astrocytes from
-amyloid toxicity. Professor Duchen is now exploring the possibility
of screening small-chemical inhibitors to target other points in the
pathway as a route to new treatments for Alzheimer’s disease.
Abramov AY, Canevari L, Duchen MR. Changes in intracellular calcium and
glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity.
J Neurosci. 2003;23:5088–95.
Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce
mitochondrial dysfunction and oxidative stress in astrocytes and death of
neurons through activation of NADPH oxidase. J Neurosci. 2004;24(2):565–75.
Abeti R, Abramov AY, Duchen MR. Beta-amyloid activates PARP causing
astrocytic metabolic failure and neuronal death. Brain. 2011;134(Pt 6):1658–72.
Abramov AY, Ionov M, Pavlov E, Duchen MR. Membrane cholesterol content
plays a key role in the neurotoxicity of -amyloid: implications for Alzheimer’s
disease. Aging Cell. 2011;10(4):595–603.
14
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
8 Hall AM, Unwin RJ, Parker N, Duchen
MR. Multiphoton imaging reveals
differences in mitochondrial function
between nephron segments. J Am Soc
Nephrol. 2009;20(6):1293–302.
9 Cantley J et al. Deletion of the von
Hippel-Lindau gene in pancreatic beta
cells impairs glucose homeostasis in
mice. J Clin Invest. 2009;119(1):125–35.
10 El-Kadi AM et al. The legs at odd
angles (Loa) mutation in cytoplasmic
dynein ameliorates mitochondrial
function in SOD1G93A mouse model
for motor neuron disease. J Biol Chem.
2010;285(24):18627–39.
11 Campanella M et al. Regulation of
mitochondrial structure and function by
the F1Fo-ATPase inhibitor protein, IF1.
Cell Metab. 2008;8(1):13–25.
12 Izawa D et al. Fission yeast Mes1p
ensures the onset of meiosis II by
blocking degradation of cyclin Cdc13p.
Nature. 2005;434(7032):529–33.
13 Kimata Y et al. A mutual inhibition
between APC/C and its substrate Mes1
required for meiotic progression in
fission yeast. Dev Cell. 2008;14(3):
446–54.
14 Kimata Y, Kitamura K, Fenner N,
Yamano H. Mes1 controls the meiosis
I to meiosis II transition by distinctly
regulating the anaphase-promoting
complex/cyclosome coactivators Fzr1/
Mfr1 and Slp1 in fission yeast. Mol Biol
Cell. 2011;22(9):1486–94.
Fibroblast cells stained to show mitochondria (red: alive; green: dead or alive).
markedly along a nephron,
with the mitochondrial
membrane potential being
markedly higher in distal
than proximal tubules8. Other
studies have examined the
role of mitochondria in betacell function and diabetes9,
survival in intensive care,
and neuromuscular
conditions such as motor
neuron disease10.
A relatively new area of
interest is the inhibitor
protein IF1, which regulates
activity of the mitochondrial
ATP-generating machine,
the F0F1 ATP synthase11.
Although its main role is to
generate ATP, powered by
the flow of hydrogen ions,
this enzyme complex can
operate in both directions,
breaking down ATP when it
spins in reverse. IF1 appears
to act as a brake on this
reverse reaction, helping
to ensure that ATP levels
are not depleted. As yet,
little is known about IF1,
but its regulation of such a
key aspect of mitochondrial
function suggests it
could play a major role in
mitochondrial biology and
disease processes.
Cycle of life
Control of the cell cycle
and cancer is the principal
interest of Professor Hiro
Yamano, who joined the UCL
Cancer Institute in 2010. He
uses a popular tool in cell
cycle research, the fission
yeast Schizosaccharomyces
pombe, which has a wellcharacterised cell cycle
and is highly amenable
to genetic dissection.
Unusually, Professor Yamano
complements work in fission
yeast with biochemical
studies in Xenopus oocyte
extracts. The high degree
of conservation of cell cycle
mechanisms ensures that
findings in one system
can be related to those
in the other.
Professor Yamano’s main
interest is APC/C (anaphasepromoting complex/
cyclosome), which attaches
ubiquitin residues to key
cell cycle proteins, targeting
them for degradation. Cells,
even cancer cells, arrest
in mitosis if APC/C activity
is blocked. Regulation of
APC/C is thus of intense
interest, and Professor
Yamano has provided
important insight into the
mechanisms controlling
APC/C activity and substrate
specificity (see page 14).
An additional interest is
meiosis, the gamete-forming
mode of cell division,
which is more complex
than mitosis as additional
steps are needed to reduce
chromosome number. This
calls for additional layers of
regulation of APC/C.
In 2005, with Professor
Masayuki Yamamoto in
Tokyo, Professor Yamano
showed that Mes1 protein
was required to prevent
the complete destruction
of cyclins at the transition
between the two main stages
of meiosis, MI and MII12.
Although cyclins do need to
be degraded at this point,
unlike mitosis, some residual
cyclin needs to be spared
for later stages to progress
efficiently.
In fact, Mes1 protein acts
in a very interesting way.
As well as being an inhibitor
of APC/C, it is also a
substrate. This creates a
self-regulatory loop which
ensures that APC/C is not
entirely inactivated during
the first phase of meiosis13.
Most recently, Professor
Yamano has uncovered a
further layer of regulation of
APC/C by Mes114.
Safeguarding the oocyte
Professor John Carroll’s
cell of interest is the oocyte.
Understanding how the
oocyte is formed, and what
happens after fertilisation, is
not just of academic interest.
Around one in seven couples
experience difficulty in
conceiving, often because of
problems with eggs. A trend
towards later conception is
also focusing attention of
the long-term fate of eggs
in the ovary.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
15
used to drive the ion currents
that maintain membrane
potentials and hence the
ability of nerves to generate
action potentials.
Differentiation of an embryonic stem cell.
Professor Carroll has also
found interesting ways in
which meiosis differs from
mitosis (see page 17). He is
also keen to explore some
of the long-term factors
affecting the oocyte in the
ovary. One key issue is DNA
damage and repair – how
does the oocyte maintain the
integrity of its genome, so
vital in cells that will give rise
to entire new organisms, over
such long periods?
In addition, it is becoming
clear that there is extensive
cross-talk between the
oocyte and its surrounding
microenvironment in the
ovary, and this has the
potential to affect offspring
many years after birth.
Although the notion of
‘programming’ has tended
to consider the impact of
a mother’s physiology of
a developing fetus, there
is also evidence that
maternal signals can also
affect oocytes. Professor
Carroll now splits his time
between Monash University
in Melbourne and UCL,
where his colleagues Dr
Hayden Homer and Dr Greg
Fitzharris continue the work.
Form and function
Cells differ markedly in form,
depending on their role in the
body. Indeed, some possess
entirely novel organelles –
such as the Weibel–Palade
bodies studied by Professor
16
Dan Cutler. These large
cigar-shaped organelles,
found in endothelial cells
lining blood vessels, are
packed full of von Willebrand
factor, a polymeric protein
important in blood clotting
(see page 17).
Weibel–Palade bodies also
have a role in inflammation.
This depends in particular
on the presence in their
membrane of a cell adhesion
molecule, P-selectin. When
the Weibel–Palade bodies
fuse with the outer cell
membrane, P-selectin is
exposed to the bloodstream
and ‘snags’ circulating
leukocytes, causing them to
begin a characteristic rolling
along the vessel wall. Other
cell adhesion molecules
strengthen the binding and
enable leukocytes to begin
burrowing through the vessel
wall into surrounding tissues.
Professor Cutler has
discovered that initial
leukocyte recruitment by
P-selectin also requires at
least one other endothelial
protein, CD63 – a well-known
component of Weibel–
Palade bodies of previously
unknown function15. Loss
of CD63 dramatically
reduced leukocyte rolling
and invasion of surrounding
tissue. CD63 is thus a
potentially exciting new
target for anti-inflammatory
drug development – being
explored with the support of
MRC Technology.
Nerve cells are among the
most specialised cells in the
body. Structurally, they are
highly modified, with long
extensions that, in humans,
can stretch up to a metre (or
a stunning five metres in the
giraffe). Hence the business
end of a neuron, the synapse,
can be a considerable
distance from the control
centre, the nucleus in the
cell body. As Dr Josef
Kittler has demonstrated,
these specialisations are
accompanied by distinct
intracellular trafficking
signalling systems, as well
as a considerable degree
of local autonomy.
Local independence
is important because
synapses are highly dynamic
structures that respond
rapidly to incoming signals
– more rapidly than is
possible through signalling
to the nucleus and changes
in gene expression. One
system allowing for rapid
modulation of synapse
behaviour is altered recycling
of neurotransmitter receptors
to and from the cell surface
(see page 18).
Dr Kittler is also interested
in the trafficking of much
larger structures, including
organelles such as
mitochondria. Although
accounting for only around 2
per cent of body mass, the
brain consumes 20 per cent
of the body’s energy. This
massive energy use is mainly
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Most of a cell’s energy is
generated by mitochondria.
It turns out that entire
mitochondria can be
shipped to parts of the cell
with high energy demands.
Although it was known that
mitochondrial recruitment
was triggered by calcium
influx, little was known about
the mechanisms involved.
Dr Kittler recently discovered
that a protein with the artistic
name Miro plays a critical
role, tethering mitochondria
to the molecular motors that
transport material along the
cell’s microtubule highways16.
Crucially, binding of Miro
to the molecular motors is
inhibited by high calcium
levels, causing mitochondria
to detach once they have
reached a point in the cell
generating high calcium
currents.
As well as generating insight
into basic mechanisms,
Dr Kittler’s group is also
exploring the potential
role of these processes
in disease. For example,
neurotransmitter receptor
trafficking has been found
to be affected by huntingtin,
the product of the mutated
gene causing Huntington’s
disease17. Impaired inhibition
of neural function, because
fewer receptors for inhibitory
neurotransmitters are
present at the synapse,
could contribute to the
motor and cognitive
problems associated with
Huntington’s disease. Dr
Kittler is also collaborating
with neurologists to explore
15 Doyle EL et al. CD63 is an essential
cofactor to leukocyte recruitment
by endothelial P-selectin. Blood.
2011;118(15):4265–73.
16 Macaskill AF et al. Miro1 is a calcium
sensor for glutamate receptor-dependent
localization of mitochondria at synapses.
Neuron. 2009;61(4):541–55.
17 Twelvetrees AE et al. Delivery of
GABAARs to synapses is mediated by
HAP1-KIF5 and disrupted by mutant
huntingtin. Neuron. 2010;65(1):53–65.
Spindle fibres (red) in a maturing oocyte.
Weibel–Palade bodies (blue).
EGG TIMING
BODY OF EVIDENCE
An understanding of the molecular processes controlling
oocyte development may provide insight into the origins
of impaired fertility.
Weibel–Palade bodies may not be the best known of
organelles but they play a critical role in blood clotting.
Unlike sperm, which are constantly generated throughout life, all
oocytes are present in the ovary at birth. They are maintained in an
immature state, part way through meiosis, until puberty, when the
machinery of cell division is switched back on and oocytes mature
in readiness for fertilisation. Working with mice oocytes, Professor
John Carroll has identified several key ways in which these
processes are controlled.
Control of cell division, both mitosis and meiosis, is critically
dependent on the so-called anaphase-promoting complex (APC).
APC degrades cyclins, the key inhibitory proteins that stop a
cell dividing. APC also breaks down an entirely different protein,
securin, as part of a programme that enables chromosome to
separate. In fact, Professor Carroll has discovered, these activities
are closely connected, as securin competes with cyclins for APC.
With excess securin, cyclins are not degraded effectively and cell
cycle progression is stalled.
APC has a further role, being required to hold oocytes in their
early arrested state. While exploring factors influencing APC
activity, Professor Carroll found that depletion of one particular
protein, BubR1, unexpectedly led a proportion of embryos to slip off
their early (prophase) arrest and re-enter meiosis. Follow-up work
revealed that BubR1 acts through an APC co-factor, Cdh, which
normally activates APC and maintains cell cycle arrest.
However, while BubR1-deficient oocytes were able to reenter prophase, they never completed the first phase of meiosis,
becoming stalled before the transition to anaphase. The diminished
activity of APC leads to increased securin levels, which interfere with
APC activity at the end of metaphase.
Even when securin levels were reduced, however, BubR1deficient oocytes did not fully recover their ability to enter
anaphase. It appears that loss of BubR1 has additional effects on
chromosome attachment to the meiotic spindle, preventing cell
division from proceeding even in the presence of functional APC.
The results point to an early role for BubR1, mediated through
Cdh1, to maintain prophase arrest, with securin an important target
of active APC. Later, BubR1 has a separate role as part of the
machinery that keeps APC in check until the cell is ready to enter
anaphase.
The findings reveal significant differences between early events
in mitosis and meiosis, highlighting the importance of Cdh1 and
securin in the latter. From a practical point of view, BubR1’s critical
role in both prophase arrest and metaphase progression makes
BubR deficiency a potentially significant factor in reduced fertility,
because the reservoir of arrested oocytes is depleted or fewer
oocytes become fertilisable eggs.
The inner surface of blood vessels is lined with endothelial cells.
Among their most notable features is the presence of strange cigarshaped organelles – known as Weibel–Palade bodies in honour of
their discoverers, Ewald Weibel and George Palade (recipient of a
Nobel Prize in 1974). Despite being important in both clotting and
inflammation, Weibel–Palade bodies have been relatively neglected
– an oversight Professor Dan Cutler has attempted to correct.
One reason Weibel–Palade bodies are important is because
they are the storage containers of von Willebrand factor, a crucial
component of the blood clotting system. When blood vessels are
damaged, von Willebrand factor is released as a long polymeric
fibre to which platelets adhere. Abnormalities in von Willebrand
factor function are actually the most common form of inherited
blood coagulation disorder.
Coordinated storage and release of von Willebrand factor is thus
highly significant in its own right, as well as providing more general
insight into cell trafficking and exocytosis.
For von Willebrand factor and its storage compartment, form and
function are highly correlated. Within the Weibel–Palade bodies,
polymeric filaments are folded into organised tubular structures
that shape their storage compartment into its characteristic shape.
If this organisation is disrupted inside the cell, Weibel–Palade
bodies become spheres containing multimers and shortened fibres
that fail to recruit platelets efficiently.
Once formed, Weibel–Palade bodies are trafficked through the
cell and held at the periphery of the cell ready for secretion. This
holding phase depends on Rab27a, a member of the Rab family
of GTPases, and its effectors, including MyRIP and a member of
the myosin family of proteins (myosin Va). These proteins anchor
the bodies to actin fibres, and prevent release of immature von
Willebrand factor polymers.
Actin fibres also turn out to be critical to the exocytosis of Weibel–
Palade bodies. Actin has long been known to play a role in secretion,
but exact mechanisms have been difficult to unpick. By combining
video and electron microscopy, Professor Cutler has been able
to gain an unusually detailed view in time and space of individual
exocytotic events. Filamentous actin initially anchors Weibel–
Palade bodies and inhibits fusion with the plasma membrane, but
following endothelial activation and just after fusion with the plasma
membrane, a contractile actomyosin ring forms on the organelles.
This ring appears to actively squeeze mature von Willebrand factor
out of the cell.
Michaux G et al. The physiological function of von Willebrand’s factor
depends on its tubular storage in endothelial Weibel-Palade bodies.
Dev Cell. 2006;10(2):223–32.
Marangos P, Carroll J. Securin regulates entry into M-phase by modulating
the stability of cyclin B. Nature Cell Biol. 2008;10(4):445–51.
Nightingale TD, Pattni K, Hume AN, Seabra MC, Cutler DF. Rab27a and
MyRIP regulate the amount and multimeric state of VWF released from
endothelial cells. Blood. 2009;113(20):5010–8.
Homer H, Gui L, Carroll J. A spindle assembly checkpoint protein
functions in prophase I arrest and prometaphase progression. Science.
2009;326(5955):991–4.
Nightingale TD et al. Actomyosin II contractility expels von Willebrand factor
from Weibel-Palade bodies during exocytosis. J Cell Biol. 2011;194(4):
613–29.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
17
Presynaptic axons (red) and postsynaptic dendrites (green).
Professor Philip Beales.
COME TOGETHER
FROM DEFENCE TO MIGRATION
Regulating receptor numbers at the synapse is an important
way of controlling neural activity.
Two proteins known only for their roles in the
complement system have turned out to have critical roles
in embryogenesis.
Synapses are highly dynamic structures. Their activity is modulated
in numerous ways, even changing in response to the electrical signals
they transmit. This ‘plasticity’ underpins many key aspects of brain
function, including learning and memory. One way in which plasticity
is achieved is by fine control of the numbers of neurotransmitter
receptors present at the synapse, and Dr Josef Kittler and colleagues
have uncovered some of the cellular mechanisms by which this
achieved – and also how it can go awry in disease.
Dr Kittler is particularly interested in the receptors for inhibitory
neurotransmitters such as GABA (gamma-aminobutyric acid). These
neurotransmitters act in opposition to excitatory neurotransmitters,
and prevent excessive neural activation.
The degree of inhibition mediated by GABA is known to depend
on the numbers of GABA receptors present at the synapse. Hence,
control of receptor numbers could provide a way to regulate the
strength of inhibitory input to a neuron. Indeed, using high-definition
imaging and other techniques, Dr Kittler has begun to identify the
mechanisms by which GABA receptor numbers are controlled at
the synapse.
With Professor Stephen Moss, for example, he has shown that
receptor numbers are regulated by recycling through endosomal
pathways. These studies have revealed key regions of the receptor
necessary for sorting, and that dictate whether receptors are tagged
by ubiquitin for degradation or are trafficked back to the cell surface.
More recently, he has teamed up with Dr Lewis Griffin in UCL’s
Department of Computing, tracking individual receptors tagged with
tiny but highly fluorescent markers (quantum dots). These studies
have revealed that an excitatory stimulus leads to the break up of
clusters of GABA receptors in the neuronal membrane. They have
also revealed key biochemical changes linked to the break up of
receptor clusters.
The work on GABA receptor trafficking has significant medical
potential. Loss of GABA receptors from synapses has been seen in
several conditions, from epilepsy to neurodegenerative conditions.
Indeed, in Huntington’s disease, Professor Kittler’s group has found
that the abnormal protein underlying the condition, huntingtin,
disrupts the intracellular delivery of GABA receptors to the synapse.
Hence a better understanding of the molecular mechanisms
controlling GABA receptor distribution promises to identify potential
targets for a range of important medical conditions.
