Investigator Awards in Science: people we've funded

This list includes current and former grantholders. Investigator Awards last up to seven years.


Dr Pavel Baranov

University College Cork

Molecular memory in human AMD1 gene: mechanisms and functions

Proteins play diverse functions in our cells as catalysts of chemical reactions, scaffolds for our cell structures, parts of molecular motors, membrane channels and receptors. Their synthesis is essential for cell growth and survival in every organism and cells expend most of their energy on producing proteins. Understanding how cells regulate synthesis of specific proteins is of paramount importance for biology and medicine.

We recently discovered a regulatory mechanism that provides an RNA molecule with the ability to remember how many protein molecules have been produced from it and to shut down their synthesis when a certain limit is reached. We will characterise the mechanism behind this process and explore how commonly it is used for regulation of different proteins in human cells.

Professor Christiane Berger-Schaffitzel

University of Bristol

Structure and mechanism of key nonsense-mediated mRNA decay factor complexes

The genetic information in our bodies is transcribed into a molecule called messenger RNA (mRNA). The mRNA message is translated into proteins which act as catalysts. At times, these mRNAs contain a translation termination signal at the wrong place and has given rise to truncated proteins, some of which are toxic and cause severe disease. The cell has devised a quality-control mechanism, called nonsense-mediated mRNA decay (NMD), to recognise and eliminate faulty mRNAs. Despite its importance, our understanding of key NMD mechanisms remains elusive. We do not know how the NMD factors orchestrate the vital step of recognising faulty mRNAs.

Recently, we discovered novel NMD factor interactions which may be the key to this process. We will test it in living cells and in vitro, using electron cryo-microscopy to visualise how these proteins function and how the protein synthesis and the quality-control machinery function in health and disease.

Dr Francesca Cacucci

University College London

Pre-configured and learned properties of hippocampal circuits

Recent technical advances have led to a rapid growth in our understanding of the molecular and anatomical diversity of the nervous system and how information is stored and manipulated by neural circuits. However, we still have a limited grasp of how the brain’s structural and functional complexity emerges during development.

We aim to find out how the neural circuits required for complex behaviours are assembled during development, which aspects of brain development rely on intrinsic, experience-independent process, and which require extensive learning about the world. We will focus on the neural circuits of the hippocampus, a brain structure we know is important for learning, remembering events and spatial orientation. We will monitor and manipulate neural activity during early development, to define the relative roles of early embryonic events and post-natal learning in the expression of memory and spatial navigation.

Our findings will contribute to the knowledge we have about the brain’s structural and functional development.

Dr Andrew Carter

MRC Laboratory of Molecular Biology

Cargo transport by dynein/dynactin

The components in our cells are arranged and moved by motor proteins walking along microtubules. The dynein motor and its cofactor dynactin form a transport machine that travels toward the centre of the cell. It carries many different cargoes, from organelles such as mitochondria to toxic aggregated proteins, and can be hijacked by disease-causing viruses and bacteria.

Many different proteins have been identified as adaptors to link dynein/dynactin to its cargoes. We aim to find out which of these proteins are crucial for transport and find any previously unidentified components. We will use cryogenic electron microscopy (cryo-EM) and X-ray crystallography to understand the structural basis by which the adaptors link dynein/dynactin to cargos. We will use recent advances in cryo-electron tomography to observe how motors are arranged on moving organelles both in vitro and in neurons.

Our work will lay the framework for understanding how dynein connects to its cargoes.

Professor Krishna Chatterjee

University of Cambridge

Disorders of thyroid hormone action: diagnosis, pathophysiology and therapy

We will study disorders that are characterised by defects in genes that control the entry of thyroid hormones into cells, their conversion to the active hormone and action via two types of receptor. Defective hormone entry causes failure of brain development.

Defects in SECISBP2 causes deficiency of selenium-containing proteins which leads to multisystem disease with impaired thyroid hormone conversion and degeneration of the aorta. We will find out how aortic degeneration occurs using selenoprotein-deficient aortic cells from mice and patients and we will test whether antioxidants can prevent this process. Defects in thyroid receptor α, cause a disorder with features of thyroid underactivity although blood thyroid hormone levels remain near normal. We will find out its genetic basis and features and develop a diagnostic test that will enable us to identify patients who may benefit from thyroid hormone treatment. We will trial whether treatment with a thyroid hormone-like drug can be used to treat this disorder.

Our findings will add to our knowledge about the pathophysiology of disorders of thyroid hormone action and form the basis for improved diagnostics and therapy.

Professor Dame Caroline Dean

John Innes Centre

R-loop coupled chromatin regulation

DNA predominantly exists as a double helix, but alternative structures are increasingly being found in our genomes. One of these, the R-loop, is formed when RNA, which is the messenger molecule made from DNA, loops back and invades the DNA double helix. The pairing between DNA and RNA is very strong, so R-loops can be stable and form ‘hairballs’ in the genome which prevent normal processes occurring because the DNA cannot be copied and more RNA cannot be made. Until recently, these R-loops were viewed as problems, but they have also been found to help specific genomic processes.

We will focus on one easy-to-study R-loop and identify what it does and how it is regulated. This will provide important information on the broader role of these structures in genome regulation.

Professor Anne Ferguson-Smith

University of Cambridge

Epigenetic inheritance: the influence of variable silencing of the repeat genome

Only a small portion of our DNA contains genes. In fact, more than half of our DNA is repeated many times and it has been thought that this might be ‘junk’ DNA with no function. We have identified some unusual repetitive elements that behave differently in different people and which have the potential to influence our genes by a mechanism that we do not understand.

We will determine whether these repeat elements play a role in regulating our DNA, whether they can act as biosensors for environmental compromise (like a canary in a coal mine), whether the differences they induce can contribute to why one person might be different to another, and whether their properties can be transmitted from one generation to the next.

Understanding the function and regulation of these special repeat elements will provide new and important insights into the function and regulation of repetitive DNA.

Professor Uri Frank

National University of Ireland, Galway

The mechanisms that induce dedifferentiation to drive regeneration in the absence of stem cells

Human cells do not normally change their fate – e.g. neurons do not become muscle – and this maintains order in complex structures. This stability also prevents cells from contributing to regeneration as this requires flexibility. In other animals, regeneration is achieved by a controlled loss of stability in adult cells that can then become stem cells and contribute to tissue and organ replacement. The underlying mechanisms are unknown and may also exist in a rudimentary form in humans. However, identifying them and studying their features should be easier in regenerative animals.

Our objectives are to characterise the mechanisms that allow differentiated adult cells to revert to stem cells and to regenerate lost organs. We will use a highly regenerative yet simple invertebrate animal that can naturally replace any lost organ.

Understanding how cells become flexible can contribute to new strategies for regenerative medicine.

Professor Richard Grencis

University of Manchester

Whipworm infection – defining and exploiting the niche biology of a parasitic intestinal nematode

Parasitic roundworms that live in the intestine infect hundreds of millions of people across the globe causing ill health in low-income communities. Current drugs to remove worms require repeated treatments and are ineffective for some parasites, such as whipworm. The immune system responds but cannot effectively remove these parasites.

We urgently require a greater understanding of how these parasites survive attack by our immune system and how they have adapted to thrive in our intestines alongside our commensal bacteria. We have discovered that whipworm changes our intestinal bacterial communities to their own advantage and produces a protein that neutralises a key immune molecule that the body uses to expel parasites. 

We will define how the parasite changes our intestinal bacteria and how the parasite protein works so that we can intervene in these processes to develop new effective methods of parasite control.    

Professor Angelika Gründling

Imperial College London

Small but mighty: investigate how c-di-AMP contributes to osmotic regulation, amino acid metabolism, respiration and beta-lactam resistance in Staphylococcus aureus

Staphylococcus aureus is an important human pathogen that can cause severe and sometimes lethal infections. Infections are becoming more and more difficult to treat due to the emergence of antibiotic resistant strains. S. aureus is a hardy organism that can grow under harsh conditions outside and inside the host. For this, the bacterium must sense and adapt rapidly to changes in the environment. Small nucleotide molecules, so-called signalling nucleotides, are the key components that allow S. aureus to rapidly adapt.

We will study the function of one signalling nucleotide, c-di-AMP. Previously, we have shown that c-di-AMP is important for the growth of S. aureus and its resistance to antibiotics. As part of this work, we will investigate why c-di-AMP is required for bacterial growth and how this molecule contributes to antibiotic resistance in S. aureus.

Our findings will advance our knowledge of the mechanisms behind antibiotic resistance.

Professor Robert Lucas

University of Manchester

Daylight vision beyond cone photoreceptors

Daytime vision is thought to originate with light sensitive cells in the retina, called cones. I have found that the light detector melanopsin can also detect images under daylight conditions.

I will determine how melanopsin and cones work together to allow us to see. My work takes advantage of the first visual displays capable of presenting images visible to melanopsin. I will also use the latest genetic tools to study melanopsin vision in mice and in an African diurnal mouse with strong daytime vision.

This project will bring a step change in our understanding of vision and has translational potential. My findings could help establish a new range of therapies targeting melanopsin to enhance vision in retinal degeneration. It could also be used to improve image quality in commercial visual displays.

Dr Megan MacLeod

University of Glasgow

Communication between immune and stromal cells is key to immunological memory within pathogen-infected tissues

Bugs that cause infection turn on immune cells. Some immune cells specifically recognise the bug and can remember what it looks like and where in the body it caused disease. If the same bug causes another infection, these memory cells quickly attack it. We call this immunological memory and it is what lies behind the success of vaccines.

We will study immune cells called CD4 T cells as they co-ordinate protective responses. We will investigate how influenza virus infection generates CD4 T memory cells in the lung, where they can quickly control the virus. We think that incoming immune cells, including CD4 T cells, talk with infected epithelial cells and fibroblasts that support other lung cells. We will test how communication between these cells supports prolonged changes in the tissue that improves immune protection to further ’flu infections.

Our findings will contribute to our knowledge about immunological memory which could inform the development of effective vaccines.

Professor Shona Murphy

University of Oxford

Beyond the pol II CTD: the expanding roles of the pol II CTD modification enzymes

The genes contained in our chromosomes direct the production of the components needed for our cells to function correctly. This is known as ‘expression’ of the gene. To ensure that the appropriate products are made at the right time and in the right place, gene expression is regulated at many steps. Failure of these controls can result in disease.

We will investigate the regulation of gene expression at several steps including the first step where the information contained in our genes is copied by transcription into RNA. We are also investigating what happens to the RNA during and after transcription. My aim is to identify the proteins involved in these processes and determine their interactions.

Defining the fundamental mechanisms that regulate gene expression will help us to fully understand the underlying causes of many diseases.    

Professor Joseph Murray

Federal University of Pelotas, Brazil

Life-course determinants and prevention of violence

Violence causes hundreds of thousands of lives every year worldwide, as well as millions of injuries and mental health problems. The highest rates of serious violence are in low- and middle-income countries, particularly in Latin America, but nearly all major research projects have been conducted in high-income countries.

Violence is the main cause of death among young people in Brazil. Causes of violence in childhood will be identified in four large studies in southern Brazil, each following more than 4,000 children from birth to adulthood. We will also use a carefully controlled study to evaluate two interventions that support low-income families to provide early childcare aimed at preventing child behaviour problems and future violence. The interventions are low-cost training programmes for parents suitable for a low- and middle-income country settings.

This research will advance understanding of the causes and prevention of violence in Brazil.

Dr Allen Orville

Diamond Light Source

Dynamic structural biology: new tools and strategies for general applications

Capturing atomic resolution ‘movies’ of functioning macromolecules has been a major challenge in structural biology ever since Nobel prize winner Max Perutz attempted to measure the structural impact of O2 binding to haemoglobin crystals. His large crystals cracked when he tested this function because it triggered significant conformational dynamics.

We are experiencing a step change in time-resolved functional studies linked to serial femtosecond crystallography. This room temperature technique exploits micron-sized crystals and fs pulses from X-ray free electron lasers (XFELs), which are nine orders of magnitude brighter than synchrotrons such as Diamond Light Source.

We will correlate room temperature, serial crystallographic and spectroscopic data to determine the time-resolved electronic and atomic structures of metalloenzymes engaged in catalysis.

Professor Laurence Pearl

University of Sussex

Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone

The normal functioning of cells is controlled by nano-molecular machines made up of protein molecules. Many of these require help from specialised nano-machines called chaperones, which look after component proteins until they are needed. Many of the mutated or overabundant protein molecules that turn a well-behaved cell into an uncontrolled cancer, are particularly dependent on chaperones. Drugs that stop chaperones working cause these aberrant proteins to be destroyed, thereby selectively killing cancer cells.

Kinases are proteins that are often aberrant in cancer and they depend on a chaperone called HSP90. We wish to understand how these cancer-associated kinase proteins gain access to HSP90 in the cell, how HSP90 binds to them and stabilises them, how they are eventually released from HSP90, and how they become destroyed when HSP90 is stopped from working by specific drug molecules.

Our findings will shed light on the process of cancer development and the way drugs that target chaperone molecules can be used in cancer treatments.

Professor Fraydoon Rastinejad

Sanford Burnham Prebys Medical Discovery Institute

Accessing the druggable genetic programmes governed by mammalian bHLH-PAS transcription factors

Cells, tissues and organs use sensory communication networks dependent on a variety of small molecules and proteins that selectively recognise them. This form of signalling is typically reliant on the metabolic state inside the cell, or changes in the extracellular environment, both of which can alter the levels of small-molecule signals. The binding proteins must form adaptive physiological responses to meet those signals.

We will explore a family of human gene regulating proteins, known as the bHLH-PAS transcription factors, whose 3D structure allows binding to small molecules and to genomic sites for controlling gene expression. We will find the cellular small molecules and synthetic drug-like compounds that can bind and modulate the activities of these proteins.

Understanding how such signalling molecules interact with bHLH-PAS transcription factors should inform future drug development for a variety of unmet human conditions including cancer.

Professor Wolf Reik

Babraham Institute

Reprogramming the epigenome: erasing memory and creating diversity

Embryo development is a remarkable process. After fertilisation of the egg by the sperm, the embryo must grow from a single cell capable of becoming any part of the body to ordered tissues each with their own identity. This requires tight regulation and we have a limited understanding of how this operates.

We have developed new technologies that enable us to research this important time in embryogenesis. We aim to understand how the genes in our DNA are marked by small chemical additions. We will study how the early embryo resets these marks, providing a clean slate from which to build a new organism. We will investigate how different genes are subsequently marked as active or silent in different cells as their identity starts to form.

By understanding the mechanism of gene regulation during development, we can ensure healthy development of embryos. This could have an important impact on regenerative medicine.

Professor Kenneth Sawin

University of Edinburgh

Regulation of fission yeast cell polarity by stress signalling pathways

Cell polarity is important for the spatial organisation and function of nearly all eukaryotic cells, including migrating cells, neurons, epithelial cells and stem cells. A key player in cell polarity is the Rho family GTPase Cdc42, which interacts with multiple effector proteins to help execute cell polarity programmes in response to internal and external cues. We used the fission yeast Schizosaccharomyces pombe to discover that the cell polarity module associated with Cdc42 is regulated by stress signalling pathways.

We aim to understand how activating stress signalling regulates the Cdc42 polarity module at a detailed molecular level. We will take a multidisciplinary approach, involving proteomics, genetics, biochemistry and live cell imaging. We will also investigate how stress regulation of cell polarity is integrated with other physiological pathways.

By determining the detailed mechanisms of stress regulation of cell polarity in a relatively simple model eukaryote, we will provide insights into how similar regulation may occur in more complex organisms.

Dr Brigitta Stockinger

The Francis Crick Institute

Environmental influences on intestinal homeostasis and inflammation

The aryl hydrocarbon receptor (AhR) is an environmental sensor that responds to environmental pollutants such as dioxin or to endogenous, non-toxic ligands. We want to study the mechanisms of how environmental triggers influence infections, inflammation and the development of cancer, particularly in the gut where AhR is highly expressed.

We will discover what genes and pathways are affected by AhR in intestinal epithelium, where the absence of AhR or its inadequate activation leads to a higher susceptibility to intestinal infections and inflammation-induced cancer. Some of our data indicate that dietary AhR ligands from vegetable sources can improve inflammatory disorders and we will study the underlying mechanism of this in mouse models as well as in cultured gut cells from humans.

This study will help us to understand the underlying mechanisms behind inflammatory disorders and inflammation-induced cancer.

Professor Ian Tomlinson

University of Birmingham

Explaining and exploiting the spectrum of isocitrate dehydrogenase driver mutations in different tumour types

Cancers mostly develop when cells in the body acquire mutations to their DNA. Mutations in genes called isocitrate dehydrogenase (IDH) cause many cancers, of which some, including brain tumours and leukaemia, have very poor survival. Different types of cancer have different types of IDH mutation and we want to find out why. IDH mutations produce a cancer-causing substance called D2HG, but different IDH mutations are more efficient at this process than others, and the most commonly found mutations do not necessarily make the most D2HG.

We shall relate D2HG levels to specific IDH mutations, finding out which mutations and D2HG levels most favour tumour growth in different parts of the body. We shall also test whether too much D2HG stops tumours from growing.

This work may lead to new anti-cancer therapies based on increasing D2HG to a level that is toxic to cancer cells.

Dr Paola Vagnarelli

Brunel University London

Chromatin re-organisation at the transition from mitosis to G1: how phospho-switches regulate the process in space and time

To support the wellbeing of an organism and the perpetuation of life, cells must conduct specific tasks in a very controlled manner. Birth defects or diseases can occur if this control fails. Cells can execute these controls via transient changes in the behaviour of molecules. One example of these changes is the addition or removal of phosphates (phosphorylation/dephosphorylation) where a molecule will be functioning or non-functioning according to this modification.

My research will identify how the molecules that remove these phosphates (called phosphatases) can change the behaviour of the genome during cell division.

The results of this study will be a major advance in cell biology and it will also have translational potential. Some of these phosphatases are emerging as important candidates in different diseases and information about their mechanism and site of action could be used when designing drugs for conditions linked to their dysfunction.

Professor Xiaodong Zhang

Imperial College London

Structures, recruitment and regulation of key components in DNA damage response

DNA can be damaged by UV irradiation, drugs, smoke, alcohol or metabolic products. Our cells have developed many strategies to detect and repair this damage, including using homologous DNA from a sister chromatin. This process is coordinated by the actions of many proteins, the workhorses of the cell. If this repair process is not working properly, such as when certain proteins are defective, the damaged DNA will not be repaired properly or promptly. This can lead to changes in DNA, causing cancer or ageing.

We want to visualise the components in this process to understand how they work and how they are controlled so that we can understand how they repair our damaged DNA.

Our findings will help us understand the cause of cancer and ageing and may also provide new avenues for therapeutic development.


Professor Wiebke Arlt

University of Birmingham

Dissecting Androgen excess and metabolic dysfunction – an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS)

Polycystic ovary syndrome (PCOS) affects 10% of all women and causes irregular menstrual cycles and difficulties when trying to conceive. Increased levels of male hormones in the blood, also termed androgens, are found in the majority of women with PCOS, who also have an increased risk of metabolic disease, such as diabetes, high blood pressure and heart disease. We have found evidence that adipose tissue in women with PCOS overproduces androgens, resulting in a build-up of toxic fat in the blood, which could cause liver damage. We also found that women with PCOS have an increased risk of fatty liver disease, the second most common cause of liver transplantation.

We will study the mechanisms underlying the adverse metabolic effects of androgens in PCOS and test whether blocking androgen production with a new drug improves metabolic function in women with PCOS.

Our overall aim is to develop new tailor-made approaches to treating and preventing metabolic complications in PCOS.

Professor Sir Shankar Balasubramanian

University of Cambridge

The chemical biology and function of natural modified DNA bases in genomes

Several modified DNA bases have been recently identified in the genomic DNA of human cells and they effectively expand the DNA alphabet. Studies have suggested these modifications may be important for transcription, development and cell identity.