Kittler JT et al. Regulation of synaptic inhibition by phospho-dependent
binding of the AP2 complex to a YECL motif in the GABAA receptor gamma2
subunit. Proc Natl Acad Sci USA. 2008;105(9):3616–21.
Arancibia-Cárcamo IL et al. Ubiquitin-dependent lysosomal targeting of
GABA(A) receptors regulates neuronal inhibition. Proc Natl Acad Sci USA.
2009;106(41):17552–7.
Muir J et al. NMDA receptors regulate GABAA receptor lateral mobility and
clustering at inhibitory synapses through serine 327 on the 2 subunit.
Proc Natl Acad Sci USA. 2010;107(38):16679–84.
18
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Because of the links between gene loss and symptoms, rare
inherited diseases often provide insight into developmental
processes. Recently, a highly unusual group of patients studied
by Professor Philip Beales and colleagues has for the first time
implicated proteins of the complement defence system in critical
cellular events in early development.
The work centred on 11 families affected by four extremely
rare inherited conditions – Carnevale, Mingarelli, Malpuech and
Michels syndromes, which have been seen in just 20 families
worldwide. The overlapping constellation of symptoms in the four
syndromes – characteristics facial abnormalities, cleft lip and
palate, learning difficulties and other clinical features – has led to
suggestions that they share underlying disease mechanisms.
Regions of homozygosity shared by affected family members,
and in different families, pointed to a section of chromosome 2
as the likely cause of the abnormalities. Sequencing of genes in
this region revealed mutations in the COLEC11 gene in affected
individuals.
COLEC11 is not an obvious candidate for a developmental
disease gene, as it codes for a component of the complement
system, part of the body’s protection against infection. Its protein
product is a member of the C-type lectin family, consisting of a
collagen-like domain and a carbohydrate-binding domain.
Elimination of COLEC11 function in zebrafish, however,
confirmed its essential role in development. In its absence,
zebrafish developed numerous defects, including striking
abnormalities in craniofacial morphology.
Although COLEC11 was normal in some families, homozygosity
mapping in other families identified another potentially important
region on chromosome 3. And within this region was another
complement system gene, MASP1. Mutations in this gene were
found in two families. In zebrafish, loss of MASP1 generated
craniofacial abnormalities similar to those seen in fish lacking
COLEC11.
These striking effects, and associated pigment abnormalities,
suggested that the genes were affecting the migration of neural
crest cells, a finely controlled process required to sculpt the
complex structures of the face. Indeed, studies in fish and
cultured cells suggested that the proteins act as chemo-attractant
guidance cues for migrating neural crest cells.
The results suggest that the four syndromes are related, and
should be grouped under the common label of M3C syndrome.
Complement-related proteins have never been implicated in
developmental conditions before, and it will be interesting to see
if others are involved in developmental processes or inherited
conditions.
Rooryck C et al. Mutations in lectin complement pathway genes COLEC11
and MASP1 cause 3MC syndrome. Nat Genet. 2011;43(3):197–203.
the potential involvement of
such processes in epilepsy,
which is characterised by
excessive neural activity.
A further strand of work is
examining whether factors
found to increase the risk of
neuropsychiatric conditions,
for example in genome-wide
screens, affect trafficking
in neurons. Early work on
a protein implicated in
schizophrenia (DISC1),
for example, has revealed
deficits in mitochondrial
trafficking18.
Cilia and ciliopathies
In 1995, during his medical
training, Professor Philip
Beales encountered a
patient with diabetes and
an unusual mix of additional
symptoms. Professor Beales
suspected he knew what
the problem was, and a
later check of his textbooks
confirmed his suspicions.
The man had the rare
genetic condition Bardet–
Biedl syndrome.
Since then Professor Beales
has helped to identify
several genetic causes of
Bardet–Biedl syndrome and
characterised their effects.
Indeed, he has become
a world authority on the
large class of diseases
which, like Bardet–Biedl
syndrome, are associated
with defective cilia.
Cilia are perhaps best known
for their ability to beat and
create fluid currents across
the surface of cells. But
they also have an important
non-motile role as cellular
‘antennae’, detecting
and transmitting external
signals. This function is
particularly important during
embryogenesis, when cells
receive signals that control
their developmental fate.
Working with Dr Nicholas
Katsanis in the USA and
others, Professor Beales
has done much to piece
together the origins of
Bardet–Biedl syndrome,
which is characterised by a
range of symptoms including
progressive blindness,
kidney problems, obesity,
additional digits (polydactyly)
and learning difficulties.
By the late 1990s, several
genes were known to be
involved in the condition, but
isolating them and working
out what they did proved
challenging. A significant
breakthrough came in 2003,
when Professor Beales and
Dr Katsanis discovered
that a new Bardet–Biedl
syndrome gene, BBS8, had
many of the hallmarks of a
cilia protein19. The work thrust
cilia firmly into the Bardet–
Biedl syndrome spotlight.
With Dr Katsanis and
others, Professor Beales
Elongated mitochondria in a cardiac cell line.
went on to characterise
other BBS genes affecting
cilia structure and function.
Furthermore, defective cilia
also turned up in a range of
other conditions, collectively
referred to as ‘ciliopathies’.
The realisation that cilia
dysfunction could be a cause
of congenital conditions,
and characterisation of
the protein components
of cilia, provided a pool of
possible candidate genes
for ciliopathies. This led to
the identification of another
new gene, BBS520. It also
helped Professor Beales
identify mutations affecting
IFT80, a protein involved
in transport of material
along the cilium, as a cause
of juvenile asphyxiating
thoracic dystrophy, where
infants are born with an
underdeveloped ribcage and
other skeletal abnormalities21.
Identification of faulty genes
also enables their function
to be studied in animal
models, shedding new
light on cilia function and
their role in developmental
processes. For example,
they have turned out to be
critical in establishing the
characteristic asymmetry
of human organ systems.
Bardet–Biedl syndrome,
for example, is often
accompanied by a condition
known as situs inversus, in
which the normal asymmetry
is reversed (a condition seen
in Professor Beales’s original
patient). Cell migration
is also often affected,
giving rise to characteristic
craniofacial abnormalities,
as seen in both Bardet–Biedl
syndrome and a related
condition, Hirchsprung’s
disease22. In terms of cell
biology, mutations have
been found to affect at least
two important cell signalling
pathways – the hedgehog
and Wnt 23 pathways.
18 Atkin TA, MacAskill AF, Brandon NJ,
Kittler JT. Disrupted in Schizophrenia-1
regulates intracellular trafficking of
mitochondria in neurons. Mol Psychiatry.
2011;16(2):122–4, 121.
19 Ansley SJ et al. Basal body
dysfunction is a likely cause of
pleiotropic Bardet-Biedl syndrome.
Nature. 2003;425(6958):628–33.
20 Li JB et al. Comparative genomics
identifies a flagellar and basal body
proteome that includes the BBS5 human
disease gene. Cell. 2004;117(4):541–52.
21 Beales PL et al. IFT80, which encodes
a conserved intraflagellar transport
protein, is mutated in Jeune asphyxiating
thoracic dystrophy. Nat Genet.
2007;39(6):727–9.
22 Tobin JL et al. Inhibition of neural
crest migration underlies craniofacial
dysmorphology and Hirschsprung’s
disease in Bardet-Biedl syndrome.
Proc Natl Acad Sci USA. 2008;
105(18):6714–9.
23 Gerdes JM et al. Disruption of the
basal body compromises proteasomal
function and perturbs intracellular Wnt
response. Nat Genet. 2007;39(11):
1350–60.
A section through the retina.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
19
the adult, with cells of the
right type ending up at the
right place at the right time.
Recently, however, there
has been growing interest
in analogous processes
acting in adults. These
exciting developments are
highly relevant to repair and
regeneration but also to
cancer.
The research of Professor
Alison Lloyd centres on
Schwann cells, which form
the insulating myelin sheath
around peripheral nerves.
They have the curious
property of being able
to ‘dedifferentiate’ into a
progenitor state after nerve
damage, and then develop
back into Schwann cells as
nerves regrow (see page 21).
Neural stem cells from the mouse hippocampus.
Although Bardet–Biedl
syndrome is a developmental
condition, an understanding
of its genetic basis opens up
the prospect of interventions
to ameliorate symptoms.
For example, blindness
is progressive, beginning
in early adulthood, and is
caused by gradual loss
of photoreceptor cells
(which are essentially
highly specialised cilia).
It may therefore be
possible to intervene early
in the process, to slow
photoreceptor degeneration
and preserve sight for longer.
Size is important
A central theme in cell
biology, being addressed
by Professor Buzz Baum,
is how cells regulate
their physical size and
appearance. Here again
cytoskeletal components
play pivotal roles.
One important but oddly
neglected question is how
cell size is regulated. Use
of Drosophila cell cultures
and RNA interference has
revealed key signalling
mechanisms involved in this
process24. More recently,
Professor Baum has worked
with nanotechnologists to
20
explore the growth of single
cells along narrow channels,
limiting cell growth to one
dimension. Cells grew to
a characteristic ‘steady
state’ length, governed by
microtubule dynamics25.
By contrast, other work on
polarisation – specialisation
of different ends of a cell –
has implicated actin-based
mechanisms. Columnar
epithelial cells are ideal for
studying such processes.
They consist of sheets
of identical cells whose
basal ends show extensive
protrusions. A combination of
genetics and cell biology has
revealed that this patterning
depends on the creation of a
gradient within the cell, which
inhibits actin polymerisation
except at the basal end of
the cell26.
Professor Baum has also
explored how cellular
interactions generate the
spatial arrangement of
bristles on the surface of
Drosophila – a widely studied
model of pattern formation.
Working with computational
biologists through the
CoMPLEX initiative (see
page 22), he has found
that bristle patterning can
be explained by simple
but dynamic interactions
between two signalling
molecules on epithelial cells.
Bristle formation is known
to depend on signalling
between Delta, present in
membranes, and intracellular
Notch in surrounding cells.
As Notch then inhibits
Delta expression, a pattern
emerges in which Deltaexpressing cells are
surrounded by a doughnut
of Notch-expressing cells.
However, these processes
alone cannot explain regular
bristle patterning. Professor
Baum’s alternative model
introduced cell dynamics,
with cell protrusions making
and breaking contacts
between neighbouring
cells, introducing ‘noise’ into
the system. Live imaging
confirmed dynamic interplay
of cell protrusions27, while
computational modelling
revealed how noise could
promote the appearance
of regular structures28.
Fateful decisions
Developmental biology has
long sought to elucidate
the seemingly miraculous
process by which a single
cell, the fertilised egg, can
generate all the cells of
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Controlled differentiation may
also be important in tissue
repair. Professor Robin Ali,
Dr Rachael Pearson and
colleagues for example, have
identified which particular
photoreceptor precursor
cells are best suited to repair
of the degenerating retina
(see page 21).
24 Sims D, Duchek P, Baum B.
PDGF/VEGF signaling controls cell
size in Drosophila. Genome Biol.
200912;10(2):R20.
25 Picone R et al. A polarised population
of dynamic microtubules mediates
homeostatic length control in animal
cells. PLoS Biol. 2010;8(11):e1000542.
26 Georgiou M, Baum B. Polarity
proteins and Rho GTPases cooperate
to spatially organise epithelial
actin-based protrusions. J Cell Sci.
2010;123(7):1089–98.
27 Cohen M, Georgiou M, Stevenson
NL, Miodownik M, Baum B. Dynamic
filopodia transmit intermittent DeltaNotch signaling to drive pattern
refinement during lateral inhibition.
Dev Cell. 2010;19(1):78–89.
28 Cohen M, Baum B, Miodownik M.
The importance of structured noise in
the generation of self-organizing tissue
patterns through contact-mediated
cell-cell signalling. J R Soc Interface.
2011;8(59):787–98.
A transplanted cell making synaptic contact with a neuron.
Interactions between Schwann cells (blue) and axons (green).
AN EYE CELL FOR AN EYE
THE ROUTE TO NERVE REPAIR
Cell transplantation may be able to repair
a degenerating retina.
The striking regenerative powers of peripheral nerves
depend on a complex cellular conversation.
Progressive loss of retinal cells, a hallmark of several forms of vision
impairment, has long been seen as amenable to cell transplantation
therapy. The retina is relatively accessible and many inherited forms
of degeneration typically affect just photoreceptor cells, leaving the
other components of the visual system intact. Working with mice,
Dr Rachael Pearson, Professor Robin Ali and colleagues have taken
an important step towards demonstrating the feasibility of the cell
transplantation strategy.
Early attempts to replace degenerating rods, using stem cells, met
with little success. Although cells survived, they typically integrated
poorly into the retina and rarely differentiated into rods. Dr Pearson
and colleagues therefore turned to more mature cells, already
destined to become photoreceptors, called photoreceptor precursor
cells. By labelling cells with green fluorescent protein, they were able
to show that cells integrated into the retina of adult mice and took on
the characteristic anatomy of rod cells.
Even more impressively, transplanted cells also integrated into
the retinas of models of inherited retinal degeneration, and in similar
numbers (several hundred cells per eye). Most encouragingly,
electrophysiological measurements and assessment of pupil
responses implied that the new cells were functional and integrated
into surviving neural circuitry.
The key question, of course, is whether the therapy actually
improves vision – and recent results suggest it can. Again working
with a mouse model of retinal degeneration, the group transplanted
far larger numbers of rod precursors – around 200,000 – at the
optimal developmental stage.
The integrated cells were seen to form characteristic synaptic
connections in the retina, while brain imaging revealed that visual
signals were being processed in visual areas of the brain. Most
critically, the performance of animals on visually guided behavioural
tests were markedly improved.
The work therefore suggests that, with the right cell populations,
cell transplantation therapy could ultimately be a viable option for
sight loss due to retinal degeneration. Positive results have now
been obtained with six different models of retinal degeneration,
emphasising the potentially wide applicability of the approach.
Dr Pearson and colleagues are now generating photoreceptor
precursor cells from embryonic stem cells for use in transplants, and
are exploring the possibility of generating cone cells as well as rods.
Although damaged nerves in the central nervous system rarely
regenerate, the peripheral nervous system has markedly better
repair potential. This ability is dependent on Schwann cells, which
form the insulating myelin sheath around peripheral neurons.
But as Professor Alison Lloyd and colleagues have discovered,
coordinated nerve regrowth is a cellular team effort.
Schwann cells are highly unusual in their ability to switch
repeatedly between differentiated and dedifferentiated states.
This property is critical to peripheral nerve repair. If a nerve is
damaged, the ‘downstream’ axon fragment is rapidly degraded.
Its associated Schwann cells, by contrast, slip back into a
progenitor state. Some also begin to migrate into the damaged
area and promote regrowth of the severed axon. As the axon
regrows, it follows the route marked by dedifferentiated Schwann
cells back to its original target tissue.
But Schwann cells are not the only cells at the site of injury.
A whole army of fibroblasts also appear, as might be expected
given their role in wound healing. Could they also be playing
a role in nerve repair?
Growing Schwann cells and fibroblasts in culture, Professor
Lloyd and colleagues noticed an interesting shift in their behaviour.
On their own, cultured Schwann cells normally repel one another,
but with fibroblasts present they showed an uncharacteristic
tendency to clump together.
This behaviour was highly reminiscent of the ‘cell sorting’ seen
in developmental processes, which often involves signalling
molecules known as ephrins. Sure enough, one member of the
ephrin family, ephrin B, was critical for fibroblast–Schwann cell
signalling. This led to relocalisation of a cell adhesion molecule,
N-cadherin, causing the Schwann cells to stick together.
As luck would have it, Professor Lloyd had previously seen
similar clumping behaviour in Schwann cells overexpressing the
stem-cell factor Sox-2. Indeed, relocalisation of N-cadherin in
Schwann cells in response to ephrin signalling was dependent
on Sox-2.
The findings suggest an elegant model in which ephrin signals
from incoming fibroblasts prompt Schwann cells to adhere so they
form tracts or ‘rails’ crossing the site of damage. The regenerating
axon follows these rails, before reaching the dedifferentiated
Schwann cells downstream of the site of damage.
The results suggest ways in which to promote nerve repair but,
potentially, the mechanism could be of wider significance. For
example, cancers derived from Schwann cells, neurofibromas,
can also spread by migrating along nerves, and it will be
interesting to test whether this has any connection with the
mechanisms uncovered in peripheral nerve repair.
MacLaren RE et al. Retinal repair by transplantation of photoreceptor
precursors. Nature. 2006;444(7116):203–7.
Pearson RA et al. Restoration of vision after transplantation of photoreceptors.
Nature. 2012;485(7396):99–103.
Barber AC et al. Repair of the degenerate retina by photoreceptor
transplantation. Proc Natl Acad Sci USA. 2013;110(1):354–9.
Parrinello S et al. EphB signaling directs peripheral nerve regeneration
through Sox2-dependent Schwann cell sorting. Cell. 2010;143(1):145–55.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
21
CoMPLEX (Centre for Mathematics and Physics in the Life
Sciences and Experimental Biology) aims to bridge the gap
between biology and medicine and the physical sciences.
COMPLEX: A MODEL
FOR INTERDISCIPLINARY
RESEARCH
Physics, mathematics and
computing have never
been so important in life
science research. As well
as theoretical insight, the
physical sciences generate
invaluable experimental tools
for capturing and analysing
data, while mathematical
and computational modelling
are finding widespread
application across biology.
To promote such fruitful
interactions, UCL’s CoMPLEX
initiative aims to build links
between biology and the
physical sciences – defined
broadly to include physics,
chemistry, engineering,
mathematics and computing
– primarily by training a
cohort of researchers who
go on to work as integrated
members of life science
research groups.
At the heart of CoMPLEX is
a four-year PhD programme,
launched in 1998, making
it one of the UK’s first.
Students spend an MRes
year on intensive courses
to build their biological
knowledge, undertake three
mini-projects, and finish with
a summer-long research
project. Throughout, there
is a strong emphasis on
modelling. The experience
not only develops students’
skills but also enables them
to make a more considered
decision about their threeyear PhD project.
22
A critical aspect of this
training is exposure to
collaborations between
life science and physical
sciences researchers.
In particular, these
presentations are a ‘pitch’
to attract CoMPLEX
students for PhD projects,
during which students are
jointly supervised by both
life science and physical
science researchers.
The aim is to ensure that
students are not just ‘hired
hands’ brought in to do the
tricky technical stuff but
make a genuine intellectual
contribution to a group’s
work.
Competition for places is
fierce. More than 40 per cent
have a first class degree
and almost 25 per cent have
already achieved a master’s
with distinction. Similarly,
CoMPLEX students are
highly prized. Less than 20
per cent of suggested PhD
projects are accepted, so
supervisors have to offer
appealing projects to attract
students.