I aim to understand the function(s) of several newly discovered base modifications by studying how they affect the structure of DNA and mechanisms at the molecular and cellular levels using interdisciplinary approaches that include chemical biology, molecular biophysics and sequencing methods, several of which were developed in my lab. 

My findings will help explain why these modified letters of the DNA alphabet exist, how they affect function in normal cells and organisms and also in disease, and may also provide new insights into future applications such as diagnostics and therapeutics.

Professor Charles Bangham

Imperial College London

Human retroviral latency: regulation and dynamics at the single-cell level

The human leukaemia virus HTLV-1, which is related to HIV, causes an aggressive leukaemia in 5 per cent of the people it infects, but how it does this is not understood. Like HIV, HTLV-1 integrates into the DNA of the infected cell, where it can lie dormant and avoid elimination by the immune response. Evidence from our studies of patients’ lymphocytes and the immune response and data from our molecular biological studies of HTLV-1-infected cells in the laboratory, show that the virus is carefully regulating its activity by causing intermittent bursts of expression of its genes, after which it returns to its dormant state.

We have assembled a set of techniques to identify the causes and quantify the kinetics of this gene bursting at the single-cell level. The results will answer fundamental questions on the persistence and pathogenesis of HTLV-1 and contribute to the growing understanding of mammalian gene bursting. We recently discovered that HTLV-1 can cause abnormal folding of DNA when integrated into host DNA. We aim to test the hypothesis that this abnormal folding in turn causes abnormal gene activity in the cell, which might be a significant cause of leukaemia.

The results of this study will help further our understanding of the mechanisms behind gene bursting and could help identify the cause of leukaemia.

Professor Zafar Bashir and Professor Elizabeth Warburton

University of Bristol

Establishing circuit, neuronal and synaptic mechanisms of associative recognition memory

Successful recall of stimuli and their previous locations is essential for us to lead normal lives. Associative recognition memory allows us to remember the association between items, places and time enabling us to recognise, for example, where we parked the car. We know that different types of memory information rely on many different parts of the brain. However, there is little idea of how communication between these different brain regions allows us to acquire and recall different memories.

We will use the rat’s innate ability to remember objects and their locations to examine which connections are essential for successful memory formation and which cellular processes control the necessary communication between different brain regions. We will achieve this by silencing specific connections between brain regions during memory tasks and using neurone recording methods from brain slices and whole animals to examine the precise chemical and transmitter mechanisms that control communication at those connections.

These advances in our understanding of memory mechanisms will pave the way for future studies into how learning and memory declines with age or dementia.

Professor Benedikt Berninger

King's College London

Lineage reprogramming of glia into subtype-specific cortical neurons

The cerebral cortex is the seat of higher cognitive functions but is often severely affected by disease or trauma. We will assess the potential for a novel strategy of cell-based therapy, involving the cell fate conversion of brain cells other than nerve cells into induced neurons. The underlying idea is that the brain harbours many so-called glial cells which have been shown to be amenable to a cell fate conversion into induced neurons in vitro. This can be achieved by forced expression of proteins that regulate cell fate decisions during development. Recent work also suggests that this might be possible in vivo and we want to rigorously scrutinise this possibility.

We aim to convert glial cells into local inhibitory neurons (interneurons) of the cerebral cortex as these cells are often afflicted in neurological and neuropsychiatric disorders. Induced neurons will be closely compared with endogenous neurons found in the brain. While many of the experiments will be conducted with mouse cells, we will expand the scope of our study by testing the possibility of converting human glia into induced neurons as a prerequisite for future translation into cell-based therapies.

The findings will inform investigations into cell-based therapies.

Dr Anne Bertolotti

MRC Laboratory of Molecular Biology, University of Cambridge

Protein quality control in health and disease

Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and prion disease are devastating and affect an increasing number of people in ageing populations. Each disease is caused by the progressive dysfunction and death of specific nerve cells in selective regions of the brain due to the accumulation of proteins of aberrant shape. We have identified selective, safe and potent small molecule inhibitors that enhance the natural defence systems against misshapen proteins and in mice, the inhibitor protects against Huntington’s disease.

In this work, we will examine the benefit of our inhibitors in models of common neurodegenerative diseases, characterise their mode of action in vitro and in cells and search for other targets that could be inhibited to enhance different cellular defence mechanisms. We will target phosphatases, a class of enzymes that were thought to be undruggable. We will manipulate fundamental cellular processes to correct the cellular dysfunction at the origin of diverse diseases.

The knowledge and the inhibitors from our work may be used to develop treatments for a group of devastating diseases.

Dr Mario de Bono

MRC Laboratory of Molecular Biology

Molecular mechanisms of neural circuit function

Our brain contains 1,011 interconnected neurons. Understanding how this structure works is daunting. Fortunately, the molecular machines that make our brains work are often found in simpler animals, like the worm Caenorhabditis elegans. Experiments using C elegans can help us identify and understand these tiny mechanisms. Animals respond to threats by changing behaviour. We isolated hundreds of mutant worms that fail to respond to a particular threat. These mutants each have defects in one protein required for the threat-response circuit to function.

I will investigate the function of these proteins and how the threat-response circuit works. A subset of proteins defines an interleukin-17 signalling pathway and show this pro-inflammatory cytokine can also be a neuromodulator. Some appear to help assemble the ion channels and G-protein-coupled receptors that mediate communication between neurons.

A molecular understanding of neural circuits will help us treat psychiatric illness and age-related mental decline.

Professor Angela Brueggemann

Imperial College London

Investigating the diversity, molecular epidemiology, competitive influence and therapeutic potential of pneumococcal bacteriocins using large genome datasets

Genomics has revolutionised science and medicine. It is now possible to obtain all the genetic information about bacteria and use that information to understand how bacteria cause disease, become resistant to antibiotics and evade the immune system. Infectious diseases are a leading cause of death in early childhood. Pneumonia is the most common and an estimated 1.3 million children worldwide died of pneumonia in 2013. The leading cause of pneumonia is the pneumococcus and it is also a major cause of paediatric meningitis and bacteraemia.

My research is on bacteriocins, which are antibiotics produced by bacteria to kill other bacteria. Pneumococci have many different bacteriocins and it is unclear why they need so many different types. We are investigating whether it might be to compete with other pneumococci and other bacterial species in the body.

If we understand these relationships better it will help us to understand the consequences of disturbing their natural dynamics, for example when we give vaccines to children. It may also be possible to develop these bacteriocins as novel antibiotics, which is important in the context of the global problem of antibiotic resistance and the need for new treatment options.

Dr A Bernardo Carvalho

Federal University of Rio de Janeiro

Evolutionary genomics of Diptera Y chromosomes

In many species including humans, mosquitoes and flies, the sex of an individual is determined by specialised sex chromosomes: females carry two copies of the X chromosome, whereas males carry one copy of the X and one copy of the Y chromosome. Usually the X resembles the other chromosomes in size and gene content, but Y chromosomes have very few genes. These Y genes have important functions: some direct the embryo to develop as a male, whereas others are essential for male fertility. Y chromosomes also contain a very large amount of repetitive DNA. The function (if any) of this repetitive DNA is unclear, but it creates many difficulties for the study of Y chromosomes, to the point that they remain uncharacterised in most species.

We have developed methods and computer programs to study Y chromosomes in drosophila and we will apply these methods to study Y chromosomes from mosquitoes which transmit human diseases such as malaria, dengue, Zika, chikungunya and leishmaniosis. We will also study the repetitive regions of the human genome that cause genetic diseases.

The results could help with the control of mosquito-borne disease and improve understanding of genetic diseases.

Dr Paul Chadderton

Imperial College London

The role of cerebellar circuitry in movement control and real-time motor learning

The cerebellum is a region of the brain that plays an important role in movement. The aim of this proposal is to determine how the cerebellum processes information about movement and measure the changes that occur in the cerebellum during learning.

We will record electrical activity from the brain while animals perform whisker movements and measure how different aspects of movement are represented by neurons in the cerebellum. To get a complete picture, we will also measure the signals coming in and going out of the cerebellum. Finally we will observe how these signals change during learning. We will turn specific neurons on and off during movement and see how this changes the activity patterns in the cerebellum.

Our studies will help us understand the precise function of different parts of the cerebellum during learning and behaviour.

Professor John Christodoulou

University College London

Integrative structural biology of protein folding during biosynthesis on the ribosome

The ribosome is the molecular machine that manufactures proteins from information encoded in our DNA in all cells. Proteins are synthesised as a chain of amino acids built one at a time and must acquire (or fold) their particular shape for them to function. Failure to fold (misfolding) can have devastating consequences, and is implicated in many diseases including neurodegeneration and some cancers. During protein synthesis, the ribosome appears to have a key role in guiding folding of nascent proteins before they are released into the cell’s environment. Despite a wealth of information on the ribosome’s ability to form peptides, the understanding of the protein folding processes on the ribosome remains sparse.

We aim to transform this understanding by applying recently developed genetic engineering methods to capture different stages of protein synthesis on the ribosome. Together with atomic-level visualisation methods we will analyse this series of 3D snapshots to describe how the ribosome guides nascent protein folding. This has important ramifications for understanding why folding can fail and how this is dealt with by the cell. Armed with this information, we can then design ways to manipulate the process, for example using novel antibiotics and antibodies, to target the nascent protein or ribosome to reconfigure protein folding and avoiding misfolds.

Professor Sir Philip Cohen

University of Dundee

The molecular mechanism by which TRAF6 regulates the immune system

The immune system is vital for defence against microbial pathogens, but when it is activated too strongly or cannot be switched off, it can cause inflammatory and autoimmune diseases such as arthritis, asthma, colitis, fibrosis, lupus, psoriasis and sepsis. These diseases affect millions of people worldwide. It is therefore critical to understand the mechanisms that switch on the immune system, prevent it from being activated too strongly and switch it off again when it is no longer needed.

My research builds on novel findings made by my research team, which have advanced our understanding of how the immune system is regulated. 

These findings may lead to the development of improved drugs to treat diseases caused by a deregulated immune system.

Professor Ilan Davis

University of Oxford

Regulated mRNA stability and translation in neural stem cell development

Human brains develop from a limited number of stem cells producing billions of diverse brain cells. Such immense complexity arises by regulating which combinations of genes are made into proteins in each brain cell. We are investigating the universal principles governing these processes in the fruit fly, whose genes and developmental mechanisms are very similar to humans. Current thinking on brain development is that the amount of protein made in each cell is regulated by the amount of RNA, an intermediate molecule that transfers the information kept in DNA that determines which proteins are synthesised.

We have discovered a cohort of genes with important brain functions regulated by unexpected additional mechanisms of RNA stability and the rate of protein production. 

Our discoveries will help explain the rules governing genetic control of brain development and further our understanding of how developmental disorders and brain tumours arise from disruptions in RNA-related processes.

Dr Marc Dionne

Imperial College London

Connecting causes and immune consequences of infection-induced metabolic change

All animals experience metabolic changes when they have infections and some of these changes can be debilitating. Tuberculosis used to be called consumption because of the slow wasting that characterised the disease, while people who have blood infections can lose 10 per cent or more of their body weight in a matter of weeks. These metabolic changes are caused by activation of the immune response, but we don’t understand how immune responses cause metabolic change and – more importantly – we don’t understand why this happens. We believe that some of the metabolic changes driven by infections must be beneficial, but we don’t know how or why.

We will study the response to infections in the fruit fly. We will identify the metabolic molecules that are changed by infection and determine how these changes are connected with the activation of the immune response. We will establish which of these changes are important for fighting infection or helping the fly survive and which are not.

By understanding these metabolic changes better, we might be able to make therapies that can inhibit the damaging changes to metabolism while allowing the changes that promote a healthy immune response.

Professor Annette Dolphin

University College London

Physiological and pathological regulation of calcium channel trafficking and function

Specialised nerve endings in the skin sense heat, cold, touch, pressure and chemical changes and send information to the spinal cord and brain where it is translated into touch, itch or pain sensation. These nerves can be damaged due to diabetes, some viral infections or after chemotherapy treatment for cancer and this alters the information transfer in the nerves, causing intense neuropathic pain. One effective treatment for neuropathic pain is gabapentin which interacts with a protein (alpha2delta-1) found in sensory nerves. Alpha2delta-1 forms a key part of N-type calcium channels that control pain signalling to the brain. The amount of alpha2delta-1 increases dramatically after nerve damage and although we know that gabapentin binds to alpha2delta-1, we don’t understand exactly how it dampens neuropathic pain.

We will study the function of N-type calcium-channels, including how they get to nerve terminals and how these actions are promoted by alpha2delta-1 protein. We have found that if we prevent alpha2delta-1 from being cut into its alpha2 and delta components by a protease enzyme, then we can block its action. Understanding this process could lead to the design of better drugs to treat neuropathic pain. 

Professor Richard Durbin

University of Cambridge

Whole genome sequence based analysis of genetic variation and genome evolution

Our ability to sequence genomes, exemplified by the human genome project, has enabled us to read the information in our DNA that underlies life. It has led to major medical advances and direct clinical applications in genetic disease and cancer. Continuing advances in technology create many opportunities in biomedical and evolutionary science, but require new computational methods to effectively use the data.

I will develop methods that will exploit our accumulated knowledge of genetic variation in the population, using advanced computing technology to allow them to scale to millions of genome sequences. As well as methods to efficiently measure genetic variation I will develop new statistical approaches to understanding the evolutionary relationship between genome sequences which will illuminate the genetic history of humans in Europe and Africa. I will address key questions about how modern humans are related to each other and our ancestors. I will also use these new methods to study speciation, natural selection and genetic adaptation, by studying the evolutionary radiation of vertebrates by looking at many hundreds of cichlid fish species in the African Great Lakes.

Professor Jeff Errington

Newcastle University

Cell envelope synthesis in Gram-positive bacteria: mechanisms, regulation and inhibition

The bacterial cell wall is an essential, highly conserved structure. It is the target for our best antibiotics and is recognised by the innate immune system as a signal for infection. Many mechanistic details of cell wall synthesis remain unsolved, especially how it is regulated spatially and temporally. Firmicutes and Actinobacteria represent ancient groups of bacteria that have evolved contrasting mechanisms to grow with a rod shape.

I will use genetic, biochemical and imaging methods to study components of the Bacillus subtilis cell wall elongation machinery and compare this with the tip extension and branching behaviour of a rare related group of bacteria called Thermoactinomycetes.

The results will help us understand wall synthesis in more global and mechanistic terms and illuminate how wall synthesis regulation evolved. I will use the information that emerges in early stage screening for potential antibiotics with novel actions that target the cell wall.

Professor Paul Fletcher

University of Cambridge

The cognitive neuroscience of overeating: normative and clinical studies of goal-driven and stimulus-driven responses

Obesity is a serious global problem with profound implications for physical and mental health. It is clearly driven by our environment but there is a strong inherited component too. Genetic studies strongly suggest that vulnerability to obesity resides in the brain, how it processes the environment, how it responds to reward stimuli such as food and how it leads us to choose actions and options that we know are not healthy. Understanding brain processes requires that we take into account external signals, such as the sight of food, as well as bodily signals of hunger together with existing learned valuations of factors such as health and taste. For example, changes in gut hormone levels can make even very bland foods seem appetising while some foods are so attractive that we override powerful signals telling us that we are not hungry.

We want to understand this complex brain-body-environment relationship, because we cannot understand overeating and obesity until we do so. We will study healthy people and in patients with unique and specific disturbances to brain circuits and to gastrointestinal signalling.

The findings will help improve understanding of the causes of obesity. By elucidating variation in the underlying mechanisms, this work will provide new insights into over-eating.

Professor Kevin Foster

University of Oxford

Understanding and engineering complex microbial communities

Our bodies all contain communities of microbes that protect us from harmful bacteria. However, taking antibiotics or having an upset stomach can remove this protection, leaving us vulnerable to infection. Moreover, many bacteria are now resistant to antibiotics making infections difficult to treat. Rather than relying solely on antibiotics, we need to learn to engineer our protective microbes to prevent, and perhaps even cure, disease. The challenge is that we carry many different species of microbes, which evolve and affect one another in complex ways.

We will develop theoretical tools that cut through the complexity of microbial communities. We will apply our theory and experimentally test our ability to design gut communities that prevent infection or are able to bounce back from antibiotic treatment. We will also ask whether probiotic communities can flexibly evolve to provide protection in response to disease bacteria, something that antibiotics cannot do.

Our findings may help find more effective ways to fight infection which avoids over-reliance on antimicrobials.

Professor Raymond Goldstein

University of Cambridge

Biomechanics of ciliated tissues

As embryos develop from the initial mass of cells formed shortly after fertilisation they go through a series of remarkable transformations to acquire the form of the adult. Many of these changes involve tissues changing shape in response to mechanical forces generated within them. While these processes are familiar and much studied from genetic and biochemical perspectives, we do not yet have a quantitative understanding of those forces and the response of the tissues to them.

We aim to achieve a quantitative understanding of the underlying biomechanics by linking theory and experiment using microscopy, micromanipulation and imaging with emerging theoretical tools. We seek to solve three outstanding problems: the link between cell shape changes and cell sheet geometry as found in such problems as gastrulation, which marks the beginning of the formation of the gastric system; the mechanism by which carpets of cilia – hair-like appendages whose motion generates fluid flow in many places in the body – develop orientational order; and the origin of metachronal waves in carpets of cilia which are the variations of the beating pattern on the scale of many cilia.

Professor Berthold Gottgens

University of Cambridge

Defining the haematopoietic system through integrated multi-scale analysis

The human body produces three million new blood cells every second to replace short-lived red and white blood cells. This constant process of blood formation depends on long-lived blood stem cells, which can divide to make all other types of blood cell. Tight regulation of blood cell formation is essential to prevent the development of fatal diseases such as leukaemia.

We will use recent technological innovations that allow analysis of regulatory processes in thousands of single cells. A combination of complementary experimental and computational methods will be used to enhance our understanding of how blood stem cells decide whether or not they need to produce new white or red blood cells. It is also proposed to build a computer model that directly links the behaviour of the entire blood system with regulatory processes in individual cells, so that we can make better predictions, for example about the effectiveness of modern targeted drugs.

This new framework will not only advance our understanding of normal blood stem cells and leukaemia, but also be broadly applicable to the study of other organs and diseases.

Professor John Greenwood and Professor Stephen Moss

University College London

LRG1 and dysfunctional vessel growth

The uncontrolled growth of abnormal blood vessels is a feature of a number of life-threatening and life-changing conditions including cancer, eye disease, atherosclerosis and arthritis. These defective blood vessels can be very harmful. Blood flow in these new vessels is often restricted, leading to a reduction in oxygenation, and they can easily rupture, causing bleeding into the surrounding tissue. Although some advances have been made in preventing abnormal vessel growth it may, in some instances, be preferable to promote normal vessel growth.

To address this problem, we first need to learn more about what causes vessels to grow abnormally in disease as this is currently poorly understood. We discovered that the levels of the molecule LRG1 are increased in many diseases and it promotes the growth of aberrant dysfunctional vessels. We also found that LRG1 subverts normal vessel growth causing them to grow in a chaotic and damaging manner. Our objective in this study is to use various systems that model eye disease and cancer in humans to investigate how LRG1 is induced and how it prevents normal vessels from growing.

This work will provide fundamental insight into a critical pathological process.

Professor Sophie Hambleton

University of Newcastle

The troubled immune system – molecular origins of immune dysregulation

The human immune system draws on a wide range of powerful weapons to protect us against infection. Those weapons also pose a threat if mistakenly targeted at our own tissues. The healthy immune system is actively held in check but when this regulation breaks down, we see diseases such as rheumatoid arthritis, inflammatory bowel disease and insulin-dependent diabetes.

My research will focus on children who develop severe problems with self-directed immune responses early in life to learn more about the mechanisms underlying immune regulation. Experience suggests that most of these children have an inherited problem with their immune system. In our research, we will sequence patients’ DNA to find the genetic spelling mistakes that cause these problems. We will try to work out how the affected genes take part in proper regulation of the immune system. We will look in great detail at immune cells from patients and healthy people and we will study the immune system of mice with similar genetic spelling mistakes to give us more insight.