Launched internally in 1998,
CoMPLEX successfully
applied for funding from the
Engineering and Physical
Sciences Research Council
(EPSRC) to expand in 2003.
Support was renewed in
2008 and additional funding
has been obtained from the
British Heart Foundation and
others. Around 18 students
are now enrolled each year.
CoMPLEX is part of an
interdisciplinary collaboration
with the University of Oxford
and Microsoft Research
which has been awarded
£6m EPSRC ‘landscape
funding’ for postdoctoral
research training in
computational modelling.
A further £1m which has
been awarded by the BBSRC
to a collaboration involving
CoMPLEX, the Open
University, Edinburgh and
Birkbeck for an e-learning
resource in systems biology.
The subjects being tackled
by CoMPLEX students are
remarkably diverse, from the
systems biology of the liver to
the origins of life. CoMPLEX
students also contributed
to several projects featured
in the publication, including
Dr Josef Kittler’s work on
neurotransmitter receptors
(see page 18), Professor
Buzz Baum’s modelling of
cellular interactions (see
page 20) and Professor
Roberto Mayor’s analysis of
neural crest cell migration
(see page 26).
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Fluorescence lifetime imaging
of NADH in cultured cells.
WORKING IT OUT TOGETHER
Siân Culley is in the first year of her PhD, having
specialised in the highly unusual combination of
cell biology and particle physics in her degree:
“I enjoyed those two things and luckily there were
things I could do with it!” Her degree exposed her
to laser technology and, after further experience
during her MRes, this is the subject of her
PhD. She is working on new methods of superresolution fluorescence microscopy, to improve
resolution from around 200 nm – determined by
the wavelength of light – to, hopefully, a few tens
of nanometres or even lower.
Despite the breadth of her earlier studies, the
MRes was challenging: “It’s sometimes quite
tricky. But because everyone comes from such
a wide range of backgrounds, if you’re stuck
on something they’ll be someone you can ask.
There’s a very community-based feeling.”
A desire to improve his mathematical skills was
a key motivation for Nicolas Jaccard, who
joined CoMPLEX after a degree in biotechnology
engineering in Switzerland. Being new to UCL,
he has appreciated the extensive contact with
UCL researchers. “What really attracted me
was the chance to meet all these UCL PIs and
supervisors, because it can be very difficult if
you are new. It’s a giant network you build in
your first year.”
Now in the second year of his PhD, he is
exploring ways to culture stem cells in reactors
– which he has himself modelled, designed and
built. The emphasis of his work has shifted to
image processing, driven by the need to find new
ways to monitor cells in the specialised reactors.
Having actively sought out UCL’s biochemical
engineering department, he has also helped
to bring them into the CoMPLEX fold.
As well as scientific development, he is
also appreciated the emphasis on generic
skills training, such as scientific writing and
presentation skills. “By the time you come to do
your PhD you already know these things, so you
can concentrate on your science. You’re much
more efficient in your first few months.”
Tom Blacker was one of the many CoMPLEX
students arriving with little background in the life
sciences, after a physics degree at Exeter. The
MRes course was an ideal transition. “It’s a crash
course in biology – you’re thrown in at the deep
end. The nice thing is they get in lecturers from
all around UCL. We’d been doing biology for
a month and were getting lectured to by these
real authorities.”
For Tom, with an interest in the life sciences
but unsure where to focus, CoMPLEX was the
ideal course. “CoMPLEX offered this array of
collaborations, and you get a chance to sample
them all. You get a chance to dip in and see what
you like. You can find your own niche in that
interface between the physical and life sciences.”
For his PhD, he is applying ultra-fast laser
techniques to analyse metabolism in living tissues.
He has also found the interdisciplinarity
challenging. “It’s tough but exciting. You worry
about becoming a jack of all trades because you
want to be a master of both.” The dual supervisor
approach has been essential, he suggests:
“You are properly embedded in two labs. You’re
really exposed to the way of working in both labs.”
For Lewis Dartnell, CoMPLEX has been
a springboard to academic success. After
completing his PhD he obtained a postdoctoral
position in UCL’s Institute of Origins and is now
hoping to secure a fellowship position. In his
MRes year, one of his mini-projects, on cancer
gene networks, led to an academic paper. And the
write up of his summer project, which suggested
that the remarkable dynamic stripes of cuttlefish
are used to create an optical illusion and confuse
their shrimp prey, earned him second place in
a Daily Telegraph science writing competition.
His Biological Sciences degree from Oxford
provided him with an excellent grounding but
CoMPLEX was still, he suggests, “a baptism
of fire: you’re expected to teach yourself an
enormous amount of stuff off your own back.
But it’s done in a very constructive way and
you do get a lot of support.”
Fascinated by the possibilities of life elsewhere
in the universe, he has gone on to establish
a niche in the emerging area of astrobiology.
As well as exploring how ‘extremophiles’ from the
most inhospitable regions of Antarctica respond
to ionising radiation, he has also studied ways
to detect the chemical ‘biosignatures’ that would
indicate the past existence of life. “It’s a great
time to be a young scientist in this field, surfing
the wave.”
He too was struck by the course’s supportive
community spirit. “There isn’t an element of
competition in projects – everyone helps each
other as much as they can. It’s a great learning
experience.”
Victor Sojo arrived at CoMPLEX after a degree
in chemistry and a master’s in computer science,
both undertaken in Venezuela. His aim was to find
a broadly based course where he could hone his
mathematical skills. “It’s been challenging,” he
admits, “but it’s what I came here for. I knew what
I was letting myself in for!” Again, the support of
fellow students has been a tremendous benefit.
“They have no problem sharing everything they
discover as they go along.”
Still early in his MRes studies, Victor is not
sure of his final specialisation, though he knows
it will involve some aspect of evolution and
the ‘big questions’ – where did life come from,
why did sex evolve, how did human behaviours
evolve? His wide range of skills should ultimately
provide a good grounding. “When they hear what
I’ve studied, some people say ‘that’s a crazy
background’. Here, they say ‘that’s really cool,
that’s just what we need’.”
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
23
SECTION 3
BUILDING TISSUES
Developmental processes sculpt collections of cells
into complex and beautiful forms. The mechanisms
underlying these processes, and the genetic
programmes that control them, are beginning
to be identified in a range of model organisms.
Cross-section through a teratoma.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
24
Mitochondria in heart muscle and endothelial cells.
In some of the most
famous experiments in
developmental biology,
during the 1920s Hans
Spemann and Hilde Mangold
showed that certain regions
of an embryo could, when
transplanted into a different
embryo, direct the formation
of well-organised new
tissues. Spemann called
these regions ‘organisers’,
and the amphibian structure
is known as Spemann’s
organiser in his honour.
Despite this insight, the exact
nature of organisers were
unclear until new molecular
and genetic techniques
enabled molecules and
genes with organising
powers to be identified.
Pulling the nanostrings
The organiser experiment
illustrated the principle of
‘induction’, the power of
certain cells to ‘induce’ new
structures. In vertebrates,
transfer of the organiser
(‘Hansen’s node’) can
generate a complete new
nervous system. As well
as important work on the
mechanisms controlling
axis development and
The exact nature of organisers were unclear until
new molecular and genetic techniques enabled
molecules and genes with organising powers to
be identified.
cell migration during
embryogenesis, Professor
Claudio Stern has spent
several decades identifying
molecules involved in this
remarkable process (see
page 26).
Although initially thought to
be driven by a single signal,
it is now becoming clear that
the real situation is far more
complex, involving many
genes and at least three
external signals. An analysis
of the times at which genes
are active has begun to
suggest how they may act
together. Professor Stern is
now taking this a step further
to see how changes in the
activity of genes affects
others in the network, using
‘NanoString’ technology
to map changes in the
expression of hundreds of
key genes at high resolution.
Working with computational
biologists, he is developing
integrated models of how
the genetic regulatory
network coordinates the
complex dynamics of cell
fate decisions underpinning
neural identity.
An interesting new area
of work, on the genetic
mechanisms influencing
twinning, has emerged
from past studies on axis
formation. Lower organisms
specify axes – front and
back, left and right – very
early in development, often in
the egg itself. In vertebrates,
however, axes appear much
later. One consequence
of this is that embryos can
divide surprisingly late in
development, giving rise to
identical twins. Remarkably,
a chick embryo made of
50 000 cells can be split
into two and give rise to two
entirely normal adults.
To identify genetic influences
on this process, Professor
Stern will combine work
on chick development with
analyses of the armadillo
which, uniquely, creates
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
25
Collective migration of cultured Xenopus neural crest cells (red).
Xenopus frog embryo, four-cell stage.
PRENATAL ATTRACTION
BERT AND ERNI BUILD A NERVOUS SYSTEM
An apparently paradoxical mix of attraction and repulsion
can drive migrating cells towards the correct destination.
A complex cascade of signalling directs the formation
of the nervous system.
Building an embryo depends on the highly coordinated migration
of cells, notably from a structure known as the neural crest.
Understanding how cells swarm en masse to the correct location
has long intrigued researchers, and its similarities to the migration
of cancer cells during metastasis makes it of considerable
medical importance. Combining studies of frog and fish embryos
with mathematical modelling, Professor Roberto Mayor and
colleagues have found that collective migration of neural crest
cells can be explained by comparatively simple reciprocal
signalling between cells.
Migrating cells in culture have long been known to show
repulsive behaviour when they meet each other. This ‘contact
inhibition of locomotion’ was first described more than half
a century ago by Michael Abercrombie, who worked in the
laboratory space now occupied by Professor Mayor’s group.
Professor Mayor has shown that contact inhibition of
locomotion also occurs in vivo, and enables cells to respond to
chemoattractants. This chemotaxis seems to be dependent on
the stabilisation of cell protrusions specifically in the direction
of a chemical gradient.
One issue with contact inhibition of locomotion is that, by
itself, it would be predicted to lead to cell dispersal. Yet when
cultured in vitro, neural crest organise themselves into packs
and migrate en masse. Perhaps, Professor Mayor hypothesised,
repulsive forces were being counterbalanced by attractive forces.
In support of this idea, a simple computer model incorporating
repulsion and attraction recreated cohesive directed locomotion
along a channel bordered by ‘no-go’ areas.
What might be responsible for the attractive forces? Looking
for genes for secreted proteins expressed in migrating cells,
Professor Mayor hit upon an excellent, albeit unexpected
candidate: the complement protein C3, which is cleaved to create
a peptide with known chemoattractant properties. Crucially,
migrating (but not stationery) neural crest cells also express the
receptor for C3. Furthermore, blocking interactions between the
two abolished the ability of neural crest cells to move as a pack.
Individual cells do have the capacity to migrate directionally.
But the addition of an attractive interaction, and consequent
group migration, seems to increase considerably the efficiency of
directed locomotion. Moreover, the principles are strikingly similar
to those governing swarming behaviour in many other organisms,
from bacteria to starlings. The simple combination of repulsion
and attraction may thus be an overarching principle for achieving
group coordination of locomotion in biological systems across
multiple scales.
In 1924, Spemann and Mangold’s landmark experiments revealed
that a small region of tissue transplanted into another embryo could
induce the development of a complete new nervous system. Many
years later, the view emerged that the transplanted ‘organiser’ only
needed to inhibit a protein known as BMP, which stopped cells from
developing along a default neural pathway. More than a decade’s
work in Professor Claudio Stern’s laboratory has not only shown that
this is an oversimplification but also identified a host of factors that
form part of a complex regulatory network controlling early nervous
system development.
An early sign that BMP was not the complete picture came from
work showing that a recipient embryo’s cells became sensitive to
BMP inhibition only after five hours’ exposure to a graft. During
this period, something must be happening to cells to render them
responsive to BMP inhibition. To find out what, Professor Stern
screened for genes that were active specifically during this early time
window. Extensive follow-up of a dozen genes identified has begun
to reveal the complex genetic circuitry controlling neural induction.
An exciting early discovery was a gene called ERNI (early
response to neural induction). As well as being switched on very
early, its site of expression suggested it was being regulated by
FGF8. Several other pre-BMP genes turned out to be activated by
FGF8, implicating it as a critical early factor in neural induction.
A second gene, Churchill, which codes for a zinc finger protein,
plays a critical role in specifying which cells exposed to FGF8 –
a widely used signalling molecules – will contribute to the nervous
system and which will give rise to other tissues. Churchill may also
be part of the system that controls responsiveness to BMP.
Recent studies have begun to characterise the remaining genes
identified in the screen, including a previously known gene (TrkC,
encoding a nerve growth factor receptor) and two new genes, Asterix
and Obelix. Notably, the times at which genes are switched on during
normal neural induction revealed three waves of gene expression.
Significantly, the analyses suggest that, as well as FGF8, at least
two other signals must be driving the expression of key genes and
defining which cells will give rise to the nervous system during
development. Thus even this complex temporal programme of gene
activity does not tell the full story of neural induction.
Carmona-Fontaine C et al. Contact inhibition of locomotion in vivo controls
neural crest directional migration. Nature. 2008;456(7224):957–61.
Theveneau E et al. Collective chemotaxis requires contact-dependent cell
polarity. Dev Cell. 2010;19(1):39–53.
Streit A et al. Initiation of neural induction by FGF signalling before
gastrulation. Nature. 2000;406(6791):74–8.
Sheng G, dos Reis M, Stern CD. Churchill, a zinc finger transcriptional
activator, regulates the transition between gastrulation and neurulation. Cell.
2003;115(5):603–13.
Papanayotou C et al. A mechanism regulating the onset of Sox2 expression
in the embryonic neural plate. PLoS Biol. 2008;6(1):e2.
Pinho S et al. Distinct steps of neural induction revealed by Asterix, Obelix
and TrkC, genes induced by different signals from the organizer. PLoS One.
2011;6(4):e19157.
Carmona-Fontaine C et al. Complement fragment C3a controls mutual cell
attraction during collective cell migration. Dev Cell. 2011.
26
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
four identical offspring from
each fertilised egg. He will
also investigate a human
population from Nigeria with
a high incidence of twins and
conjoined twins, to identify
possible genetic causes.
A connected programme of
work is focused on cultured
chick embryonic stem cells.
In part, this is to gain a better
understanding of these
cells, which appear to be
surprisingly heterogeneous,
showing marked variation
in gene expression and
significant differences
from bona fide embryonic
stem cells. In addition,
they also provide a way to
explore the developmental
effects of programmes of
gene expression. If key
genes are identified in
other studies, the cells will
provide a ‘blank slate’ for
assessing the developmental
consequences of gene
activity.
Professor Stern has also
explored the migration
of neural crest cells, in
collaboration with Professor
Roberto Mayor. The striking
collective migration of cells
is reminiscent of swarming
behaviour seen at all scales
from bacteria to flocks of
locusts and birds. Indeed,
computational modelling
suggests that relatively
simple principles can
generate this swarming
behaviour. Professor Mayor
has identified some of
the molecules involved in
coordinated migration of
amphibian neural crest cells
(see page 26).
Curiously, this work
implicated components of
the complement system
in development – as did
Professor Philip Beales’
entirely independent work on
rare human developmental
conditions (see page 18).
The processes that build a chick or a frog are
more or less the same as those that build a
human baby.
These processes are of
more than academic interest.
The processes that build a
chick or a frog are more or
less the same as those that
build a human baby. If the
developmental programme
does not play out correctly,
a child may be born with
significant physical or
mental abnormalities, as
well illustrated by Professor
Beales’ work on ciliopathies.
Similarly, problems with
neural tube development can
have serious consequences.
More than a decade ago,
Professor Andrew Copp
identified problems with
folate metabolism leading
to non-closure of the neural
tube as a possible cause
of spina fida. His group
has gone to provide further
insight into the mechanisms
of neural tube closure in
experimental models.
Fishing for clues
Over the past decade,
Professor Steve Wilson
has put together one of
Europe’s largest zebrafish
labs. For developmental
biology, zebrafish have
many advantages. They
are easy to grow, they can
be manipulated genetically
and, because their embryos
are transparent, tissue
development is easier to
visualise. Furthermore,
being vertebrates, their
developmental processes
resemble those seen in
humans.
Ovaries of the fruit fly, Drosophila melanogaster.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
27
Confocal image of four-day-old zebrafish visual system.
Salamanders are well known for their unique
ability to regenerate limbs and tails. This striking
ability extends to other tissues, including jaws,
eyes, intestine and even parts of the heart.
Among several areas of
research, Professor Wilson
has examined various
stages of eye development.
These include some of the
earliest signals regulating
eye formation, which has
revealed a key role for
Wnt signalling in defining
areas that will give rise to
the adult eye29.
Other work has focused
at later stages and the
development of the retina.
Of particular interest are
the events that lead to the
sealing of the spherical
eyeball (see page 29).
Professor Wilson also has a
growing interest in stem cells
in the eye, and coordination
of cell division and
differentiation. In the flotte
lotte mutant, for example,
retinal progenitor cells
continue to divide but fail to
28
differentiate into neurons.
However, when transplanted
next to functioning retinal
neurons, they are induced to
differentiate. Hence neurons
seem to provide a signal that
can overcome the defect
in cell cycle progression.
The work highlights the
importance of stem cell
niches and external signals in
regulating progenitor cells30.
To find out more about
the genes involved in this
regulation, and in other
aspects of eye development,
Professor Wilson’s group
is currently undertaking a
large-scale screen, mutating
genes throughout the
zebrafish genome. He is also
collaborating with medically
oriented groups keen to
understand more about the
function of disease genes.
Hail the salamander
Salamanders are well known
for their unique ability to
regenerate limbs and tails.
This striking ability extends to
other tissues, including jaws,
eyes, intestine and even
parts of the heart. Given how
useful organ regeneration is,
its existence within just one
family is perhaps surprising.
The standard evolutionary
argument is that regeneration
was the ancestral state
but has been lost in most
organisms, perhaps
because of accompanying
disadvantages such as
increased risk of cancer.
The question is of more
than academic interest:
salamanders could be
a source of insight and
inspiration for the burgeoning
field of regenerative
medicine.
Professor Jeremy Brockes
was drawn to this fascinating
issue through one of its
other unusual features. For
nearly 200 years – since the
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
29 Cavodeassi F et al. Early stages
of zebrafish eye formation require the
coordinated activity of Wnt11, Fz5, and
the Wnt/beta-catenin pathway. Neuron.
2005;47(1):43–56.
30 Cerveny KL et al. The zebrafish flotte
lotte mutant reveals that the local retinal
environment promotes the differentiation
of proliferating precursors emerging
from their stem cell niche. Development.
2010;137(13):2107–15.
Limb regeneration in the newt.