Our research will improve patient outcomes by describing new diseases of the immune system and their mechanisms.

Professor David Holden

Imperial College London

Suppression of adaptive immunity by Salmonella

Salmonella causes both diarrhoea and typhoid fever. There are more than 21 million cases of typhoid fever worldwide each year, with many people who are infected becoming chronic carriers. Resistance to Salmonella requires the development of an adaptive immune response in which specialised white blood cells display small fragments of bacteria to other immune cells, which then mount a defence response targeted at Salmonella to eliminate these bacteria. However, it is known that Salmonella can disable these defences and cause disease. We will use a variety of approaches to understand the mechanisms by which this happens.

Knowledge gained from these studies could be used to help in the design of next-generation vaccines.

Professor Stephen Jackson

University of Cambridge

Genetics and functional interactions in the mammalian DNA-damage response

DNA is continually being damaged by factors that arise from normal cell metabolism and from environmental agents. Our cells have evolved a large number of sophisticated proteins that detect this damage and, in most instances, mediate its effective repair. Defective repair of such damage occasionally occurs in normal cells and more often in cells with DNA-damage response (DDR) defects. This leads to mutations that disrupt cell function and can lead to cancer and other diseases.

Our proposed research builds on our past experience in identifying and characterising DDR proteins, and couples this with our recent successful implementation of novel CRISPR-Cas9 (a genome editing tool) and other technologies to systematically screen for new DDR proteins and regulators and characterise how they function.

Our research should provide new mechanistic insights into fundamental DDR processes. Furthermore, it will help explain how certain DNA-damaging chemotherapeutic agents and novel DDR enzyme targeted drugs kill cancer cells, and how cancers can evolve resistance to these therapeutic agents. This knowledge may also suggest ways to more effectively treat cancers, as well as various other genetic diseases that are caused by DDR defects.

Dr Babak Javid

Tsinghua University

Molecular characterisation of antibiotic tolerance in Mycobacterium tuberculosis

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, killed 1.8 million people in 2016 which is more than any other single pathogen. It is one of the leading causes of death by a curable disease worldwide. However, unlike most bacterial infections, the treatment for TB involves taking hundreds of pills for at least six months and up to two years. One of the reasons it takes so long to cure TB is the effects of antibiotic tolerance. Anti-TB antibiotics kill most, but not all, of the bacteria and it takes a very long time to eradicate the few ‘tolerant’ bacteria. Understanding how mycobacteria become tolerant to antibiotics will allow us to develop treatments that may be able to cure TB much more rapidly. We have recently shown that one of the mechanisms that cause tolerance in TB is that mycobacteria make frequent mistakes when making new proteins – termed mistranslation.

We propose to find out precisely how mycobacteria control the mistranslation rate. We will also use genetic screens to identify other mechanisms that cause tolerance in TB from samples taken from patients and in a mouse model of the disease.

Professor Ole Jensen

University of Birmingham

Phase coding in the visual system: neuronal processing coordinated by brain oscillations

We receive a wealth of visual input when driving down a busy street. Our brains are unable to process all this input but have a remarkable ability to decide what to process and what to ignore. My previous research suggests that ‘brain oscillations’ are essential for controlling the visual flow. Brain oscillations are generated by coordinated activity of thousands of neurons. The strongest oscillation measured in people when they are awake is the ‘alpha rhythm’ which is produced by neural activity pulsing at more than 10 times per second.

I propose a novel neuronal mechanism according to which different objects in a visual scene are represented sequentially along an alpha cycle. According to this framework, information between brain regions is exchanged when the regions oscillate together. This theory provides a mechanistic explanation for how brain oscillations coordinate neuronal activity to prioritise the information flow which is presently lacking. We will test the theory by measuring brain oscillations from many brain regions simultaneously using magnetoencephalography (MEG) as well as intracranial recordings. 

This research will eventually help us understand what goes wrong in people who have problems focusing in busy settings such as those with attention deficit hyperactivity disorder. 

Professor Robert Klose

University of Oxford

Understanding the link between CpG islands and gene transcription

Every human begins as a single cell with a blueprint in the form of DNA that contains the instructions necessary to build a fully functioning human being. This cell grows in the womb, copies its DNA and divides to create new cells which then specialise to form the tissues and organs necessary for human life. This cellular specialisation relies on individual cells using only a subset of their DNA blueprint in a highly precise and controlled manner. Despite extensive efforts to study this process, many of the most basic molecular mechanisms that allow controlled usage of DNA information remain enigmatic.

I will investigate how CpG islands regulate the use of the DNA blueprint in cells.

These findings will allow the development of new approaches to combat human diseases where CpG islands are perturbed and will ultimately improve human health.

Professor Helen McShane

University of Oxford

Defining mechanisms of mycobacterial protective immunity using human experimental medicine and murine models

Most of what we know about how to develop a better tuberculosis (TB) vaccine comes from studies in mice and human studies in the blood. Responses in humans are not always the same as in mice and responses in the lung and blood can differ. We need to understand more about what happens in the lungs in humans when people are infected with TB, as this is where the bacteria enters the body.

We cannot deliberately give people TB. However, I have developed a safe way of giving BCG, which is similar to TB and is used as a vaccine, directly into the lungs of healthy volunteers, to help understand which parts of the immune system respond to mycobacteria. I will also identify which of these responses can kill TB in a test tube. Working out how BCG vaccinations work is vital, but we need to improve upon them. I will also identify new proteins that are in TB which are naturally presented to the human immune system. I will then see whether these proteins can work as a vaccine in mice.

These research findings could be used to develop a stronger vaccination for TB.

Dr Joanna Morris

University of Birmingham

Regulation of small ubiquitin-like modifiers in DNA double-strand break repair

Our cells protect their DNA from long-term damage by actively repairing it. This process is vital to healthy ageing and without it cancer can arise. Cells have several rapid response mechanisms to call their internal repair services to damaged DNA. Recently we have found out that one of these mechanisms uses tiny proteins called small ubiquitin-like modifiers (SUMO). We think SUMO might act like sticky tape and it alerts repair services by sticking them to each other and to the damaged region. However, there are fundamental aspects of the way that SUMO is involved that are not understood. How does the cell initiate the ‘sticking’ processes? Too much ‘stickyness’ would be dangerous to the repair process, so how do cells stop it and what determines where they are stuck?

We aim to address how SUMO is directed to damaged DNA, how the amount of SUMO at damaged sites is controlled and whether special mechanisms exist to put it in the right place.

The regulation of SUMO is an understudied aspect of DNA repair so the knowledge we will gain is likely to provide the basis for new developments in medicine regarding cancer and healthy ageing.

Professor Richard Morris

University of Edinburgh

The retention of memory and creation of knowledge

We automatically form memories of the events of the day as part of our daily life. A key job of the memory system is to filter out unnecessary information and keep the important or interesting parts. These memory traces are then either retained as they are, such as memories of special events (such as the birth of a child), while others are stripped of information about where and when they happened so that merely factual information is added to our knowledge base. There is a great deal of research investigating memory selectivity and the accumulation of knowledge in humans, but it is impossible to do mechanistic causal research in people.

We will investigate these issues by examining memory tasks in animals using molecular engineering tools in conjunction with new cognitive tasks for laboratory animals that mimic the typical events of daily life in humans.

We hope to secure definitive information about the neurotransmitters involved in enhanced memory retention and the networks of neurons that must communicate for new information to be assimilated with what we already know.

Dr Mahdad Noursadeghi

University College London

Human immune response variation in tuberculosis

Tuberculosis (TB) remains a major threat to global health. Infection with the bacteria that causes this illness is widespread, but not everyone who is infected develops the disease and we do not understand why. I aim to test whether our individual risk of tuberculosis disease may be due to differences in the way our immune systems respond to infection and that these differences are genetically inherited.

We will measure the activity of immune genes at the site of a skin test for TB as a model for how the immune system functions at the site of real disease. We will then link differences in immune responses between people with the infection with differences in their genetic code and the likelihood of their infection progressing to disease. These studies will reveal how and why some people develop the disease while others control the infection.

The findings will help us target preventive therapies to those who need them most and to develop better vaccines or new treatment for TB aimed at improving immunity.

Professor Hiroyuki Ohkura

University of Edinburgh

Oocyte-specific pathways that compensate for lack of centrosomes

Transmitting genetic information carried by DNA from generation to generation is fundamental to life. Genes are carried on chromosomes and sophisticated machinery mediates their accurate transmission. However, there is a high incidence of errors in chromosome transmission to human eggs. As a result, 10–30 per cent of all human eggs have an incorrect number of chromosomes. This is a major cause of infertility, miscarriages and birth defects, such as Down’s syndrome. The molecular and genetic basis of this process is still not understood. The machinery that transmits chromosomes to egg cells is distinct from the ones in other cells of the body, but little is known about this specialised machinery.

We aim to find out how this machinery is built and maintained using fruit flies as a model system and taking advantage of genetic similarities between humans and flies. We discovered new pathways important for building and maintaining this specialised machinery and we will investigate how these pathways work at the molecular level, revealing why they are used only for transmitting chromosomes to eggs.

Our studies may provide unique insights into how errors occur in chromosome transmission.

Professor Massimo Palmarini

University of Glasgow

Host determinants of disease outcomes in arboviral infections

We will study bluetongue, one of the most important diseases found in livestock to address a fundamental question in infectious diseases: how can a pathogenic virus render some infected hosts seriously ill while causing only mild disease in others, despite abundant viral replication in both? Bluetongue disease is caused by bluetongue virus (BTV), a virus transmitted to animals by bites from midges. BTV can infect all domestic and wild ruminant species, but infection results in variable levels of disease. Sheep are more susceptible to bluetongue disease but goats and cows are more resilient and develop high levels of virus in their blood but rarely show signs of sickness.

We believe that these differences in clinical outcome are caused by events during the early stages of infection when the virus is attempting to replicate in a cell that is urgently mounting an antiviral immune response. We will experimentally test this idea and the results will advance our understanding of individual susceptibility to bluetongue disease, inform the design of appropriate control measures and serve as a model to study disease susceptibility in many other viral diseases that affect humans and animals.