The zebrafish eye.
A SALAMANDER SPECIALITY
MIND THE GAP
Salamanders’ remarkable ability to regrow their limbs may
be something they alone have evolved, rather than being
a general capacity lost by other vertebrates.
Probing the mechanisms of fish eye development may
shed light on the origins of human eye abnormalities.
If a salamander loses a limb to a predator, it can grow an almost
perfect replacement. As well as its intrinsic biological interest, the
process has also been seen as potentially relevant to regenerative
medicine. But, the work of Professor Jeremy Brockes and colleagues
suggests, limb regeneration depends in part on components that are
unique to salamanders.
At least two features of salamander limb regeneration are notable.
First, regrowth matches perfectly the amount of limb lost: if a limb is
severed at the shoulder, an entire new arm develops; if it is cut at
the wrist, just a hand is formed. Secondly, regeneration depends on
a regrowing nerve. If the nerve is transected at the base of the limb,
no regrowth occurs. In an elegant series of studies, Professor
Brockes has been able to tie seemingly unrelated aspects of this
mechanism together.
Patterning of salamander limbs is known to respecified in a
graded manner by retinoic acid. A search for genes whose activity
was regulated by retinoic acid led to the identification of Prod1, a
cell-surface protein, as a key factor in salamander limb patterning.
Further, a screen for factors interacting with Prod1 identified its
ligand – nAG (newt anterior gradient).
Moreover, nAG had some very interesting properties. It is made
by Schwann cells that encapsulate the regenerating nerve and at
later stages in groups of cells in the specialised wound epidermis
at the end of the stump. Most significantly, even in the absence of
a redeveloping nerve, nAG on its own can drive the regeneration
of an entire limb. Hence nAG is responsible for nerve dependency.
The evolutionary significance of salamander limb regeneration
has long been contentious. It is often assumed to be an ancestral
trait that has been preserved in salamanders but lost in other
vertebrate species with limbs. However, Professor Brockes’s studies
with Dr Acely Garza-Garcia at the National Institute for Medical
Research, Mill Hill, suggest that Prod1 is a salamander invention –
no homologues exist in other species. These remarkable
regenerative powers therefore may have evolved in salamanders.
Although the results are significant for regenerative medicine, they
do not support the idea that humans have a dormant ‘regenerative’
programme that could be reactivated to enable us to mimic the
salamander’s skills.
One of the advantages of research on zebrafish is the immediate
relevance to human biology. Discoveries made in fish may give
clues to mechanisms of disease in people and, conversely, the
function of genes causing medical conditions can be explored in
fish. Professor Steve Wilson’s work on eye development illustrates
this two-way flow.
An area of particular interest is the closure of the choroid fissure
– a channel at the bottom of the eye that allows blood vessels and
nerves to enter and exit the developing eye. Eventually, the fissure
must be sealed to create the spherical eyeball, a process that
requires carefully coordinated cell migrations. Occasionally, the
fissure does not close completely, leading to the condition known
as ocular coloboma, a rare congenital eye condition.
Professor Wilson has been attempting to identify the genetic
factors controlling the closure of the choroid fissure. Although it is
known to depend on retinoic acid receptor signalling, the cellular
targets and genetic programmes activated have proven hard to
identify. Recently, in contrast to previous studies, his group has
shown that there are actually two populations of cells affected by
retinoic acid receptor signalling. Furthermore, markedly different
sets of genes are activated in the two populations, suggesting two
independent processes are at work to close the fissure. Potentially,
these genes could be involved in ocular coloboma.
In other work Professor Wilson has collaborated with clinical
ophthalmologist Dr Nicky Ragge to investigate the genetic basis
of branchio-oculo-facial syndrome (BOFS), a severe congenital
condition affecting the face and eyes. Mutations affecting the
TFAP2 transcription factor can cause this condition in humans, and
blocking the function of the equivalent gene in fish leads to similar
abnormalities, including coloboma. What has been less clear is why
the severity of the defects varies so widely among BOFS patients.
Professor Wilson’s team showed that, if the function of TFAP2
is partially reduced, this makes fish embryos much more
susceptible to the effects of other genetic mutations affecting eye
development. On their own, these mutations might have no obvious
consequences but when they occur in embryos with compromised
TFAP2 function, they lead to coloboma or even loss of the eyes
altogether. The presence or absence of similar genetic variants
in humans could explain why individuals have very different
susceptibility to defects in TFAP2.
da Silva SM, Gates PB, Brockes JP. The newt ortholog of CD59 is implicated
in proximodistal identity during amphibian limb regeneration. Dev Cell.
2002;3(4):547–55.
Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP. Molecular
basis for the nerve dependence of limb regeneration in an adult vertebrate.
Science. 2007;318(5851):772–7.
Garza-Garcia A et al. Solution structure and phylogenetics of Prod1,
a member of the three-finger protein superfamily implicated in salamander
limb regeneration. PLoS One. 2009;4(9):e7123.
Lupo G et al. Retinoic acid receptor signaling regulates choroid fissure
closure through independent mechanisms in the ventral optic cup
and periocular mesenchyme. Proc Natl Acad Sci U S A. 2011;108(21):
8698–703.
Gestri G et al. Reduced TFAP2A function causes variable optic fissure
closure and retinal defects and sensitizes eye development to mutations
in other morphogenetic regulators. Hum Genet. 2009;126(6):791–803.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
29
Synapses on hippocampal neurons.
Artificially coloured carbon nanotubes.
WNTS BUILD A SYNAPSE
CATCH THE TUBE
Wnt signalling has a surprising role to play in strengthening
synaptic connections.
Carbon nanotubes are exciting new tools with many
potential applications in biomedicine.
The Wnt cell signalling pathway is one of the most widely studied in
biology. It has been implicated in an enormous diversity of biological
processes, during development and in adult organisms. In part, this
flexibility arises from the variety of both Wnt signalling proteins –
around 20 in humans – and Wnt receptors. Wnt proteins repeatedly
turn up in key biological processes, and Professor Patricia C
Salinas and colleagues have recently added another – control of
synaptic strength.
Wnt signalling is well known to be critical to development of
the embryonic nervous system and to the formation of synaptic
connections. The latest work suggests that Wnt proteins can
also modulate the strength of connections after they have been
established.
In 2005 Professor Salinas showed that one particular Wnt
protein, Wnt7b, promoted the formation of new dendrites in cultured
hippocampal cells. Furthermore, this effect depended on a
specific signalling pathway, through the scaffold protein known as
Dishevelled (Dvl). Later work in knockout mice revealed that Wnt7a
promoted fine modelling of complex synapses in the cerebellum,
again by acting through the Dvl pathway.
Recent work has expanded on these findings. In particular, Wnt7a
appears to be playing a significant role in ‘synaptic plasticity’ –
changes in the properties of synapses after they have transmitted
a signal, an important factor in learning and memory.
During the formation of new synapses in the mouse hippocampus,
Wnt7a signalling was found to be dependent on the Wnt receptor,
Frizzled-5 (Fz-5). Furthermore, neuronal activity led to increased
numbers of Fz5 receptors at the synapse, enhancing Wnt signalling.
Interestingly, Wnt7a appears to enhance connections at
excitatory but not inhibitory synapses (at the latter, neurotransmitter
release inhibits rather than activates neurons). These effects at
excitatory synapses depended on calcium signals and the calcium/
calmodulin-dependent protein kinase II, which had previously been
implicated in modulation of synaptic strength.
The results suggest that Wnt7a, unlike other Wnt proteins,
promotes the formation of just certain types of synapse. Potentially,
abnormal Wnt function could therefore contribute to conditions in
which the balance between excitatory and inhibitory signalling is
disturbed, such as epilepsy.
First rising to prominence in the 1990s, carbon nanotubes consist of
sheets of carbon atoms rolled up into tubes just a nanometre or so in
diameter. Among their many possible uses is as a delivery platform
for therapeutic agents – an area where Professor Kostas Kostarelos
and colleagues have generated highly promising results.
Although pure carbon nanotubes are insoluble, they can be
chemically modified to increase their solubility. They can also have
biologically active molecules chemically attached to them – anything
from anti-cancer drugs to DNA for gene therapy.
Crucially, such ‘functionalised’ carbon nanotubes offer
advantages over existing delivery technologies. In 2007, Professor
Kostarelos and colleagues found that, although some nanotubes are
taken up by standard endocytotic mechanisms, others penetrate the
membrane directly, acting as a kind of ‘nano-syringe’. This would
allow material to be delivered directly into the cytoplasm – one of
the major challenges in cell engineering.
This advantage is tempered somewhat by difficulties in targeting
– receptor–ligand binding tends to promote endocytosis rather than
direct entry. So Professor Kostarelos has looked for applications
where biochemical targeting is not required, with a focus on ‘small
interfering RNAs’ (siRNAs) to silence the expression of target genes.
One exciting possibility is delivery of siRNA to localised areas
of the brain. In rodent models of stroke, for example, the approach
has been used to inhibit programmed cell death after oxygen
starvation, thereby limiting tissue damage and promoting recovery.
And in Parkinson’s disease, surgical techniques could be used to
deliver siRNA directly to the dopamine-containing cells affected
in the condition – a strategy being explored in collaboration with
neurosurgeon Professor Marwan Hariz at the Institute of Neurology.
It remains early days for nanotube-based therapeutics. In the
long term their clinical use will hinge on safety as well as efficacy, so
Professor Kostarelos is also studying the fate of carbon nanotubes
within the cell and in body tissues. With extensive programmes in
nanoscale delivery systems, he also aims to convince others of their
enormous potential. One possible use is the reprogramming of cells
into a pluripotent state, bringing carbon nanotube technologies into
the burgeoning area of cellular engineering.
Rosso SB, Sussman D, Wynshaw-Boris A, Salinas PC. Wnt signaling
through Dishevelled, Rac and JNK regulates dendritic development. Nature
Neurosci. 2005;8(1):34–42.
Ahmad-Annuar A et al. Signaling across the synapse: a role for Wnt and
Dishevelled in presynaptic assembly and neurotransmitter release. J Cell
Biol. 2006;174(1):127–39.
Sahores M, Gibb A, Salinas PC. Frizzled-5, a receptor for the synaptic
organizer Wnt7a, regulates activity-mediated synaptogenesis. Development.
2010;137(13):2215–25.
Ciani L et al. Wnt7a signaling promotes dendritic spine growth and synaptic
strength through Ca² +/Calmodulin-dependent protein kinase II. Proc Natl
Acad Sci U S A. 2011;108(26):10732–7.
30
Kostarelos K et al. Cellular uptake of functionalized carbon nanotubes
is independent of functional group and cell type. Nature Nanotechnol.
2007;2(2):108–13.
Al-Jamal KT et al. Functional motor recovery from brain ischemic insult
by carbon nanotube-mediated siRNA silencing. Proc Natl Acad Sci USA.
2011;108(27):10952–7.
Nunes A et al. In vivo degradation of functionalized carbon nanotubes after
stereotactic administration in the brain cortex. Nanomedicine (Lond). 2012
[Epub ahead of print].
Singh R et al. Tissue biodistribution and blood clearance rates of
intravenously administered carbon nanotube radiotracers. Proc Natl Acad
Sci USA. 2006;103(9):3357–62.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Confocal microscope image of a section of the cochlea.
pioneering studies of Tweedy
John Todd in the 1820s –
it has been known that limb
regeneration is dependent
on nerve regrowth. In recent
years Professor Brockes has
been able to tie together
this dependency with the
uncannily accurate regrowth
of limbs, by which only the
structures that have been lost
are regenerated (see page
29). The paper describing
the remarkable discovery
that a single molecule, nAG,
could substitute for the
presence of a nerve, and
drive the development of an
entire new limb, was winner
of the 2008 AAAS Newcomb
Cleveland Prize, awarded
to the ‘outstanding’ paper
published in Science
each year.
What are the implications
of these findings for our
understanding of evolution
and for regenerative
medicine? The fact that
the key mediator, Prod1,
is a salamander-specific
protein strongly suggests
that salamanders have
evolved some aspects of
the mechanisms of limb
regeneration, and these
have not been lost by
Neurons in the zebrafish brain.
other organisms. Professor
Brockes has continued
to uncover some of the
molecular mechanisms
driving this process,
including ‘upstream’
factors regulating Prod131
and Prod1’s downstream
targets32. He also found
that regulation of nAG
expression by the nerve
in limb development can
explain why, under certain
experimental conditions, limb
regrowth can occur in the
absence of innervation33.
Regeneration thus appears
to be a complex, highly
regulated process. It is also
not simply a reactivated
embryonic developmental
pathway. Similarly, the
blastema, the mass of cells
that develops at the site
of injury and gives rise to
the new limb, is a highly
specialised structure,
not simply a collection of
reprogrammed stem cells.
Nothing like it has been seen
in mammals.
into the systems-level
specification of complex new
tissue, in adults, will surely be
of value to those working in
regenerative medicine.
A recurring feature in
developmental biology
is the reappearance of
key proteins, or families
of proteins, in a range of
different developmental
context. A classic example
is the Wnt family of proteins.
As well as having multiples
roles in the initial wiring
of the nervous system,
Professor Patricia Salinas
has uncovered a further
neurobiological role for Wnt
proteins – strengthening
synaptic connections after
nerve transmission, a key
process in neural plasticity
and hence learning and
memory (see page 30).
31 Shaikh N, Gates PB, Brockes JP.
The Meis homeoprotein regulates the
axolotl Prod 1 promoter during limb
regeneration. Gene. 2011;484
(1-2):69–74.
32 Blassberg RA et al. Functional
convergence of signalling by GPIanchored and anchorless forms of a
salamander protein implicated in limb
regeneration. J Cell Sci. 2011;124
(Pt 1):47–56.
33 Kumar A et al. The aneurogenic
limb identifies developmental cell
interactions underlying vertebrate limb
regeneration. Proc Natl Acad Sci USA.
2011;108(33):13588–93.
Thus salamander limb
regeneration is unlikely
to translate directly to
regeneration in people.
Nevertheless, insights
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
31
SECTION 4
ALL SYSTEMS GO
Reductionist approaches have
dominated science for the past century.
Yet biology is dominated by complex
dynamic systems, and biological
problems are increasingly being
analysed at a systems level.
Calcium signalling in a spinal motoneuron culture.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
32
Confocal microscope image of rat cerebellum (red: blood vessels; green: neurons).
The biochemical advances
of the mid-20th century
revealed complex metabolic
pathways such as the iconic
Krebs cycle. The late 20th
century saw a surge of
interest in cell signalling,
generating equally complex
pathways and networks.
A growing quest is to
understand not just how a
pathway operates in isolation
but also how it fits into
the greater systems-level
understanding of the cell.
A systems view
of the cell
A good place to apply
integrative, systems-based
approaches is in singlecelled organisms. The
best-known single-celled
eukaryotic models are the
yeasts, and Professor Jürg
Bähler is using one such
organism – fission yeast,
Schizosaccharomyces
pombe – with the ambitious
long-term aim of developing
a complete systemslevel understanding of its
behaviour.
S. pombe was first extracted
from East African beer at
the end of the 19th century
S. pombe was first extracted from East African
beer at the end of the 19th century (‘pombe’ is
Swahili for beer).
(‘pombe’ is Swahili for beer).
Its genome has been fully
sequenced, and its 14 million
base pairs contain around
5000 genes. Although
sharing part of its name with
the other main model yeast,
Saccharomyces cerevisiae
(brewer’s yeast), the two
actually have little in common
– they probably diverged
around half a billion years
ago – and in several ways
S. pombe is a better model
of mammalian systems.
As well as a complete
genome sequence, genetic
tools are available to modify
S. pombe genes. It grows
easily and rapidly in the lab,
and is thus well suited to
large-scale studies of gene
expression. Professor Bähler
is particularly interested in its
responses to external stress,
such as nutrient limitation.
It is already clear that
control of gene expression
in S. pombe is enormously
complex. Although recent
decades have been
dominated by studies of
protein transcription factors,
they are only a small part
of the story. Regulation is
also happening at the RNA
level. The amount of DNA
transcribed far exceeds that
coding for proteins, and it
will be a major challenge to
determine the role of noncoding RNAs (or perhaps,
more accurately, non-protein
coding RNA) in control
of gene activity and cell
behaviour.
As well as environmental
stress, Professor Bähler has
a growing interest in ageing.
Cellular pathways affecting
ageing are beginning to be
discovered (see page 37),
and S. pombe is a valuable
model in which to investigate
them. These studies will take
advantage of new work on
120 natural S. pombe isolates
collected from 20 countries.
Fission yeast strains show
natural variation in lifespan,
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
33
Fission yeast, Schizosaccharomyces pombe.
Levels of the gut hormone PYY affect food intake.
THE HARD CELL
FOOD ON THE BRAIN
Fission yeast, Schizosaccharomyces pombe, is an
ideal organism in which to investigate control of gene
expression across the entire genome.
The gut hormone PYY may be the key to weight control.
Wilhelm BT et al. Dynamic repertoire of a eukaryotic transcriptome surveyed
at single-nucleotide resolution. Nature. 2008;453(7199):1239-43.
Weight control reflects a deceptively complex integration of multiple
inputs. At its heart lies the body’s energy balance, which matches
food intake with energy usage. Overlaying these homeostatic
mechanisms are complex psychological influences that can affect
food intake. In today’s ‘obesogenic’ environment, where high-calorie
food is widely available and opportunities for exercise reduced,
energy intake frequently exceeds energy use, ultimately leading to
weight gain and obesity. A critical player in these processes, the
work of Dr Rachel Batterham and colleagues suggests, may be the
gut hormone peptide YY3–36 (PYY).
Much is now known about the control of food intake and the critical
role played by the hypothalamus. PYY, for example, is released after
a meal and acts as a ‘satiety signal’ in the hypothalamus. Notably,
infusion of PYY directly into the bloodstream reduces appetite
and food intake. Nevertheless, it remains unclear how the wider
neurobiological influences on food intake – those linked to emotional
reactions (‘comfort eating’) or the pleasurable sensations associated
with food, linked to activity in reward pathways – integrate with basic
homeostatic processes.
To address this question, Dr Batterham teamed up with Professor
Steven Williams of King’s College London to assess brain activity and
eating behaviour after infusion of PYY. As expected, food intake was
markedly lower after people were infused with PYY. Crucially, though,
while variation in food intake in the control group was associated
primarily with the level of brain activity in the hypothalamus, in the
PYY-treated group it was linked to activity in areas of the cortex and
limbic system (emotional brain areas).
Hence, in the absence of PYY, corresponding to an unfed state,
food intake seems to reflect core homeostatic mechanisms. In the
presence of PYY, however, it is far more dependent on emotional and
cognitive processes, reflecting the pleasurable rather than functional
aspects of eating.
Dr Batterham has also generated PYY knockout mice to gain
insight into PYY’s physiological actions. Notably, PYY was found
to mediate the satiety-promoting effects of high-protein diets.
PYY was also required for weight loss after gastric bypass surgery.
In overfed obese mice, PYY levels were suppressed and when
mice were returned to a healthy diet, PYY levels did not return to
weight-appropriate levels. Suppression of PYY could therefore be
one be one reason why weight loss is so hard to maintain.
Thus PYY seems to play a key role in mediating the weight
loss effects of gastric bypass surgery, currently the only effective
treatment for patients with complex obesity. A fuller understanding
of the role played by PYY could lead to much-needed interventions
based on dietary modifications or pharmacological interventions.
Lemieux C et al. A Pre-mRNA Degradation Pathway that Selectively Targets
Intron-Containing Genes Requires the Nuclear Poly(A)-Binding Protein.
Mol Cell. 2011;44(1):108–19.
Batterham RL et al. PYY modulation of cortical and hypothalamic brain areas
predicts feeding behaviour in humans. Nature. 2007;450(7166):106–9.
Much has been learned about the control of gene expression
from studies of individual genes. But to work out how a cell
operates and responds to its environment, a more integrated
approach is needed, to identify coordinated programmes of gene
activity. New sequencing and other high-throughput technologies
are now making this possible, and Professor Jürg Bähler has
applied them with considerable success in the fission yeast
Schizosaccharomyces pombe.
S. pombe has many advantages as an experimental organism,
including a well-characterised genome and an extensive toolbox
for genetic manipulation. It ultimately offers the realistic possibility
of a complete systems-level understanding of cellular function.
Regulation of gene activity will of course be central to this
understanding. In 2008, while at the Wellcome Trust Sanger Institute,
Professor Bähler’s team took a major step towards understanding
fission yeast’s genetic programmes in a landmark whole-genome
analysis of gene expression, under a range of experimental
conditions.
One notable feature – also seen in other organisms, including
humans – was the surprising amount of the genome transcribed
into RNA. Only a few per cent of the genome is protein-coding, but
well over 90 per cent is copied into RNA. The likelihood is that gene
expression is controlled not just by proteins but also by legions of
newly discovered non-coding RNAs – hinting at substantial degrees
of complexity.
Professor Bähler is continuing to explore genome-wide control
of gene activity, in his own lab and in multiple international
collaborations. As an example, splicing patterns depend on
environmental stimuli and even, surprisingly, the rate at which
genes are transcribed. In addition, work with colleagues in Canada
has revealed that a new pathway of pre-mRNA degradation in the
nucleus controls the expression of certain intron-containing genes.
Other studies have identified histone deacetylases as critical
repressors of gene expression, potentially of greater significance
than histone methylation. And work with Professor Paul Nurse at
Rockefeller University in the USA has revealed that fission yeast has
the ability to modulate gene expression globally over a range of cell
sizes. As a single cell, S. pombe is supposedly a ‘simple’ model
organism. Even so, fully understanding its biology will undoubtedly
be a daunting task.
Hansen KR et al. H3K9me-independent gene silencing in fission
yeast heterochromatin by Clr5 and histone deacetylases. PLoS Genet.
2011;7(1):e1001268.
Zhurinsky J et al. A coordinated global control over cellular transcription.
Curr Biol. 2010;20(22):2010–5.
34
Batterham RL et al. Critical role for peptide YY in protein-mediated satiation
and body-weight regulation. Cell Metab. 2006;4(3):223–33.
Chandarana K et al. Diet and gastrointestinal bypass-induced weight loss:
the roles of ghrelin and peptide YY. Diabetes. 2011;60(3):810–8.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Astrocytes in the hippocampus.
and it will be interesting to
search for gene variants
affecting longevity and
to identify their effects on
gene expression and cell
biochemistry.
Systems-level behaviour
can also be seen in the
cells of higher organisms,
an example being the
endogenous clock
mechanisms present in
all cells. Professor David
Whitmore has studied
the circadian clock of
zebrafish, which is entrained
by light34 and depends
on cryptochrome 1a35.
Remarkably, the clock is
active on the first day of fish
development and requires
no external stimulus to set in
motion – fish kept in darkness
and at constant temperature
still show characteristic daily
patterns in activity of key
clock genes36. And not only
can cells from very early
embryos detect light, but
being able to do so is
a survival advantage37.
Body talk
Physiology is by its very
nature an integrative
discipline. At its most
challenging, it requires
integration not just of
biochemical and cellular
mechanisms but also of
brain activity and conscious
thought.
Dame Professor Linda Partridge.
Dr Alex Gourine is
investigating an entirely
subconscious process –
the control of breathing by
carbon dioxide. His team
has identified the cells in the
cerebellum responding to
high carbon dioxide levels,
as well as the signalling
mechanisms used to transmit
this information to other areas
of the brain (see page 37).
Dr Rachel Batterham, by
contrast, is tackling the
deceptively complex issue of
appetite control and eating,
particularly the effects of a
signalling molecule known as
peptide YY. Ultimately, this
may provide a route to new
weight control measures
(see page 34).
Perhaps the most challenging
of all is a systems-level
understanding of brain
function. One approach
offering considerable
promise is computational,
exemplified by the work of
Professor Peter Dayan and
colleagues in the Gatsby
Computational Neuroscience
Unit (see page 36).
The Unit’s work is based on
the use of computational and
mathematical modelling to
understand brain function,
particularly in areas such as
plasticity, neural dynamics
and population coding,
applied in areas such as
perception, vision and
decision-making. Extensive
collaborations with practical
Heightened platelet activation could be a reason
why some patients are at increased risk of a
heart attack after an emotional experience.
neuroscience underpin a
two-way dialogue between
theory and experimental
studies (see companion
volume on Neuroscience and
Mental Health).
Humans are inherently
social animals, so arguably
a fully integrative view of
human biology also needs
to reflect the impact of
social interactions. Until
recently, little attention was
given to the physiological
impact of social and
psychological factors. That
picture is changing, with
the recognition that there
is considerably interplay
between psychology and
brain function, endocrinology,
and the immune system.
Pioneering work bridging
these diverse domains
has been carried out by
Professor Andrew Steptoe
and colleagues. Much of this
work is population-based,
but a central theme of his
work is to understand the
mechanisms underpinning
population-level effects. For
example, heightened platelet
activation could be a reason
why some patients are at
increased risk of a heart
attack after an emotional
experience38.
Ageing: from molecules
to minds
Superficially, ageing might
be equated simply with
years lived. But biological
age is not the same as
chronological age – a 60 year
old may have the body of a
30 year old or vice versa. In
fact, ageing is a complex and
poorly understood process,
with characteristic changes
at molecular, cellular and
tissue levels. Notably, many
conditions are associated
with increasing age. If the
mechanisms underpinning
ageing could be identified,
it might be possible to
intervene and slow not just
the ageing process but also
34 Whitmore D, Foulkes NS, SassoneCorsi P. Light acts directly on
organs and cells in culture to set the
vertebrate circadian clock. Nature.
2000;404(6773):87–91.
35 Tamai TK, Young LC, Whitmore D.
Light signaling to the zebrafish circadian
clock by Cryptochrome 1a. Proc Natl
Acad Sci USA. 2007;104(37):14712–7.
36 Dekens MP, Whitmore D.
Autonomous onset of the circadian
clock in the zebrafish embryo. EMBO J.
2008;27(20):2757–65.
37 Tamai TK, Vardhanabhuti V, Foulkes
NS, Whitmore D. Early embryonic light
detection improves survival. Curr Biol.
2004;14(3):R104–5.
38 Strike PC et al. Pathophysiological
processes underlying emotional
triggering of acute cardiac events.
Proc Natl Acad Sci USA.
2006;103(11):4322–7.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
35
Dialling down TOR activity – already possible
with rapamycin – could therefore be beneficial
across a wide spectrum of ageing-related
diseases.
the development of these
conditions.
Serotonin and dopamine may act in opposition.
ACTION STATIONS
Computational models may be able to integrate the
contrasting effects of dopamine and serotonin.
Humans, like all animals, are constantly faced with choices.
How do we know what the right course of action is at any
given moment? Despite the enormous complexity inherent in
such a question, Professor Peter Dayan and colleagues are
developing computational models to provide a conceptual
framework for decision making, looking in particular at two
critical modulators of behaviour, dopamine and serotonin.
Superficially, decision making is straightforward: any organism
should choose options that maximise rewards and minimise
punishments, over the long term. To make these judgements, an
animal needs to have absorbed learning from past experience.
However, this simple notion suffers significant problems.
In any typical environment, there is so much information to
process and so many sequences of possible choices that it
is computationally challenging to arrive at optimal decisions.
Further, important aspects of choice are pre-programmed
by evolution – having to learn by experience that tigers are
dangerous would be a disastrous strategy.
In the face of these challenges, human and animal decision
making employs a more sophisticated approach, combining
multiple mechanisms, each of which works well in a limited
set of circumstances. The UCL team’s approach is to build
computational models to characterise these mechanisms and
their complex interactions. Dopamine and serotonin lie at the
heart of two such systems.
One long-standing but still controversial idea is that
dopamine and serotonin oppose each other’s influences, with
dopamine responsible for reward and serotonin for punishment.
The newer computational models point to richer forms of
opponency, integrating the ‘vigour’ with which goals are
pursued. On this axis, dopamine is responsible for invigoration
and serotonin for inhibition. The interactions between these
opponencies leads to a complex set of situations in which
the systems may reinforce one another or come into conflict,
scenarios that can be modelled in quantitative computational
models and tested experimentally.
While a model based on these two modulators can scarcely
explain all the complexity of decision making, it does provide
a framework for exploring the impact of these two critical
molecules in human behaviour. Ultimately, it may also provide
input into understanding some of the suboptimal decisionmaking seen in a range of debilitating neurological and
psychiatric conditions such as Parkinson’s disease, depression
and anxiety, which are characterised by abnormalities in these
critical brain chemicals.
Guitart-Masip M, Beierholm UR, Dolan R, Duzel E, Dayan P.
Vigor in the face of fluctuating rates of reward: an experimental
examination. J Cogn Neurosci. 2011;23(12):3933–8.
Boureau Y-L, Dayan P. Opponency revisited: Competition
and cooperation between dopamine and serotonin.
Neuropsychopharmacology. 2011 doi:10.1038/npp.2010.151.
36
Hopes that this might be
possible have been boosted
by numerous studies showing
that lifespan can be reliably
extended in numerous
model organisms, from
yeast to mice, by genetic
manipulation or by controlling
food intake – caloric or
dietary restriction.
Dietary restriction is too
extreme to be a practical
option for people. But if
the biochemical pathways
by which it acted could
be identified, it might be
possible to mimic its effects.
An early candidate was the
sirtuin pathway, of particular
interest as it was affected
by the plant chemical
resveratrol, found in the
skin of red grapes and
(in minute quantities) in red
wine. Despite much early
excitement, the sirtuin story
may be on the wane (see
page 37).
Meanwhile, an alternative set
of pathways being studied by
Professor Linda Partridge,
Dr David Gems and their
colleagues is looking more
promising. Dietary restriction
triggers an adaptive
response that enables cells
to survive longer in resourcepoor conditions. Central to
this response is a protein
known as TOR (target of
rapamycin). This and a
second pathway known to
affect ageing, the insulin-like
growth factor-1 pathway,
converge on an important
regulatory enzyme, ribosomal
S6 protein kinase 1 (S6K1).
Recent exciting work, carried
out with Professor Dominic
Withers, now at Imperial
College, revealed that S6K1
could be a significant player
in mammalian ageing39.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Female knockout mice
lacking S6K1 lived longer
than controls and showed
significantly fewer signs of
age-related decline. TOR,
S6K1 or downstream factors
are therefore potential
targets for pharmacological
intervention. Indeed, there
is already evidence from
experimental models that
rapamycin has lifespanenhancing properties40.
Such work puts cell
metabolism at the heart
of ageing. Conventionally,
ageing has been ascribed to
‘wear and tear’, with a central
role played by charged
reactive oxygen species
generated by respiration.
Yet this appealing hypothesis
may not be the full picture –
preventing oxidative damage,
for example, has little impact
on lifespan41.
Indeed, a radical alternative
has been proposed that
places TOR at the heart
of ageing. Problems may
arise because baseline TOR
activity is too high. This drives
a set of cellular changes
that, over the long term,
have harmful consequences
in a wide variety of cell
types. According to this
view, ageing is not about
damage and loss of function,
but of overactivity. Dialling
down TOR activity – already
possible with rapamycin –
could therefore be beneficial
across a wide spectrum of
ageing-related diseases.
39 Selman C et al. Ribosomal protein S6
kinase 1 signaling regulates mammalian
life span. Science. 2009;326(5949):
140–4.
40 Bjedov I et al. Mechanisms of life
span extension by rapamycin in the fruit
fly Drosophila melanogaster. Cell Metab.
2010;11(1):35–46.
41 Doonan R et al. Against the oxidative
damage theory of aging: superoxide
dismutases protect against oxidative
stress but have little or no effect on life
span in Caenorhabditis elegans. Genes
Dev. 2008;22(23):3236–41.
Astrocytes, carbon dioxide sensors in the brain.
The nematode worm Caenorhabditis elegans.
EVERY BREATH YOU TAKE
AWKWARD QUESTIONS IN AGEING RESEARCH
Surprisingly, astrocytes have turned out to be the
critical carbon dioxide-detecting cells in the brain.
When it comes to life extension, some findings look more
robust than others.
Breathing both supplies the body with oxygen and disposes of
waste carbon dioxide (CO2). Monitoring of bloodstream oxygen
and CO2 levels are both important homeostatic mechanisms,
carried out by carotid bodies and the brainstem, respectively.
Although the brainstem has been known for many years to play
a critical role in respiratory CO2 sensing, only recently have the
critical cells been identified, thanks to the work of Dr Alexander
Gourine and colleagues.
In 2005, with Professor Michael Spyer, Dr Gourine identified
the purine nucleotide ATP as the critical signalling molecule
linking CO2 levels to breathing rate. Best known as a cellular
energy source, ATP also has an important role in intercellular
signalling, binding to a specific class of receptors. In rats,
blocking these receptors in chemosensitive areas of the
brainstem abolished the stimulatory effects of increased CO2
levels on breathing rate.
More recently, Dr Gourine and colleagues in Bristol and
Stanford honed in a particular class of cells in the brainstem,
astrocytes, as possible brain chemosensors. Astrocytes are
highly numerous in the brain – they actually outnumber neurons
– but have generally been seen simply as providing physical
and metabolic support for neurons. Recently, however, there
has been a growing awareness that they also play more
functional roles.
Indeed, using molecular imaging, Dr Gourine and colleagues
identified significant calcium fluxes in astrocytes in response to
small changes in pH, leading to the release of ATP, activation
of nearby neurons and an increase in respiratory activity.
Furthermore, using optogenetic techniques – genetically
introducing ion channels that open in response to light of a
specific wavelength – they were able to show that cell-specific
light-induced calcium activation of astrocytes was sufficient to
trigger changes in breathing, mimicking the effects of CO2.
Astrocytes are well positioned in the brainstem to carry out
their chemosensing role, being intimately connected both
to incoming blood vessels and the neurons responsible for
controlling breathing activity. Interestingly, they appear to be
a specific type of astrocyte as those present elsewhere in the
brain do not respond to pH changes.
These findings add weight to the idea that astrocytes are
more important to information processing in the brain than once
suspected – an idea becoming widely accepted but currently
backed up by little convincing experimental evidence.
Genetic studies in model organisms – such as yeast, fruit flies,
nematode worms and mice – have identified genes that affect
lifespan. As Professor David Gems, Professor Linda Partridge and
their colleagues have shown, however, great care is needed before
it can be said with certainty that a gene affects ageing.
Ageing is a complex and poorly understood biological process.
Several factors have been reliably shown to lengthen lifespan (see
main text) and in several organisms genetic changes have been
found that cause organisms to live considerably longer than usual.
In such studies, it is important to be sure that an observed
phenotype is actually the result of a specific genetic change.
As is often pointed out, correlation does not imply causation.
An early example of this came from work on flies, in particular a
mutant fly known as Indy (short for I’m not dead yet), which lives
twice as long as normal flies. The UCL group planned to use Indy
flies as positive controls. But to their surprise, they found that, when
crossed into other genetic backgrounds, Indy mutations had no
impact on lifespan. In one case, increased longevity was seen –
but the new strain did not include the Indy mutation. Longevity in
the original Indy strain was also abolished when antibiotics were
used to kill Wolbachia, a bacterium often found in insect cells.
More recently, and potentially more seriously, similar results
have been obtained with sirtuin mutations. Sirtuins have generated
considerable excitement since the discovery that overexpression
could extend lifespan in a range of experimental organisms.
Despite this excitement, sirtuins have also attracted controversy,
with sometimes conflicting findings on their role in ageing.
Professor Gems and Professor Partridge’s research has dealt
them a further blow. Outcrossing experiments in the worm, for
example, eliminated increases in longevity even though sirtuin
overexpression was maintained. Instead, longevity was associated
with a different genetic change associated with sensory neuron
function. In flies, sirtuin overexpression did remain linked to longer
life compared to unadulterated flies, but not when compared with
genetically modified controls without sirtuin overexpression.
Laboratory strains are artificial, and it is possible that adaptation
to laboratory life may affect lifespan. Rather than truly extending
life, it is possible that some supposedly longevity-enhancing
genetic changes are simply counteracting this lost survival ability.
Gourine AV, Llaudet E, Dale N, Spyer KM. ATP is a mediator of
chemosensory transduction in the central nervous system. Nature.
2005;436(7047):108–11.
Toivonen JM et al. No influence of Indy on lifespan in Drosophila after
correction for genetic and cytoplasmic background effects. PLoS Genet.
2007;3(6):e95.
Burnett C et al. Absence of effects of Sir2 overexpression on lifespan in
C. elegans and Drosophila. Nature. 2011;477(7365):482–5.
Gourine AV et al. Astrocytes control breathing through pH-dependent
release of ATP. Science. 2010;329(5991):571–5.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
37
An evolutionary perspective on human behaviour integrates
genes, environment and culture.
GENES, CULTURE AND
HUMAN BEHAVIOUR
Charles Darwin recognised
that humans, like all other
organisms, were subject
to the forces of natural
selection. Today, the idea
is anathema to some on
principle. Even for those
happy to accept biological
explanations for the evolution
of modern humans, the
enormously greater role of
culture may seem to have
lessened the significance,
and explanatory power,
of biological evolutionary
forces.