Professor Jonathon Pines

Institute of Cancer Research

Towards a quantitative comprehension of the spindle assembly checkpoint

Mitosis is the means by which a mother cell divides its genetic material between two daughter cells. It is essential that the two daughter cells receive an equal and identical copy of this material in the form of chromosomes. There is a control mechanism in normal cells that prevents chromosomes from separating until they are properly arranged in the mother cell. Cells usually perish when chromosomes are divided unequally and when it is tolerated it is often associated with poor outcomes in cancer.

We seek to determine the control mechanism by which the cell detects misaligned chromosomes and how this prevents chromosomes from separating. We will use methods to measure the number of molecules involved in this process and how quickly they can transmit information to the rest of the cell.

Our findings will be able to shed light on this control mechanism which will contribute to our understanding of poor outcomes in people with cancer.

Professor Mani Ramaswami

Trinity College Dublin

Inhibitory representations: their formation, modulation and function in memory circuits

Feelings, images, ideas and events are stored in our brains to be retrieved at appropriate times. The proposed research seeks to explain how this occurs. Percepts are represented in the brain by the positive activity of assemblies of excitatory neurons. We have recently proposed that the brain creates negative representations of these perceptual assemblies to prevent inappropriate activation. When appropriate, context-specific neuronal pathways may turn off the negative representations to reveal latent perceptions or memories.

This project builds on our observation that olfactory habituation in fruit flies, a process in which they learn to ignore a familiar inconsequential odour, arises from the formation of negative images of odour-evoked excitatory patterns. We will study how these negative representations are constructed in the simple fruit fly brain and how these representations and their effects are regulated by environmental or behavioural context. Additional studies will ask whether and how negative representations promote suppression of predator-presence memory in fruit flies.

The findings are relevant to humans, whose brain circuits share key features with the fly brain. The work is clinically relevant because defects in habituation, memory encoding and recall are associated with conditions including autism, schizophrenia and post-traumatic stress disorder.

Professor David Rowitch

Wellcome Trust-MRC Stem Cell Institute, University of Cambridge

Understanding astrocyte regional and functional heterogeneity

The central nervous system develops to become regionally specialised to carry out vital roles such as vision, cognition and movement. Although many of the specialised functions that neurons have in the brain have been identified, very little attention has been given to cells called astrocytes. These cells create the environment in which neurons function.

The proposed research will investigate ways that astrocytes might be regionally diversified to interact with neurons to enhance their activity. Establishing this notion would provide a new basis for understanding how neuronal function and connectivity between brain regions is regulated.

The results of this study could lead to insights into neurological diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease that damage integrity of local neural circuits in the spinal cord and brain.

Dr Bénédicte Sanson

University of Cambridge

In vivo mechanisms of epithelial tissue morphogenesis

During animal development, a ball of cells (the blastula) forms from division of a single cell, the egg. This ball elongates to form the main body axis (gastrulation), which becomes divided into repeated regions (segmentation). The human vertebrate column is made from the embryonic regions generated by segmentation (somites). These processes are important and defects in body axis elongation can lead to neural tube problems, such as spina bifida.

We will investigate how embryos are shaped by studying tissue elongation and segmentation in fly embryos. These embryos can be watched live and easily manipulated both genetically and physically. We will study the role of the actomyosin cytoskeleton, which is an essential cellular structure, in tissue elongation and segmentation. This structure, which can be thought of as the cell’s ‘muscle’, is a contractile web made of proteins called actin and myosin, closely associated with the cell’s membrane. In tissue elongation and segmentation, the cells redistribute their actomyosin cytoskeleton, so that it is found more commonly along certain sides of the cell. This redistribution can cause cells to contract and push past each other, which causes tissue elongation.

Professor Christopher Smith

University of Cambridge

Molecular mechanisms of alternative splicing regulation

Alternative pre-mRNA splicing (AS) is a mechanism that allows genes to direct the manufacture of more than one protein. The different proteins produced by AS often have different functions that are suitable for the type of cell in which they are produced.

We will study AS in vascular smooth muscle cells (VSMCs), which line the blood vessels and control blood pressure and flow. AS is controlled by RNA-binding proteins that bind to the RNA molecule that is copied from the DNA of genes and influence the way in which the coding RNA segments are joined together to form the instructions to make a particular protein. We recently discovered an RNA-binding protein that is a master regulator of AS in VSMCs.

This study aims to gain a deep understanding of how AS occurs in VSMCs.

Professor Jaclyn Smith and Professor Maria Belvisi (Imperial College London)

University of Manchester

Role of ATP in chronic cough

Cough is the most common condition for which patients see their doctors, and yet there are very few treatments for it. Coughing occurs when airway nerves are activated, for example by irritating chemicals in the air, changes in temperature and choking on food. For many people with a chronic cough we think the nerves controlling cough are overactive and this may be caused by a chemical in the airways known as ATP. This idea comes from recent studies showing that a treatment that blocks the effect of ATP on nerves improved cough by 75 per cent in chronic cough of unknown cause. However, not everyone responded to the treatment and we don’t know whether the new treatment might work in all types of cough, such as in asthma, smoking-related lung conditions, lung fibrosis or other lung diseases.

Our research aims to understand why this new treatment works in some people. We will develop tests that would tell a doctor which patients and which types of coughs might respond best to new treatments and work out what sort of other new treatments might help to treat cough and other ATP-related symptoms or overactive airway nerves.

Professor Liz Sockett

University of Nottingham

Combating Gram-negative AMR pathogens by understanding the envelope-breaching mechanisms of predatory bacteria

There is a significant threat to world health from antibiotic-resistant bacterial infections. The majority of these resistant superbugs are Gram-negative, a term that describes the usage of an outer membrane that helps shield the bacteria from the action of antibiotics. It would be advantageous to find new ways of bypassing or compromising this outer membrane. Nature has already found a solution to this problem when bacterial predators hunt and consume other bacteria, but are not harmful to humans. One of these predators, Bdellovibrio bacteriovorus, can burrow through the outer surface of superbugs and consume them from within.

We will investigate the function and coordination of the Bdellovibrio bacteriovorus  when it is breaching its prey.

This information will assist our ultimate goal of making new medicines (be it whole Bdellovibrio, the invasion apparatus, or isolated components) to tackle Gram-negative superbugs when antibiotics are ineffective. 

Professor Azim Surani

University of Cambridge

Principles of human development and germ cell program

Primordial germ cells (PGCs), the precursors of eggs and sperm, emerge in the human embryo on day 17 of development, while the surrounding cells develop into somatic tissues of the body. Tracing the origin and development of PGCs will reveal the organisation of the early human embryo. At fertilisation, germ cells pass on about 20,000 genes, the blueprint for development, and non-genetic information that can regulate gene expression. They are critical for how the brain and other organs develop and function. The transfer of this information from parent to offspring by the ‘immortal’ germline is repeated for every generation and has consequences for human health and disease. Germ cells undergo extensive reprogramming which rejuvenates the lineage and is essential for their distinctive potency. By contrast, somatic tissues become prone to age-related diseases.

Detailed understanding of the mechanism of germline reprogramming might provide approaches to address age-related diseases in bodily tissues.

Professor Irina Udalova

University of Oxford

Molecular control of pathogenic neutrophil responses in inflammation

Chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis and diabetes, are increasing in prevalence all over the world. Despite progress in understanding how they develop and what components of the immune system may be involved, much remains unknown.

I will focus on neutrophils, which I have previously shown are important in inflammatory arthritis and are dependent on the activation of other immune cells, macrophages. I will study how neutrophil function is guided by intrinsic molecular regulators and influenced by extrinsic protein and lipid signals produced by macrophages.

These studies will help to redefine the role of these cells in chronic inflammatory diseases and lead to development of new therapeutic targets and biomarkers to guide diagnosis and treatment.

Professor Joris Veltman

Newcastle University

Unravelling genetic causes and risk factors for severe male infertility

We will study the biological process of sperm production in fertile and infertile men. We will look at the genomes of large groups of men with severe male infertility, aiming to identify mutations in the DNA that can explain their infertility. We will also study the genome of children born through the use of assisted reproductive technologies (ART) to determine whether these technologies carry any health risk to these children.

This research will inform us about the biology of normal and abnormal human sperm production, identify the genetic causes of male infertility and provide insight into any risks of ART. This is useful to provide infertile men with information about the cause of their disorder and will help us develop novel and safer ART.

Dr Jean-Paul Vincent

The Francis Crick Institute

From patterning signals to growth and back

As embryos develop, systemic signals, which convey hormonal and nutritional information, control the growth of its various tissues and organs. At the same time, local signals, sometimes called morphogens, are produced within each tissue to organise positional information, ensuring that various cell types are produced in the correct pattern. In well documented cases, these patterning signals have been found also to promote growth, perhaps allowing coordination between patterning and growth. These observations show that individual tissues must integrate local and systemic pro-growth signals. So far, relatively little is known about how morphogens promote growth.

We propose to first develop means of precisely controlling morphogen signal transduction using light or changes in temperature. This will enable us to identify the molecules that mediate the pro-growth activity of morphogens and to find out how this activity is coordinated with that of other pro-growth signals, local and systemic. We will also ask if known growth regulators affect morphogen signalling as this could explain the observation that patterns scale with tissue size.

Our experiments will uncover in molecular detail how various signals are integrated to ensure that tissues grow in a timely and proportionate manner.

Professor Helen Walden

University of Glasgow

Mechanisms of ubiquitin signalling in Parkinson’s disease

Mitochondria are the energy providers of the cell and it is important that they stay healthy. Mitochondrial health is maintained by an intricate system of signals that are attached and removed from the mitochondrial machinery. If a mitochondrion becomes defective, it must be removed by the cell's waste disposal system. To do this, the signal ubiquitin must be attached to proteins on the mitochondrion to flag it for removal. The enzymes that create the waste disposal signal do not function correctly in neurodegenerative diseases such as Parkinson’s.

We aim to understand how these enzymes create signals and attach them to the correct targets to ensure that defective mitochondrion are removed from the cells.

By investigating this process at the atomic level, we aim to be able to understand what goes wrong in Parkinson’s disease, and find ways to modify each step to restore normal function.

Professor Elizabeth Ward and Professor Raimund Ober

University of Southampton

Defining the Fc receptor-mediated trafficking of IgG-antigen complexes in macrophages

Antigen-presenting cells form a key part of the immune system due to their ability to transmit information about the components of the body, including cancers, and foreign invaders or tissues such as bacteria, viruses or organ transplants. This leads to the destruction of infectious agents but also transplant rejection or the attack of body components caused by autoimmunity. Macrophages represent an important class of antigen-presenting cells. These cells are present throughout the body and accumulate at sites of inflammation and tumours. Macrophages ingest proteins called antigens derived from pathogens or, in the case of autoimmune disease or cancer, from self-proteins.

It is essential to define how and where an antigen travels within the macrophage to understand how macrophages transmit information to other immune cells. Until recently, methodology to study processes such as the movement of antigens within cells that occur on microscopic scales (around one millionth of a centimetre) has been unavailable. We have developed the necessary microscopy tools for use in this project to investigate these processes. Our studies are expected to reveal important information that will allow the development of next generation treatments for diseases such as cancer and autoimmunity.

Professor Fiona Watt

King's College London

Dynamic cell transition states in mammalian epidermis

The epidermis forms the outer covering of the skin. It contains stem cells that divide to produce cells that differentiate into the specialised cells of the epidermal barrier, hair follicles, sweat and sebaceous glands. We want to understand how cells change from stem cells into specialised cells in the epidermis. Our current knowledge comes from studying groups of cells for days or weeks but we know that events occurring in minutes or hours in individual cells are also important.

We have developed new methods to study rapid changes in cell state which we will use to examine how the decision to stop being a stem cell is controlled in space and time and whether it depends on the type of differentiated cell being produced. We will determine whether different types of epidermal stem cell are interconvertible and whether they compete with one another to produce differentiated cells. We will also discover how differentiated cells can become stem cells again after the skin is wounded. Finally, we will test how abnormalities in cell state transitions contribute to epidermal inflammation and cancer.

This research will provide new insights into the role of dynamic cell state changes in healthy and diseased tissue.

Dr Finn Werner

University College London

Mechanisms and regulation of RNAP transcription

The first step in gene expression is transcription which is carried out by molecular machines that produce an RNA copy of DNA. Transcription is carried out by RNA polymerase (RNAP) enzymes aided by general transcription factors but the mechanisms are poorly understood. When viruses infect cells they can radically change host transcription. Virus encoded regulators take over the host RNAP for their own purpose and the host responds to counter the infection.

We propose four lines of investigation to deepen our understanding of this process. The action of RNAP is orchestrated by many specific regulatory factors and we want to identify novel factors and characterise their function to explain how transcription is regulated in the cell. The DNA is packed into more or less compact protein-DNA complexes (chromatin) and is not always readily available for RNAP. We will characterise how different types of chromatin allow or prevent transcription. We will also investigate the molecular mechanisms by which both virus and host factors alter transcription in the context of this arms race.

The results of this study will help deepen our understanding of the transcription process.

Professor Dale Wigley

Structure and mechanism of the INO80 chromatin remodelling complex

DNA in human cells is protected by being packaged into nucleosomes which are in turn packaged into chromatin. However, access to the genetic material is required so localised unpacking is required to make RNA, replicate DNA or repair it.

Protein machines control the packing in a variety of ways. We will investigate how one such machine – INO80 complex – carries out this task as a part of the process to repair DNA breaks. Two INO80 complexes act together to slide nucleosomes and these also sense the presence of other nucleosomes and space them evenly. The enzyme complex is highly regulated through a number of different mechanisms and these will be investigated. We will also investigate how the subunits contribute to the functions of INO80 complex.

This research will give us greater insight into the processes involved in DNA repair.

Professor Peijun Zhang

University of Oxford

Molecular mechanisms of HIV-1 restriction by capsid-sensing host cell proteins

During early stages of HIV-1 infection, the viral capsid, a protein shell enclosing the HIV-1 genome, intimately interfaces with the host’s cellular proteins. These essential molecular interactions occur during a pivotal period in the infection process when the virus is highly susceptible to disruptive interventions, thus, representing promising targets for the development of new drugs and therapeutic strategies for HIV-1 prevention and treatment. Among these proteins are host cell defence factors that specifically bind the viral capsid by recognising its surface pattern and disrupting its function, thus potently blocking HIV-1 replication. How the host cell defence proteins sense the incoming viral capsid, however, is not understood.

We aim to determine the common mechanism(s) of capsid pattern sensing by host cell defence proteins using an integrative approach combining structural methods with retrovirology, cell biology and computer simulations. We will also examine the consequences for HIV-1 infection when the host proteins’ pattern-sensing ability is altered. These studies will reveal a major host immune defence mechanism targeting the viral capsid and advance our understanding of viral pattern sensing by the host.

Information derived from our studies will generate a framework for the development of new therapeutic interventions for HIV-1 and other pathogenic viruses.


Professor Mark Achtman

University of Warwick

Deep evolutionary history of bacterial pathogens

How old are bacterial pathogens and what evolutionary steps have they undergone? Despite all the genomes that have been analysed since 1995, we do not understand the broad evolutionary history of the bacterial pathogens that threaten humanity. 

Comparative genomics has reconstructed the demographics of pathogens that emerged a few decades ago. With the help of ancient genomes (aDNA), genetic lineages that caused diseases such as plague, cholera, tuberculosis and leprosy, have also been reconstructed. These pathogens were easy to deal with because of limited genetic diversity and he rarity recombination. However, other approaches are needed to address the evolutionary history of most bacterial pathogens.
We will use an approach that combines ancient DNA sequences with a broad overview of modern genetic diversity.

We will use the latest developments in aDNA sequencing, devise new bioinformatic approaches for metagenomic analyses and combine them with a big-data overview of modern genetic diversity. We will initially use Salmonella enterica to develop this strategy and then apply it to other pathogens found in aDNA metagenomic samples.

The project will illuminate the global breadth of current bacterial diseases, which has been obscured by the absence of an historical framework.

Professor Oreste Acuto

University of Oxford

Initiation, dynamic control and long-term consequences of T-cell antigen receptor signalling: understanding etiology and therapy of immune diseases

T cells clear the body of pathogenic microbes while maintaining a ‘good neighbour’ relationship with useful symbiotic gut microbes. T cells also ensure that the immune system does not mistakenly attack our own tissues and organs.

Our studies look at the molecular mechanisms by which T cells ensure maximum protection with limited or no collateral damage and what helps maintain this healthy balance. Our research has uncovered the mechanism by which T cells receive and process signals elicited by ‘peptide antigens’, the portions of foreign proteins belonging to invading microbial pathogens that can be seen by T cells, allowing them to prepare adequate defensive responses. This very same signalling process also helps minimise the risk of autoimmunity.

Our research should lead to the identification of more effective and better-tolerated drugs that protect against organ graft rejection, and also improve early diagnosis of autoimmunity and management and/or cure of autoimmunity.

Professor Hilary Ashe and Professor Magnus Rattray

University of Manchester

Global dynamics of mRNA accumulation and translation in embryonic development

Cells change their gene expression programme to make new, distinct sets of proteins that turn the cells into particular types such as skin or blood cells. There are multiple steps in the gene expression pathway, including transcription, mRNA processing, export, degradation and translation.

We aim to understand how the efficiency of each of these steps is controlled and coordinated to generate the required amount of each protein, so that cells can become the correct cell type. We will generate large data sets and develop computational tools to extract information about all the steps in the gene expression process. To confirm our findings we will use advanced imaging methods to visualise the different steps in the gene expression process in real time in living cells. We will then change the efficiencies of particular steps to determine how this affects the ability of a cell to become the correct cell type.

Results from this study will provide new insight into how each gene expression step is regulated and will be relevant to many other cell types, including stem cells where the ability to manipulate their fate is critical to their therapeutic use.

Professor Wendy Barclay

Imperial College London

Adaptation of avian influenza virus polymerase to humans during pandemic emergence

Influenza viruses cause devastating pandemics when they emerge from animals and cross over into humans. In 1918, 50 million people died after being infected by the ‘Spanish’ influenza virus. Other viruses that emerge from animal sources such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and Ebola virus also cause very severe disease in people. What is especially interesting about influenza is that once the new pandemic virus has infected nearly everyone, it evolves further to become a seasonal influenza virus associated with less severe disease, at least in previously healthy people.

We do not currently understand why the viruses that cross over to humans from animals are so lethal or how they adapt over time to become less severe. The explanation must be in the way the virus interacts with the host. In birds, influenza virus infection is silent but when an avian influenza infects humans, the mismatch between virus and host factors leads first to replication block and later to severe disease after some adaptive mutations.

I intend to discover the key host factors that underlie these observations. These might be excellent new targets for antiviral strategies. It will also assist with pandemic preparedness and therapeutic options for severe influenza.

Dr Elizabeth Bayne

University of Edinburgh

Understanding mechanisms of small RNA-mediated silencing

RNA interference (RNAi) is a fundamental regulatory pathway by which small RNAs turn off – or  ‘silence’ – genes. It is important for the normal function of the cell, and defects in the pathway are linked to diseases including cancers. 

We aim to understand how this pathway works using the model organism fission yeast, which has an RNAi pathway similar to that in humans but in a simplified form. We want to investigate the important but poorly understood first steps in the RNAi pathway, aiming to identify the proteins that help to initiate small RNA production and silencing. We want to understand their roles and determine what mechanisms ensure that only certain genes are selected for silencing. We also want to investigate RNAi pathways in alternative types of yeast to determine whether these might be even better model systems for understanding key aspects of the more complex RNAi pathways in humans.