Yet there is a strand of
anthropology, typified by
the work of Professor Ruth
Mace, who leads a Human
Evolutionary Ecology
Group in the Department of
Anthropology, which views
human activities through an
evolutionary lens. Notably,
the work often generates
insights that would not have
been apparent through
other approaches.
Although an evolutionary
perspective naturally brings
in the question of genes, it
also places humans firmly
within a geographical
and cultural context, and
is highly empirical, thus
avoiding some of the pitfalls
of simplistic evolutionary
psychology. To minimise the
impact of complex artificial
environments, research
often focuses on traditional
societies (though it is
increasingly hard to find any
that are genuinely untouched
by modern life), but also
addresses life in developed
societies.
38
Naturally, reproduction is
a key theme. In industrial
societies, it is also an
evolutionary conundrum,
as the general association
between wealth and
reproductive success
(numbers of offspring)
is broken. Is low fertility
adaptive? How economics
affects reproductive decision
making is a complex area,
but work with the ‘Children
of the 90s’ cohort in Bristol
has provided evidence of
a ‘quality–quantity tradeoff’1. Smaller families may
now be favoured so that
individual offspring are not
disadvantaged by sibling
competition, lower parental
investment, or loss of
economic benefits owing to
child-bearing.
The evolutionary perspective
also sheds light on a
curious and unexpected
consequence of a scheme to
improve water supply in rural
Ethiopia. Women spent less
time and energy obtaining
water, but these benefits
were associated with a
sudden surge in fertility.
Evolutionary theory suggests
that any energy saved on
‘survival’ activities will be
routed into reproduction,
and that is exactly what
appeared to happen2. Follow
up studies are examining the
factors influencing take up of
contraception in such rural
communities.
Another theme is the
potential evolutionary
significance of the
menopause. Traditional
theories suggest that it
is simply a consequence
of ageing and greater
longevity. An alternative idea
is that it provides selective
benefits, as grandmothers
can provide input into their
daughters’ child-rearing.
Indeed, empirical studies
have shown benefits
associated with input
from grandmothers.
One of the most controversial
areas of evolutionary theory
is that of group selection –
the idea that natural selection
can operate on groups rather
than just individuals. The
work of W D Hamilton (see
page 10) suggested how
genetic relatedness – kinship
– could explain socially
beneficial behaviour. Selfless
behaviour that benefits a
relative can ensure better
propagation of genes in the
long run. But humans are
also notable for the degree
of cooperation between
unrelated individuals.
Belonging to a cooperating
group may directly benefit
an individual. A more
provocative suggestion is
that selective pressures are
operating on the group itself.
A group may prosper even if
individuals within it do not.
Although still a minority view
– group benefits can usually
be assigned to individuals –
it is possible to envisage a
process of ‘cultural evolution’
that can operate at a group
level. Successful cultural
traits can adapt, compete
and provide a selective
advantage, promoting their
wider dissemination.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Cultural group selection has
been proposed as a model
to explain cooperation,
which is frequently tested
in economic games across
different cultures. However,
the idea that cooperation is a
stable feature of societies is
not supported by Professor
Mace’s recent work showing
that even within one cultural
group, the Pahari Korwa of
central India, cooperation
varied markedly between
subpopulations, reflecting
local demographic and
ecological factors.
On the other hand, a study
examining striking patterns
in language distribution
offers more support for
cultural group selection.
The size of language areas
shows a marked gradient,
with areas growing in size
further from the equator.
After testing a wide range
of environmental and other
possible explanations, only
political complexity emerged
as a likely contributory factor.
Thus languages may spread
when a society becomes
large and complex enough
to assimilate neighbouring
regions. In other words, one
culture outcompetes another.
This focus on culture also
leads to the interesting notion
of ‘cultural phylogenetics’ –
family trees of cultural traits
modelled on those used
to represent evolutionary
relationships among living
organisms. This approach
has been used to deduce
the ancestral matrimonial
relationships in Austronesian
societies, a shift from
matrilineal kinship after the
adoption of animal farming 3
and, more dramatically, the
rise and fall of civilisations
(see page 44).
With Dr Andrea Migliano
recently joining the group,
future work will have a
greater focus on genetics.
In notable earlier work,
Dr Migliano related the
short stature of African
pygmies to their dangerous
environment. She suggested
that evolution had favoured
rapid development and
early sexual maturity, as life
expectancy is low4. Short
stature was not directly
selected for, but a byproduct
of selection for early
reproductive maturity.
Milk and modern culture
Professor Mark Thomas’s
work on lactase persistence
(see page 44) also illustrates
the interplay between
culture and human evolution.
A notable point about
lactase persistence is that
the mutation only became
advantageous under
the appropriate cultural
conditions – after milkproducing animals had
been domesticated.
human behaviour could only
take root when populations
grew to a critical density.
This contingency underpins
a theory developed by
Professor Thomas to
explain the emergence
of sophisticated ‘modern’
human behaviour – the
first use of symbolic
representations, art, toolmaking and music. This
remarkable blossoming,
which marks humans out
from other animals, began
in the late Stone Age,
around 45,000 years ago.
Curiously, though, similar
traits appeared much earlier,
around 90,000 years ago,
in sub-Saharan Africa,
but petered out.
The reason, suggests
Professor Thomas, relates to
population density. Modern
This conclusion was
supported by modelling
of skill propagation. Skills
can be passed on but
rarely with complete fidelity,
creating variation in skill
levels in the next generation.
Occasionally, though, an
individual will develop
superior skills. The total
skills level in the population
can therefore increase,
if the population is large
enough for the imperfect
transmission of skills to
be outweighed by the
presence of sufficient skilled
individuals from whom a
learner can choose to copy.
Using realistic assumptions
based on ethnographic data,
Professor Thomas was able
to simulate these processes
in the stone age. Essentially,
simulations suggested that
population size was the
critical factor in achieving
skills accumulation in a
population5.
The ‘tipping point’ population
densities appeared in
Eurasia around 45,000 years
ago, but they also were also
achieved in sub-Saharan
Africa 45,000 earlier. Other
parts of the world took
longer to reach threshold
population densities, which
could explain why modern
behaviour took root later
even though modern humans
were present. One puzzle
is why modern behaviour
did not survive in subSaharan Africa. Detailed
demographical change
is uncertain, and there is
at least some evidence of
worsening climate, which
would have led to swings in
population sizes and minor
bottlenecks snuffing out
incipient complex culture.
The model has distinct
advantages over biological
explanations – that cognitive
changes directly drove the
new behaviours.
It would be hard to explain
the emergence of modern
behaviour twice, while the
speed at which modern
culture emerged and spread
argues against direct genetic
and biological adaptation.
A more likely scenario is
that anatomically modern
humans, thought to have
evolved around 195,000
years ago, may have had
the cognitive capacity
for modern behaviour
but it could only become
embedded and transmitted
once populations grew
above a threshold size. The
rest, as they say, is history.
High population densities
may have had further
important impacts. Once
people began to live closer
together, with domesticated
animals, new niches and
opportunities were created
for pathogens. Professor
Thomas and Dr Ian Barnes
have discovered that
human evolution driven
by pathogens may also
have been shaped by
demography. By examining
the prevalence of a
gene variant associated
with protection against
tuberculosis, they found
a correlation between the
length of time an urban
area had existed and
the prevalence of the
protective allele6.
1 Lawson DW, Mace R. Optimizing
Modern Family Size: Trade-offs between
Fertility and the Economic Costs of
Reproduction. Hum Nat. 2010;21(1):
39–61.
2 Gibson MA, Mace R. An energy-saving
development initiative increases birth
rate and childhood malnutrition in rural
Ethiopia. PLoS Med. 2006;3(4):e87.
3 Holden CJ, Mace R. Spread of cattle
led to the loss of matriliny in Africa: a coevolutionary analysis. Proc R Soc Lond
Ser B: Biol Sci. 2003; 270(1532):24–33
4 Migliano AB, Vinicius L, Lahr MM. Life
history trade-offs explain the evolution
of human pygmies. Proc Natl Acad Sci
USA. 2007;104(51):20216–9.
5 Powell A, Shennan S, Thomas MG.
Late Pleistocene demography and the
appearance of modern human behavior.
Science. 2009;324(5932):1298–301.
6 Barnes I, Duda A, Pybus OG, Thomas
MG. Ancient urbanization predicts
genetic resistance to tuberculosis.
Evolution. 2011;65(3):842–8.
Neolithic mother figure idol.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
39
SECTION 5
ORIGINS: GENES AND EVOLUTION
Genes provide insight current-day biology, but
also act as a time machine for looking back at
the evolution of life, including humans.
Charles Darwin’s notebook entry on his views of family relations among species.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
40
Gene sequences now provide a way to identify family relationships.
It is fitting that UCL
occupies the site of
Charles Darwin’s former
house, on London’s Gower
Street. Some of the most
significant developments in
20th century evolutionary
thinking occurred in UCL
(see page 10), and today
UCL researchers continue to
make important contributions
to evolution research.
The most obvious difference
between Darwin’s and
modern research in evolution
is the central position of
DNA. Differences in DNA
sequence generate the
phenotypic variation on
which natural selection acts.
As a result, genomic DNA
sequences provide a record
of past evolutionary history.
Darwin’s profound insight
that all organisms were
related, with new species
being generated from
existing ones, connected
all livings things in a
phylogenetic tree of life.
Although shared physical
characteristics can be
used to position organisms
on a phylogenetic tree,
DNA provides a more
fundamental way to identify
The explosive growth in DNA sequence data
has created extraordinary new opportunities
for research in multiple fields, from ecology to
oncology. Yet analysing this torrent of data is
a formidable challenge.
family relationships.
Indeed, morphology can
be positively misleading,
as Professor Max Telford’s
research has illustrated.
Simple-looking worms may
look like genuine flatworms
(platyhelminthes) but actually
sit on an entirely different
branch of the tree of life
(see page 43).
The explosive growth in
DNA sequence data has
created extraordinary new
opportunities for research
in multiple fields, from
ecology to oncology. Yet
analysing this torrent of data
is a formidable challenge.
Professor Ziheng Yang
has developed widely used
computational methods
and statistical applications,
and has collaborated with
groups in UCL and globally
to analyse genetic data.
One area of interest is the
timing of key evolutionary
events. Over deep time,
timescales have primarily
been obtained from
geophysical analysis of fossil
finds. More recently, DNA
sequence comparisons have
provided an alternative way
to look back in time. The
general principle is that two
related gene sequences
will independently accrue
changes over time after
they diverge from a shared
ancestral sequence. If DNA
changes are assumed to
arise at a constant rate, then
the time of divergence can
be calculated.
This ‘molecular clock’
approach has been widely
used, but has significant
drawbacks – not least the
fact that the clock has
probably not ticked at a
constant rate. Professor Yang
has developed statistical
techniques that incorporate
uncertainty into clock pacing,
and has been involved in
several projects reconciling
fossil and DNA evidence.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
41
Skulls in UCL’s Grant Museum of Zoology.
Fossil and genetic
dating often show large
discrepancies. For example,
the fossil record suggests
that multicellular animals
burst onto the evolutionary
scene between 500 and 590
million years ago, but genetic
analyses put their origins –
based on molecular clock
assumptions – far earlier, at
700 million years or earlier.
A Bayesian model, which
allows the molecular clock
to vary over time, brought
this figure down to 580
million years – more in line
with fossil dates42. A similar
approach has been used
to narrow the discrepancy
in the origins of ray-finned
fishes – which account
for more than half of all
vertebrate species43.
With colleagues in
Nottingham, Cambridge
and the USA, Professor
Yang has also attempted
to integrate fossil and
molecular evidence to date
the key events in primate
evolutionary history. This
work suggested that the first
anthropoids (monkeys and
apes) appeared around 47.2
million years ago44. Other
analyses have suggested
that for most of hominoid
evolution, population sizes
were 5–10 times larger
than for modern humans,
confirming that humans have
diverged from a remarkably
small starting population45.
42
Notably, these studies have
suggested that molecular
data cannot by themselves
generate accurate speciation
dates. Despite its inherent
limitations, the fossil
record provides essential
information about absolute
times that needs to be
incorporated into models
for molecular data. Better
dating is going to depend on
additional fossils, and better
analysis of them, rather than
on more sequence data46.
DNA sequence analysis
can also be used to identify
sites that have undergone
‘positive selection’ –
changes resulting from
Darwinian natural selection.
The challenge here is to
distinguish changes due to
positive selection from those
that have simply spread
by chance. The general
approach is to compare
DNA changes that alter
amino acid sequences with
those that do not. If proteinaltering changes occur faster
than those than those that
preserve protein sequence,
they are likely to have been
actively selected for.
Using this approach,
Professor Yang and
colleagues at Cornell
University were able to infer
that female reproductive
proteins, like male
reproductive proteins,
have been evolving
Professor Mark Thomas.
rapidly, driven by positive
selection, possibly due to
sexual selection or sexual
conflicts47. Computational
tools for these analyses are
widely used, particularly
by virologists looking for
positively selected amino
acid residues in rapidly
evolving viral genomes. This
approach was used to map
signs of positive selection in
the HIV-1 envelope protein
gene over the past 20 years
in Japan48.
adopt the farming lifestyle?
DNA evidence from ancient
remains strongly suggests
that Europe’s farmers
were entirely distinct from
earlier hunter-gatherers.
It was the people, not just
the technology, that swept
across Europe49.
Human evolution
42 Aris-Brosou S, Yang Z. Bayesian
models of episodic evolution support
a late precambrian explosive
diversification of the Metazoa.
Mol Biol Evol. 2003;20(12):1947–54.
Genetics also provides an
opportunity to explore recent
events in human history,
complementing traditional
archaeological studies.
Professor Mark Thomas’s
unusual interdisciplinary
perspective combines
practical work on ancient
DNA with computational
modelling and an interest in
demography and cultural as
well as biological evolution.
DNA evidence has helped
to answer one of the most
contentious issues in early
European history. Around
8000 years ago, Europe
was transformed from a
land of hunter-gatherers to
agriculture-based societies.
But were the huntergatherers displaced by a
wave of farmers from the
Middle East, or did they
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
43 Hurley IA et al. A new time-scale for
ray-finned fish evolution. Proc Biol Sci.
2007;274(1609):489–98.
44 Wilkinson RD et al. Dating primate
divergences through an integrated
analysis of palaeontological and
molecular data. Syst Biol. 2011;60(1):
16–31.
45 Burgess R, Yang Z. Estimation of
hominoid ancestral population sizes
under bayesian coalescent models
incorporating mutation rate variation
and sequencing errors. Mol Biol Evol.
2008;25(9):1979–94.
46 Warnock RC, Yang Z, Donoghue PC.
Exploring uncertainty in the calibration
of the molecular clock. Biol Lett. 2011
[Epub ahead of print]
47 Swanson WJ, Yang Z, Wolfner MF,
Aquadro CF. Positive Darwinian selection
drives the evolution of several female
reproductive proteins in mammals. Proc
Natl Acad Sci USA. 2001;98(5):2509–14.
48 Yoshida I et al. Change of positive
selection pressure on HIV-1 envelope
gene inferred by early and recent
samples. PLoS One. 2011;6(4):e18630.
49 Bramanti B et al. Genetic discontinuity
between local hunter-gatherers and
central Europe’s first farmers. Science.
2009;326(5949):137–40.
An acoelomorph, a distant human relation.
Professor Ziheng Yang.
SHAKING THE TREE OF LIFE
BUILDING A TREE OF LIFE
A nondescript worm from a Swedish fjord has an
unexpectedly important position in the tree of life.
Powerful statistical methods can be used to identify
species relationships based on DNA data.
Initial attempts to draw up a tree of life were based on shared
physical features but they now typically reflect DNA sequence
comparisons. Using such techniques, Professor Max Telford
has had the rare distinction of identifying an entirely new phylum –
one of only around 35 in the animal world – based on the analysis
of a worm-like creature living deep in the mud of a Swedish fjord.
The most interesting phylogenetic questions typically centre
on the major branch points of the tree of life. In the animal world,
a key point was when the deuterostomes split from the protostomes
(the two groups differ in the order in which the mouth and anus
form during embryonic development). The protostome lineage
gave rise to arthropods, nematodes, annelids and molluscs,
while deuterostomes include vertebrates and echinoderms.
Professor Telford’s initial interests lay with the flatworms
(platyhelminthes), protostomes thought to resemble the earliest
bilaterally symmetrical organisms. In the late 1990s, to much
surprise, a group analysed the DNA of one obscure member of
this family, Xenoturbella, and concluded that it was not a flatworm
after all but a member of the mollusc family.
Since Xenoturbella has little in common with molluscs, Professor
Telford was sceptical. Indeed, bivalve molluscs are Xenoturbella’s
favourite food, suggesting that the DNA results reflected
contamination. By carefully excising the gut before extracting DNA,
his team was able to generate a DNA profile that excluded the
worm’s lunch and convincingly removed the link to molluscs.
However, one controversy followed another. Xenoturbella might
not have been a mollusc but it was not a flatworm either. In fact, it
was almost unique, forming a lonely sister taxon to the three other
deuterostome phyla (chordates, hemichordates and echinoderms).
Xenoturbella was actually a relative of humans, albeit a distant
one – their common ancestor lived around 600 million years ago.
In 2011, Professor Telford and collaborators sprung a further
surprise. Another group of morphologically simple flatworms,
acoelomorphs, had been believed to represent an early branch of
animal evolution – a link between the earliest radially symmetrical
animals (such as jellyfish) and more complex bilaterally symmetrical
animals. Unfortunately, additional DNA sequence information
suggested the acoelomorphs were, like Xenoturbella, deuterostomes,
providing Xenoturbella with company in its new phylum.
The results raise the intriguing possibility that both Xenoturbella
and acoelomorphs are not ‘primitive’ but have ‘evolved simplicity’,
losing many of the more elaborate features seen in other
deuterostomes. Additional insight should come from more detailed
genome sequencing and analysis of representative species,
currently being carried out by Professor Telford and colleagues
in Oxford, Spain, Japan and Germany.
In his notebook, Charles Darwin sketched the world’s first
phylogenetic tree, indicating how he thought new species
developed from existing ones. Although family relationships have
typically been based on morphological similarities, DNA-based
methods are increasingly widely used. A method developed
by Professor Ziheng Yang with Professor Bruce Rannala at the
University of California Davis delimits species on the basis of
genetic or genomic data. Although adopted by others, the method
has raised questions about the place of wholly genetic-based
approaches in taxonomy.
The species concept is one of biology’s most controversial,
with some 30 different definitions proposed to date. Traditionally,
taxonomists define species on the basis of morphological
or behavioural features. However, this approach has several
drawbacks. In particular, taxonomic practice varies across fields,
introducing subjectivity into species designations.
The evolution of gene sequences from ancestral forms in
related organisms provides an alternative way to assess family
relationships. Professor Yang’s method uses Bayesian statistical
methods to accommodate the uncertainty associated with low
sequence divergence and potential ambiguities in family tree
reconstruction. It also allows existing phylogenetic information
– based on morphological characters or molecular data – to be
incorporated. A prototype family tree for the population is specified
as a starting point and the model tests which variation of it is most
compatible with the genetic data.
Applied to test gene sequence datasets, the method successfully
positioned four well-recognised rotifer species and correctly
concluded that samples from six ethnically diverse human
populations all belonged to the same species. Its third task was
to categorise a group of five North American fence lizards of
disputed evolutionary ancestry. Until recently, four of the species
were grouped as a single, morphologically diverse species, but an
analysis of 29 nuclear genes from 17 individuals strongly supported
a phylogenetic tree with five distinct species, confirming an earlier
analysis of mitochondrial sequences.
Compared with traditional taxonomic practices, the new method
has several advantages. It has a strong foundation in evolutionary
history and population genetic theory. It is far more objective, so
results are more comparable across species groups, and can be
applied across the entire tree of life.
A US team has already used the method to clarify species
relationships among African forest geckos. However, it has also
stimulated an energetic debate about the use of genetic data
alone to delimit species. Without wishing to be drawn on the issue,
Professor Yang points out that, at the very least, the avalanche
of sequence data provides a way for taxonomists to test their
concepts and hypotheses.
Bourlat SJ et al. Deuterostome phylogeny reveals monophyletic chordates
and the new phylum Xenoturbellida. Nature. 2006;444(7115):85–8.
Philippe H et al. Acoelomorph flatworms are deuterostomes related to
Xenoturbella. Nature. 2011;470(7333):255–8.
Yang Z, Rannala B. Bayesian species delimitation using multilocus
sequence data. Proc Natl Acad Sci USA. 2010;107(20):9264–9.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
43
The lactase persistence allele probably arose in east Europe.
Children from Fenualoa in the Reef Islands.
THE WHITE STUFF
THE RISE AND FALL
Lactase persistence illustrates the powerful interplay
between genes and culture.
Complex societies develop in small steps, but can slide
back several stages at once.
Like all mammals, human babies are brought up on a diet of
mother’s milk. Unlike all other mammals, however, many humans
retain the capacity to digest its principal sugar, lactose, into
adulthood. This trait, lactase persistence, shows a global
association with pastoralism and dairy farming, and Professor Mark
Thomas and colleagues have combined genetic, archaeological
and anthropological evidence to explain the links between genetic
and cultural changes of profound historical importance.
The ability to digest lactose in adulthood is a classic Mendelian
trait. In the default state, lactase production is switched off during
childhood. Lactase persistence results from a single nucleotide
change in the promoter of the lactase gene. In areas such as northwest Europe, the prevalence of lactase persistence is very high
(approaching 100 per cent in Ireland), yet in other parts of the world
– notably the Far East, where few people drink milk – it is almost zero.
The genetic evidence strongly suggests that lactase persistence
in Eurasian populations arose once and then spread rapidly. The vast
majority of people share the same mutation and DNA sequences
show all the hallmarks of positive selection. Interestingly, though,
lactase persistence seems to have risen independently on several
occasions – at least three completely different mutations occur in
African and Middle Eastern population with pastoral lifestyles.
A central question is which came first – milk consumption or the
genetic change? Studies of ancient human remains from multiple
sites across Europe, mostly dating from 5000–6000 years ago,
provided a likely answer. No evidence was found for the Eurasian
lactase persistence allele. Since evidence of milk fats has been
found on pots from the period, the mutation appears to have arisen
after dairying had been established.
A computer model, integrating genetic and archaeological
evidence, has painted a more detailed picture of the likely
sequence of events. The lactase persistence allele was probably
first selected for around 7500 years ago in a region of central/
east Europe, before spreading in a wave across Europe (and
elsewhere). This corresponds with the regional rise of the
‘Linearbandkeramik’ culture and cattle-based dairy farming.
Notably, once both the culture (dairy farming) and the genetics
(lactase persistence) were in place, the mutual advantages set
the stage for rapid expansion. Initially, milk was probably used
for products such as cheese and yoghurt, which contain less
lactose. Once unadulterated milk became a suitable food source
– nutritious, available throughout the year, and uncontaminated –
humans would have been much better equipped to colonise the
challenging north European environment.
Can past events be reconstructed on the basis of present-day
evidence? Professor Ruth Mace, Dr Thomas Currie and colleagues
have applied rigorous quantitative tools used in phylogenetic
analyses to shed light on the rise – and fall – of cultures in SouthEast Asia and the Pacific.
Biological evolution has been marked by the appearance of
ever-greater levels of organisation. Similarly, the ways in which
human societies are organised vary in complexity, with complex
political systems developing from more simple ones. Typical levels
of organisation range from ‘tribes’ to ‘chiefdoms’ to ‘states’.
Exactly how this happens has been controversial, however.
At its simplest, cultures could develop sequentially through
a series of organisational arrangements, like steps on a ladder.
But could they also skip stages – jumping two rungs on the ladder?
Or do societies arrive at the same organisational endpoint via
different pathways? And although most work has looked at evolution
of greater complexity, can societies also descend the ladder,
becoming more simple?
Interestingly, these transitions can be studied using the tools
developed to analyse biological evolutionary relationships. The
reason lies in the evolution of language, which shows striking
similarities with biological evolution, particularly the concept of
‘descent with modification’. As a result, relationships between
languages, like species, can be represented in phylogenetic
trees. Political organisation can be overlaid on such ethnolinguistic
phylogenetic trees, revealing how political organisation has
changed over time.
Using this approach, Professor Mace and Dr Currie evaluated
six possible models for evolution of political complexity, ranging
from a unidirectional ladder to a ‘free for all’ where all transitions
are possible. The best fit was with a model allowing only singlestep upward evolution – high-complexity societies cannot form
spontaneously from low-complexity beginnings. Good support
was also found for a model in which societies can also slide down
the complexity scale, sometimes dropping several steps at once.
The results are consistent with the idea that states have to
evolve through a series of intermediary steps, generally by the
fusion of smaller organisational units. Over historical timescales,
such changes have been witnessed in Madagascar in the late
1700s and Hawaii in the early 1800s. They also confirm that
societies can revert to more simple organisations. More generally,
the work illustrates how quantitative, hypothesis-based research
can complement traditional disciplines such as archaeology in
elucidating human history.
Ingram CJ et al. A novel polymorphism associated with lactose tolerance in
Africa: multiple causes for lactase persistence? Hum Genet. 2007;120(6):
779–88.
Currie TE, Greenhill SJ, Gray RD, Hasegawa T, Mace R. Rise and fall
of political complexity in island South-East Asia and the Pacific. Nature.
2010;467(7317):801–4.
Burger J et al. Absence of the lactase-persistence-associated allele in early
Neolithic Europeans. Proc Natl Acad Sci USA. 2007;104(10):3736–41.
Itan Y et al. The origins of lactase persistence in Europe. PLoS Comput Biol.
2009;5(8):e1000491.
44
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
advantage, it is likely to
become embedded and
passed on. Culture can
therefore be considered from
an evolutionary perspective.
Professor Thomas’s research
frequently reflects the
interplay between genes
and culture (see page 44),
while in the Department of
Anthropology, Professor
Ruth Mace is leading a
group that has adopted an
evolutionary perspective
on human culture and
behaviour, embracing
subjects as varied in scale
as individual decisions on
contraception and the rise
and fall of entire political
systems (see page 44).
A model developed by Professor Thomas,
incorporating this ‘Anglo-Saxon apartheid-like
social structure’, was able to explain modern
distributions of Y chromosomes.
More controversially,
Professor Thomas’s work has
also uncovered unexpected
features of British genetic
history. Traditionally, the
fifth-century Anglo-Saxon
conquest of Britain was
viewed as a take-over
by an influx of people
from Continental Europe.
Archaeologists later began to
favour an alternative model
in which only a small elite
invaded but had a strong
cultural influence. However,
analysis of Y chromosome
sequences indicated that
large numbers of AngloSaxon men made Britain
their home.
The discrepancy between
archaeological and genetic
estimates of the scale of
the Anglo-Saxon migration
could be resolved if smaller
numbers of immigrants
settled across Britain but
used their superior wealth
and power to outbreed
indigenous Britons. A model
developed by Professor
Thomas, incorporating this
‘Anglo-Saxon apartheid-like
social structure’, was able to
explain modern distributions
of Y chromosomes50.
Archaeologists have been
reluctant to accept this
idea, though more detailed
analyses lend support to
this picture.
Professor Thomas’s ability to
analyse and extract meaning
from genetic data has led
him into a range of unusual
collaborations. Having
been the first to read woolly
mammoth DNA sequences,
he has also been involved in
a project identifying fallow
deer as the closest living
relative of the extinct Irish
elk51 – notable for having
the largest antlers ever
seen, some 10 feet across.
A collaboration with Swedish
and Spanish scientists
suggested that genetic
diversity in the endangered
Iberian lynx has been low
for thousands of years,
so may not necessarily
impede its future survival52.
And, bizarrely, all living
polar bears can trace their
maternal ancestry to brown
bears that lived in the
British Isles during the
last Ice Age53.
Big, and clever
Sometimes, historical
studies have contemporary
relevance. In work led by
Professor Marta Korbonits
at Barts and The London
School of Medicine and
Dentistry, Professor Thomas
helped to show that the
mutation affecting an 18thcentury ‘Irish giant’ is still
around today54. Analysis of
DNA extracted from the teeth
of the Irish giant, Charles
Byrne, whose remains are
on display in the Hunterian
Museum of the Royal College
of Surgeons, revealed a
mutation in a gene known
to lead to tumours of the
pituitary gland. He and
Professor David Balding
calculated that mutation
probably arose around 1500
years ago, and perhaps
200–300 people currently
carry it. Those potentially at
risk can now be tested for
carrier status and patients
can be identified early and
treated.
Although some animals show
signs of culture, in none is
it as highly developed as
in humans. Like genetically
encoded information, culture
is also passed on from
generation to generation
and is subject to selective
pressures – if a cultural
tradition offers a selective
Genes and health
The human genome has
been shaped by our
evolutionary history. Whether
it is still being shaped by
natural selection is a moot
point, but this legacy does
have significant implications
for our health.
Although humans are
genetically very similar, the
variation that does exist
has significant implications
for our health. Extensive
searches are underway
to identify genetic loci
affecting health, with many
UCL researchers involved
in multicentre genome-wide
studies across multiple
diseases (see, for example,
Professor Nick Wood’s
work in neurodegenerative
diseases, featured in the
companion volume on
Neuroscience and Mental
Health and Professor Steve
Humphries and Professor
Aroon Hingorani’s work in
the volume on Translation
and Experimental Medicine).
Statistical analysis is also
fundamental to association
studies, calling on the
expertise of statistical
geneticists such as
Professor David Balding.
As well as contributing to
several medical genomewide association studies,
Professor Balding has also
worked in agricultural and
dog genetics, and has
made a number of notable
contributions to forensic
use of genetics.
Although individually less
common, collectively
single-gene disorders and
developmental syndromes
have major health
consequences, and their
impact on individuals can
be profound. Researchers
such as Professor Philip
Beales (see page 18)
and Professor Peter
Scambler have provided
important insight into
developmental disorders.
And researchers in the
Institute of Ophthalmology,
including Professor Shomi
Bhattacharya, Professor
David Hunt and Professor
Anthony Moore, have
identified numerous
genes underlying a
host of eye diseases.
50 Thomas MG, Stumpf MP, Härke H.
Evidence for an apartheid-like social
structure in early Anglo-Saxon England.
Proc Biol Sci. 2006;273(1601):2651–7.
51 Lister AM et al. The phylogenetic
position of the ‘giant deer’ Megaloceros
giganteus. Nature. 2005;438(7069):
850–3.
52 Rodríguez R et al. 50,000 years
of genetic uniformity in the critically
endangered Iberian lynx. Mol Ecol.
2011;20(18):3785–95.
53 Edwards CJ et al. Ancient
hybridization and an Irish origin for the
modern polar bear matriline. Curr Biol.
2011;21(15):1251–8.
54 Chahal HS et al. AIP mutation
in pituitary adenomas in the 18th
century and today. N Engl J Med.
2011;364(1):43–50.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
45
BASIC LIFE SCIENCE RESEARCH AT UCL
Component institutes
Most of the basic life science research at UCL is carried out
by groups in the Faculty of Life Sciences, which comprises:
• UCL Division of Biosciences
• Gatsby Computational Neuroscience Unit
• MRC Laboratory for Molecular Cell Biology
The Basic Life Sciences Domain encompasses
researchers across the whole of the UCL School of Life
and Medical Sciences and their work with colleagues
outside the school.
Domain Chairs: Professor Michael Duchen, Dr Paola Oliveri
www.ucl.ac.uk/slms/domains/basic-life-science
• UCL School of Pharmacy
Dean: Professor Mary Collins
www.ucl.ac.uk/lifesciences-faculty/homepage
UCL in London
Partners
Researchers in the UCL School of Life and Medical
Sciences occupy a range of buildings on UCL’s central
Bloomsbury Campus, at the nearby Royal Free Hospital
and Whittington Hospital/Archway Campus sites,
and other central London locations.
UCL School of Life and Medical Sciences works closely
with a range of local, national and international partners.
Of particular significance are its close links to local NHS
bodies, collectively forming UCL Partners, one of just
five UK Academic Health Science Centres. These links
underpin UCL’s NIHR Biomedical Research Centres
at UCLH, the UCL Institute of Child Health (with Great
Ormond Street Hospital) and the UCL Institute
of Ophthalmology (with Moorfields Eye Hospital).
1 UCL Main Campus
2 UCL Hospital
3 Great Ormond Street Hospital and
UCL Institute of Child Health
4 Moorfields Eye Hospital and
UCL Institute of Ophthalmology
5 Royal Free Hospital and UCL School of Medicine
6 Whittington Hospital and Archway Campus
With the MRC, Wellcome Trust and Cancer Research
UK, UCL is also a founding partner of the Francis Crick
Institute, led by Professor Sir Paul Nurse, which is due
to open in 2015.
UCL also establishes wider partnerships in the UK,
for example with Imperial College to set up the London
Centre for Nanotechnology, and with Imperial, King’s
College London, the MRC and GlaxoSmithKline on the
‘Imanova’ clinical imaging initiative.
6
5
2 1 4
3
46
The School has also developed ties with nearby academic
centres, including the London School of Hygiene and
Tropical Medicine and Birkbeck College. As well as many
joint research initiatives, the institutions also liaise at a
strategic level.
London As well as numerous international research collaborations,
UCL has developed a strategic alliance with Yale
University, the Yale–UCL Collaborative, to promote
cross-fertilisation and joint ventures across education,
research and application.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Support: Resource centres and platforms
Research income
The scale of UCL’s research enables it to provide a range
of technical infrastructure platforms to support research.
These include outstanding facilities and technical expertise
in molecular and cellular imaging, as well as pre-clinical
and clinical imaging, and several sites specialising in
high-throughput sequencing and genome analysis.
‘Live’ grants as at 1 September 2011
Other core platform technologies cover small-chemical
libraries, proteomics, biological services and transgenics,
and informatics. UCL researchers are also involved in
numerous biobanking initiatives and cohort studies,
providing access to extensive collections of materials
and data.
UCL also provides capital infrastructure funding to
enable labs to develop their equipment base.
For clinical research, a Research Support Centre
provides access to essential support for work on people
and patients, including liaison with the UCLH/UCL NIHR
Biomedical Research Centre, UCL Clinical Trials Unit
and UCLH/UCL Clinical Research Facility.
The Translational Research Office works to promote the
translation of research into therapies, techniques and
products with therapeutic value.
www.ucl.ac.uk/platforms/
www.ucl.ac.uk/slms/research_support_centre
NIHR and other UK Government
£177.1m
MRC
£194.6m
Other UK Research Councils
UK charities
£83.3m
£500.4m
£53.6m
Commercial (UK and international)
EU£78.4m
£62.6m
Other international, inc. NIH
Other£14.7m
UCL Research Strategy
The UCL Research Strategy calls for a transformation
of the understanding of the role of our comprehensive
research-intensive university in the 21st century.
Total£1164.7m
Figures refer to research within the UCL School of Life and Medical Sciences.
NIHR: National Institute for Health Research; MRC: Medical Research Council;
NIH: National Institutes of Health.
In addition to highlighting the need to nurture and
celebrate individual curiosity-driven research, the strategy
sets out for UCL an innovative cross-disciplinary research
agenda – designed to deliver immediate, medium- and
long-term benefits to humanity.
UCL will marshal the breadth of its expert perspectives,
in order to address issues in their full complexity and
contribute to the resolution of the world’s major problems.
Its key aims are to:
• continue to foster leadership grounded in excellence in
discipline-based research
• expand the distinctive cross-disciplinarity of our
research, collaboration and partnerships
• increase the impact of our global university’s research,
locally, regionally, nationally and internationally.
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
47
Sponsors of research
We are grateful to all the individuals and organisations who support
research in the UCL School of Life and Medical Sciences.
Abbott France, Abbott Laboratories, Ablynx NV, Academy of Medical Sciences,
Action Medical Research, Action on Hearing Loss, Adam Dealy Foundation,
Against Breast Cancer, Age UK (Formerly Research Into Ageing), Agennix AG,
Aims 2 Cure, Alcohol Education and Research Council, Alder Hey Children’s NHS
Foundation Trust, Alexion Pharmaceuticals, Allergan Inc., Alpha-1 Foundation,
Alzheimer’s Society, Alzheimer’s Research UK, Amyotrophic Lateral Sclerosis
Association, Anatomical Society of Great Britain & Ireland, Anna Freud Centre,
Anthony Nolan Bone Marrow Trust, Apatech Ltd, Apitope Technology (Bristol) Ltd,
Aqix Ltd, Argonne National Laboratory, Ark Therapeutics Ltd, Arthritis Research
UK, Arts and Humanities Research Council, Assisted Conception Unit, Association
for International Cancer Research, Association Francaise Contre les Myopathies,
Association Monegasque Contre Les Myopathies, Association of Coloproctology
of Great Britain and Ireland, Asthma UK, Astra Zeneca (UK) Ltd, Ataxia UK,
Autonomic Disorders Association – Sara Matheson Trust, AVI BioPharma Inc.,
AXA Research Fund, Bachmann-Strauss Dystonia and Parkinson Foundation,
Baily Thomas Charitable Trust, Baily Thomas Charitable Trust, Barts and The
London Charity, Batten Disease Family Association, Baxter Healthcare Corp.,
Bayer – AG, Bayer SAS, Big Lottery Fund, Bill & Melinda Gates Foundation,
Biochemical Society, Biocompatibles Ltd, Biogen, Biogen Idec Inc., Biomarin
Pharmaceutical Inc., Biorex R&D, Biotechnology and Biological Sciences
Research Council, Birkbeck College, Biss Davies Charitable Trust, Boehringer
Ingleheim, Bone Cancer Research Trust, Brain Research Trust, Breast Cancer
Campaign, Bristol Myers Squibb, British Academy, British Council for Prevention
of Blindness, British Heart Foundation, British HIV Association, British Lung
Foundation, British Medical Association, British Neurological Research Trust,
British Orthodontic Society, British Pharmacological Society, British Psychological
Society, British Retinitis Pigmentosa Society, British Skin Foundation, British
Society for Haematology, British Tinnitus Association, British Urological
Foundation, BUPA Foundation Medical Research Charity, Burdett Trust for
Nursing, Burroughs Wellcome Fund, Cambridge University Hospital NHS
Foundation Trust, Camden and Islington Health Authority, Canadian Institutes of
Health Research, Cancer Fund, Cancer Research Institute USA, Cancer Research
UK, Carbon Trust Ltd, Carl Zeiss Surgical GMBH, Celera Corp., Cell Medica Ltd,
Centocor Inc., Central and East London CLRN, Central Research Fund, Cephalon
Inc., Charles Wolfson Charitable Trust, Chemel AB, Child Growth Foundation, Child
Health Research Appeal Trust, Children Living with Inherited Metabolic Diseases
(CLIMB), Children With Cancer UK, Children’s Brain Diseases, Children’s Cancer
and Leukaemia Group, Children’s Liver Disease Foundation, Children’s Research
Fund, Children’s Trust, Chordoma Foundation, Chronic Fatigue Syndrome
Research Foundation, Chronic Granulomatous Disease Trust, Chugai Pharma
Europe Ltd, Cincinnati Children’s Hospital Medical Center, Circulation Foundation,
CLEFT – Bridging The Gap, Clement Wheeler Bennett Trust, CMT UK, Cobra
Bio-Manufacturing PLC, Cochlear Research and Development Ltd, Coda
Therapeutics Inc., Cogent (Holdings) Ltd, Colgate-Palmolive Europe, College of
Optometrists, Colt Foundation, Creating Resources for Empowerment and Action
Inc., Cure Parkinson’s Trust, Cure PSP – Society for Progressive Supranuclear
Palsy, Cyberonics Inc., Cystic Fibrosis Research Trust, Cystinosis Foundation
Ireland, Cystinosis Research Network Inc., David and Elaine Potter Charitable
Foundation, Davis Schottlander & Davis Ltd, Deafness Research (Formerly
Defeating Deafness), Defense Advanced Research Projects Agency, Department
for Children, Schools and Families, Department for Education and Skills,
Department for International Development, Department of Health, Department of
Health and Human Services, Department of Trade and Industry, Dermatitis and
Allied Diseases Research Trust, Deutsche Forschungsgemeinschaft, Diabetes
Research and Wellness Foundation, Diabetes UK, Diagenode SA, Doctors
Laboratory, Dowager Countess Eleanor Peel Trust, Duchenne Parent Project,
Dystonia Medical Research Foundation, Dystrophic Epidermolysis Bullosa
Research Association, East Midlands Specialised Commissioning Group,
Economic and Social Research Council, Edinburgh University, Edmond J Safra
Philanthropic Foundation, Effort – Eastman Foundation, Efic, Eisai (London)
Research Laboratories Ltd, El.En. S.p.A, Elan Pharmaceuticals Ltd, Eli Lilly and
Co. Ltd, Emergency Nutrition Network, Engineering and Physical Sciences
Research Council, Epic Database Research Company Ltd, Epilepsy Action,
48
Epilepsy Research UK, Eular – European League Against Rheumatism,
Eurocoating S.P.A, European and Developing Countries Clinical Trials, European
Association for the Study of Liver, European Commission, European Huntington’s
Disease Network, European Organisation For Research and Treatment of Cancer,
European Orthodontic Society, European Parliament, European Respiratory
Society, European Society for Immunodeficiencies, Eve Appeal, Experimental
Psychology Society, F Hoffmann La Roche Ltd, Fidelity Foundation, Fight For Sight,
Fondation de France, Food Standards Agency, Foundation for Fighting Blindness,
Foundation for Liver Research, Foundation for the Study of Infant Deaths,
Foundation Leducq, Frances and Augustus Newman Foundation, Frost Charitable
Trust, Fundacao Bial, Gatsby Charitable Foundation, Gen-Probe Life Sciences Ltd,
Genentech Inc., General Charitable Trust of ICH, General Medical Council,
Genethon, Genex Biosystems Ltd, Genzyme Corp., Gilead Sciences Inc.,
GlaxoSmithKline, Glaxosmithkline (China) R&D Co. Ltd, Global Alliance for TB
Drug Development, Government Communications Planning Directorate, Great
Britain Sasakawa Foundation, Great Ormond Street Hospital Charity, Great
Ormond Street Hospital Special Trustees, Grifols UK Ltd, Grovelands Priory
Hospital, Grunenthal GMBH, Guarantors of Brain, Guide Dogs for the Blind
Association, Gynaecological Cancer Research Fund, H J Heinz Co. Ltd, Harbour
Foundation, Health and Safety Executive, Health Foundation, Health Protection
Agency, Healthcare Commission, Healthcare Quality Improvement Partnership,
Heart Research UK, Helpage International – Africa Regional Development, Henry
Smith Charity, Hestia Foundation, High Q Foundation, Histiocytosis Research
Trust, Hospital For Sick Children, Human Early Learning Partnership, Human
Frontier Science Program, Human Genome Sciences Inc., Huntington’s Disease
Association, Ichthyosis Support Group, Illumina Cambridge Ltd, Imperial College
Consultants Ltd, Imperial College of Science, Technology and Medicine, Inhibox
Ltd, Institut de Recherche Servier, Institut Straumann AG, Instrumentarium Science
Foundation, Intensive Care Society, International Association for the Study of Pain,
International Balzan Foundation, International Child Development Programme,
International Glaucoma Association, International Primary Care Respiratory Group,
International Serious Adverse Events Consortium, International Spinal Research
Trust, Ipsen Fund, Ipsen Ltd, Iqur Ltd, ISTA Pharmaceuticals, ITI Foundation,
Jabbs Foundation, James S McDonnell Foundation, James Tudor Foundation,
Janssen Pharmaceutica NV, Janssen-Cilag Ltd, Japan Society for the Promotion
of Science, Jean Corsan Foundation, Jerini Ophthalmic Inc., John Templeton
Foundation, John Wyeth & Brother Ltd, Johns Hopkins University, Johnson &
Johnson Consumer Services EAME Ltd, Juvenile Diabetes Foundation, Katherine
Dormandy Trust, Kay Kendall Leukaemia Fund, Kidney Research UK, Kids
Company, Kids Kidney Research, King’s Fund, King’s College London, Legal and
General Assurance Society Ltd, Leonard Cheshire Disability, Leukaemia and
Lymphoma Research, Leverhulme Trust, Lincy Foundation, Linkoping University,
Linnean Society of London, Lister Institute of Preventive Medicine, Liver Group,
London Borough of Camden, London Deanery, London School of Hygiene and
Tropical Medicine, Lowe Syndrome Trust, Lowy Medical Research Institute,
Ludwig Institute for Cancer Research, Lund University, Lupus UK, Lymphoma
Research Trust, Macmillan Cancer Relief (UK Office), Macular Disease Society,
Marc Fisher Trust, Marie Curie Cancer Care, Mars Symbioscience, Mary Kinross
Charitable Trust, Mason Medical Research Foundation, Matt’s Trust Fund for
Cancer, Maurice Hatter Foundation, Max Planck Institute for Molecular Genetics,
Max Planck Institute of Biology and Ageing, Medac GmBH, Medical Research
Council, Medical Research Council of Canada, Medical Research Foundation,
Melford Charitable Trust, Mend Central Ltd, Meningitis Research Foundation,
Meningitis Trust, Merck Ltd, Merck Serono, Mermaid, Michael and Morven Heller
Charitable Foundation, Michael J Fox Foundation for Parkinson’s Research,
Middlesex Hospital Special Trustees, MIND, Mologic Ltd, Monument Trust,
Moorehead Trust, Moorfields Eye Hospital (LORS), Moorfields Eye Hospital
Development Fund, Moorfields Eye Hospital Special Trustees, Moorfields Hospital
NHS Foundation Trust, Motor Neurone Disease Association, Moulton Charitable
Trust, Mr and Mrs Fitzpatrick, MRCP(UK), MSS Research Foundation, Multiple
Sclerosis International Federation, Multiple Sclerosis Society of Great Britain and
Ireland, Mundipharma Research Ltd, Muscular Dystrophy Association, Muscular
Dystrophy Campaign, Myasthenia Gravis Association, Myeloma UK, National
Association for Colitis and Crohn’s Disease, National Brain Appeal, National
Cancer Institute, National Centre for Social Research, National Centre for the
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
Replacement, Refinement and Reduction of Animals in Research, National Contest
for Life, National Eye Institute, National Geographic, National Health and Medical
Research Council, National Institute for Health and Clinical Excellence, National
Institute for Health Research, National Institute of Academic Anaesthesia, National
Institute of Mental Health, National Institutes of Health, National Kidney Research
Fund, National Multiple Sclerosis Society, National Osteoporosis Society, National
Screening Committee, Natural Environment Research Council, NCL Stiftung,
Netherlands Organisation for Scientific Research, Neuroblastoma Society,
New England Research Institutes Inc., Newlife Foundation For Disabled Children,
NHS Blood and Transplant, NHS Executive, NHS Patient Safety Research
Programme, Nicholls Foundation, Nicox SA, NIHR School of Primary Care
Research, Nippon Telegraph and Telephone Corporation, No Surrender Charitable
Trust, Nobel Biocare AB, North Essex Mental Health Partnership NHS Trust,
Northern California Institute for Research and Education, Novartis Pharma AG,
Novartis Pharmaceuticals Corp., Novartis Pharmaceuticals UK Ltd, Novo Nordisk
Pharmaceuticals Ltd, Nuffield Foundation, Ocean Park Conservation Foundation,
Ocera Therapeutics Inc., Octapharma, Office for National Statistics, Options
Consultancy Services Ltd, Organisation for the Understanding of Cluster
Headache, Organon Laboratories Ltd, Orphan Europe (UK) Ltd, Ovarian
Cancer Action, Overweight and Heart Diseases Research Trust, Oxalosis
and Hyperoxaluria Foundation, Oxford Optronix Ltd, Oxigene Inc., Ozics OY,
Paediatric Rheumatology Discretionary Fund, Palaeontological Association,
Pancreatic Cancer UK, Parkinson’s Disease Society, Path Vaccine Solutions,
Pathogen Solutions UK Ltd, Pathological Society of Great Britain and Ireland,
Paul Hamlyn Foundation, PCI Biotech, Pelican Cancer Foundation, Peptide Protein
Research Ltd, Pervasis Therapeutics Inc., Peter Samuel Fund, Petplan Charitable
Trust, Pfizer Ltd, Philips Medical Systems NL BV, Philips Oral Healthcare Inc.,
Physiological Society, Planer Plc, Polycystic Kidney Disease Charity, Primary
Immunodeficiency Association, Procter and Gamble Technical Centre Ltd,
Progressive Supranuclear Palsy (PSP Europe) Association, Prostate Action,
Prostate Cancer Research Centre, PTC Therapeutics Inc., Qatar National
Research Fund, Race Equality Foundation, Rank Bequest, Raymond and Beverly
Sackler Foundation, Raynaud’s and Scleroderma Association, Repregen Ltd,
Research in Motion Ltd (Canada), Research into Childhood Cancer, Rheumatology
Discretionary Fund, Rho Inc., RMS Innovations UK Ltd, Roche Bioscience, Roche
Products Ltd, Rockefeller Foundation, Roddick Foundation, Ronald McDonald
House Charities UK, Rosetrees Trust, Roslin Cells Ltd, Royal Academy of
Engineering, Royal Centre for Defence Medicine, Royal College of Anaesthetists,
Royal College of General Practitioners, Royal College of Ophthalmologists, Royal
College of Paediatrics, Royal College of Physicians, Royal College of Radiologists,
Royal College of Surgeons of England, Royal Free Cancer Research Trust, Royal
Free Hampstead NHS Trust, Royal Free Hospital Special Trustees, Royal National
Institute for the Blind, Royal Society, Samantha Dickson, Sanofi Pasteur,
Sanofi-Aventis, Santhera Pharmaceuticals Ltd, Sarah Cannon Research UK Ltd,
Sarcoma Alliance for Research Through Collaboration, Save The Children, Science
and Technology Facilities Council, Scope International AG, Selcia Ltd, Sheffield
Teaching Hospitals NHS Foundation Trust, Shire Human Genetic Therapies AB,
Siemens plc, Sir Halley Stewart Trust, Sir Jules Thorn Charitable Trust,
Skeletal Cancer Action Trust Plc, SMA Trust, Smith & Nephew Plc, Society for
Endocrinology, Society for Pediatric Radiology, Sport Aiding Medical Research
For Kids (SPARKS), St George’s Hospital Medical School, St Peter’s Research
Trust, Stanford University, Stanley Medical Research Institute, Stanley Thomas
Johnson Foundation, Stanmore Implants Worldwide Ltd, Stroke Association,
Sue Harris Bone Marrow Trust, Summit plc, Supreme Biotechnologies Ltd, Susan G
Komen Breast Cancer Foundation, Swiss National Science Foundation, Syngenta,
Sysmex Ltd, Takeda Cambridge Ltd, Takeda Europe Research and Development
Centre Ltd, Takeda Pharmaceutical Co. Ltd, Tana Trust, Target Ovarian Cancer,
Tavistock and Portman NHS Trust, Tavistock Trust for Aphasia, Technology and
Medicine, Technology Strategy Board, Teenage Cancer Trust, Thomas Pocklington
Trust, Thrombosis Research Institute, Tissue Regenix Group Plc, Tourette
Syndrome Association Inc., Toyota Motor Europe, Tuberous Sclerosis Association
of Great Britain, UBS AG, UCB Pharma SV, UCB S.A, UCLH/UCL Comprehensive
Biomedical Research Centre, UK Clinical Research Collaboration, UK Human
Tissue Bank, UK Stem Cell Foundation, Unilever UK Central Resources Ltd, United
Kingdom Continence Society, United Therapeutics Corporation, University College
London Hospitals, University College London Hospitals Charities, University
Medical Center Hamburg–Eppendorf, University of Alabama at Birmingham,
University of California, University of Coimbra, University of Iowa, University of
Kansas Medical Center, University of Kwazulu-Natal, University of London,
University of Oulu, University of Oxford, University of Rochester, University of
Southampton, University of Sussex, University of Washington, University of
Western Australia, Varian Ltd, Ventana Medical Systems Inc., Veterinary
Laboratories Agency, Vitaflo International Ltd, Vital Therapies Inc., Vitol Charity
Fund, Wayne State University, Weight Concern, Weizmann UK, Wellbeing of
Women, Wellchild, Wellcome Trust, Welton Foundation, Wockhardt UK Ltd, Wolfson
Foundation, World Cancer Research Fund, World Health Organization, World
Vision International, Wyeth Laboratories and Wyeth Pharmaceuticals Inc.
CREDITS
Cover: Dr Patrick Wingfield Digby; p. 2: Dr Jay Patel; p. 3: Dr Tom Hawkins;
Dr Arantza Barrios; Professor Gabriel Waksman; p. 4: Professor Gabriel
Waksman; p. 5: Dr Amanda Price, Dr Leo James; pp. 6, 7: Professor Gabriel
Waksman; p. 7: Dr Claudia Bauer; p. 8: Dr Amanda Price, Dr Leo James;
p. 8: Professor Finn Werner; p. 9: David Bishop; p. 12: Mr Paul Mondragonteran; p. 13: Dr Alessandro Fantin; p. 14: Steve Gschmeissner/SPL; p. 14:
Professor Michael Duchen; p. 15: Dr Yaron Silberberg; p. 16: Dr Sion Lewis;
p. 17: Dr Caroline Dalton; p.17: Professor Dan Cutler; p. 18: Dr Katharina
Seiferth; p. 18: David Bishop; p. 19: Dr Sang-bing Ong; p. 19: Dr Lisa Clayton;
p. 20: Dr Andreas Charidimou; p. 21: Dr Rachael Pearson; p. 21: Professor
Alison Lloyd; p. 22: Manos Protonotarios; p. 24: Dr Sayandip Mukherjee;
p.25: Professor Derek Yellon; p. 26: Professor Roberto Mayor; p. 26: Michel
Delarue, ISM/SPL; p. 27: Dr Emily Richardson; pp. 28, 29: Dr Kara Cerveny;
p. 29: Professor Jeremy Brockes; p. 30: Professor Patricia Salinas; p. 30
Professor Kostas Kostarelos; p. 31: Dr David Greenberg; p. 31: Dr Monica
Folgueira p. 32: Dr Karli Montague; p. 33: Dr Kate Harris; p. 34: Professor Jürg
Bähler; p. 34: webphotographer/iStockphoto; p. 35: Dr Laura Mantoan;
p. 36: Gannet77/iStockphoto; p. 37: Professor Alexander Gourine; p. 37:
Dr David Gems; p. 39: Heritage Images/Corbis; p. 41: Pablo Rojas/Wellcome
Images; p. 42: Grant Museum of Zoology; p. 42 David Bishop; p. 43:
Dr Bernhard Egger; p. 43: David Bishop; p. 44: Pohopetch.
Text: Ian Jones, Jinja Publishing Ltd
Design: Jag Matharu, Thin Air Productions Ltd
© UCL. Text may not be reproduced without permission. The UCL ‘dome’ logo
and the letters ‘UCL’ are the registered trademarks of UCL and may not be
used without permission.
TAP1559/08-03-13/V9
BASIC LIFE SCIENCES UCL School of Life and Medical Sciences
49
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