Professor Sir Tom Blundell

University of Cambridge

Achieving selectivity in space and time with DNA double-strand break response and repair: molecular stages and scaffolds come with strings attached

DNA is subject to a barrage of insults arising inside and outside the cell, such as ionising radiation and attacks by reactive oxygen species. These can generate severe lesions in DNA, known as double-strand breaks. Double-strand breaks can kill cells, while their sloppy repair can lead to tumour-inducing mutations or chromosomal disruptions. Thus the ability to repair DNA damage rapidly and accurately is fundamental for cell survival and health.

DNA double-strand break repair is carried out by two distinct molecular pathways: homologous recombination and non-homologous end joining. I will use a combination of structural approaches, biophysical and computational analyses and cell imaging to investigate how reparatory proteins are brought together and assembled into complexes during non-homologous end joining. I aim to decipher the different, complementary mechanisms that coordinate this process in time and space, thereby ensuring precise and efficient DNA repair.

Dr Daniel Bradley

Smurfit Institute of Genetics, Trinity College Dublin

Ancient genomics and the Atlantic burden

Researchers are sequencing hundreds of thousands of human genomes in order to help understand the genetic aspects of disease. However, understanding human variation by looking at modern people’s genetics is only part of the story. The past is a different country and we already know that when we examine genomes from ancient people they can make us revise our views about how our modern genomes relate to each other and how disease-related variation came about.

This project will build on our finding that the petrous bone, the hardest bone in the body, is a time capsule preserving DNA through thousands of years. We will sequence full genomes from 160 bones sampled from Irish and Portuguese prehistory to build the detailed story of how genetic variations in Altantic populations came about. The Atlantic edge is important because of its disease burdens, its relatively uncomplicated population history and its hundreds of millions of descendants worldwide.

A complete genomic history will help us understand the origins of known disease variants and also help us pinpoint those newly discovered genetic differences which might be harmful in modern patients.

Dr Ian Brierley

University of Cambridge

Protein trans-activation of ribosomal frameshifting: a new paradigm in gene expression

The macromolecular machine responsible for protein synthesis, the ribosome, translates messenger RNAs (mRNAs) by decoding triplets of bases (codons) as amino acids.The ribosome sticks to the triplet code (the reading frame) until it reaches a stop signal, at which point the completed protein is released. However, many viral and cellular mRNAs have embedded signals that instruct the translating ribosomes to change reading frame, frameshifting at a defined position and to continue translation in an overlapping coding frame. These are not errors as the frameshift products have distinct biological functions. The mRNA signals that induce frameshifting include a structured RNA, referred to as the stimulatory RNA, that blocks ribosome progression until a frameshift takes place. 

We have recently identified examples of viral frameshift signals that lack such RNAs and instead require the participation of viral and cellular proteins to be active. Such trans-activation of frameshifting by proteins is completely novel. We will investigate how these proteins promote frameshifting by analysing their structure and function. 

This work promises to provide new insights into ribosome function and gene expression strategies.

Professor Matteo Carandini and Professor Kenneth Harris

University College London

Organisation of large neuronal populations during behaviour

Until recently, our understanding of brain activity relied on recordings from tens or hundreds of neurons in a single brain region in a single behaviour. In our previous joint project we used these recordings to characterise the activity of local populations of about 100 neurons and to start understanding the circuit mechanisms and behavioural relevance of this activity.

The brain, however, operates through the coordinated activity of vast and distributed populations of neurons, which work in flexible teams to achieve diverse behaviours. New techniques are available to capture this coordinated activity. This will allow us to characterise the basic structure of activity in the whole brain during multiple behaviours, and to understand how every neuron in a local population participates. It will also allow us to see how activity in one population influences activity in another and how these populations underlie the performance of different behaviours.

Our study will use a combination of multiple advanced experimental techniques and computational data processing to provide an unprecedented view on the neuronal-level organisation of populations across the brain during behaviour.

Dr Albert Cardona

University of Cambridge

The complete synaptic-level connectome of a nervous system and experimental connectomics

The nervous system enables animals to sense their surroundings and respond appropriately to specific events using previous experiences and innate biases as a guide. The building blocks are neurons, which are cells that integrate input from external stimuli or other neurons and then communicate them to other neurons or to actuators such as muscles. The only complete map of neural connections was produced for a nematode with only 300 neurons.

We propose to map the pattern of connections of the far more numerically complex nervous system of the fruit fly maggot, an organism whose embryonic development and the overall architecture of its nervous system has numerous parallels with humans. Neural circuits are dynamic and changing connections between neurons is one way that memories can be stored. Building on previous work, we will train animals to like an odour and others to dislike it, and we will compare how the exact same circuit differs in its connections, revealing the ‘engram’: a persistent alteration that represents a memory. We will also study the changes to neural circuits caused by genetic mutations related to neural diseases.

Professor Pedro Carvalho

University of Oxford

The mechanisms and physiology of ER-associated protein degradation

All cells in our body are highly compartmentalised by small membrane-bound structures or ‘organelles’, each with a unique identity and a specialised set of functions. The endoplasmic reticulum (ER) is the largest of these organelles and it carries out several essential functions, including the production of cell surface and secreted proteins through which cells communicate with their environment and the lipids used to build cellular membranes and store energy. In addition, the ER assembles the ‘nuclear envelope’, a membrane that wraps around DNA and keeps it away from other cellular events.

We will investigate how these different functions depend on a process that degrades ER proteins because they are abnormal, they are no longer needed or they are present in the wrong place. Accumulation of these unwanted proteins in the ER has dire consequences to cellular physiology and might result in diseases such as atherosclerosis and cancer. We will examine how they are selected from the thousands of proteins of the ER, which signals are involved and how they are decoded.

Professor Mike Cheetham

Institute of Ophthalmology, University College London

The mechanisms of photoreceptor cell death

Vision is our most precious sense and it is important to understand what happens when vision fails so that we can develop new treatments. Inherited changes in the rhodopsin gene are the most common cause of the retinal dystrophy, retinitis pigmentosa (RP). RP shares some features with other diseases like Alzheimer's, Parkinson's and Huntington's disease where nerve cells die because the genetic changes associated with the disease lead to faulty proteins upsetting the balance in nerve cells.

We will study the inherited changes that cause RP in the UK and define why they lead to blindness. We will do this using model organisms and patient cells to make artificial retinas in the laboratory. We will then test a range of new therapies for this currently untreatable disease.

These therapies could be used individually or in combination to help delay the progression of RP and extend the length of time a patient can have useful vision. The findings could also be used to understand other types of neurodegeneration.

Dr Claudia Clopath

Imperial College London

Memory across multiple timescales

Some memories last for a lifetime and others last only a few hours. For example, one typically remembers travel to an exotic country for many years, but Monday’s lunch menu for only a couple of days.

My team aims to better understand how some memories last and how the brain achieves this. When learning, we change the connections between the main elements of our brain - the neurons. This process can last for different amounts of time, as if each connection could choose to listen to one of multiple clocks that all tick at different rates: fractions of seconds, hours, years. My hypothesis is that the imbrication of these clocks helps memories to last. We will also study how the content of memories can influence their duration.

Dr Francesco Colucci and Professor Ashley Moffett

University of Cambridge

Maternal NK cell recognition of the placenta determines reproductive outcome

About 10 per cent of the burden of disease worldwide is linked to problems of pregnancy, childbirth and infancy, particularly in Sub-Saharan Africa. In the pregnant uterus, specialised NK cells have receptors (KIR) that can bind to fetal HLA-C molecules. Because both KIR and HLA genes are extremely variable, different combinations of maternal KIR and fetal HLA variants characterise each pregnancy.

By comparing these maternal KIR/fetal HLA-C combinations in normal pregnancy to those with pregnancy disorders (such as pre-eclampsia or recurrent miscarriage) in 10,000 mothers and children, including 2,000 in Africa,we will pin down the immune system genes responsible for disorders of pregnancy. We will also use transformative new methods to understand how this NK allo-recognition system between maternal immune cells and fetal cells affects the establishment and development of the placenta and thus, the supply of nutrients and oxygen to the fetus.

Professor Michael Cousin

University of Edinburgh

Determining the role of activity-dependent bulk endocytosis via new molecules

Brain cells (neurones) communicate by releasing chemical neurotransmitters from small compartments called synaptic vesicles (SVs). The maintenance of neurotransmitter release is dependent on SVs being reformed by a process called endocytosis. There are different mechanisms of endocytosis and during very high brain activity the dominant mechanism is activity-dependent bulk endocytosis (ADBE). A number of essential processes are triggered by high brain activity, such as generation of learning and memory, suggesting ADBE will be an important mechanism in these events. However, research in this direction has been hindered by the absence of identified molecules that are specific to ADBE.

We propose to discover new ADBE-specific players, determine how they work and then disrupt their normal function to discover how ADBE controls neurotransmitter release, brain communication and animal behaviour. We have a series of candidate ADBE molecules to investigate.

This work will reveal how neurones communicate during high brain activity and how this communication could be altered by manipulating ADBE. It has the potential to allow a specific and selective intervention to modulate brain communication in healthy people or restore normal function in people with neurological disease.

Professor Anke Ehlers and Professor David Clark, Joint Principal Research Fellowship Renewal and Investigator Award

University of Oxford

Advancing cognitive therapy for anxiety disorders and PTSD

Anxiety disorders and post-traumatic stress disorder (PTSD) are very common, persistent and disabling. We have developed leading psychological therapies for social anxiety disorder, panic disorder and PTSD.

We now plan to harness the power of the internet to make the treatments more widely available and to further improve their effectiveness. Internet-delivered versions of their treatments that require much less therapist time and can be delivered anywhere will be developed and tested in randomised controlled trials.

Dissemination of the treatments within NHS Improving Access to Psychological Therapies (IAPT) services will create a large database that will enable rigorous study of moderators (who respond less well) and mediators (key psychological mechanisms) of therapeutic improvement, in order to identify targets for further treatment development. Modifications of the treatments will then be evaluated.

Professor Mark Field

University of Dundee

A systems approach for understanding cell surface dynamics in trypanosomes

Infectious organisms exploit many varied approaches to surviving within their hosts, but one of the more spectacular and successful is antigenic variation. This process involves the constant alteration of the surface so that the host is unable to mount a successful immune response. In African people, this mechanism has become extremely sophisticated and relies on a superabundant surface protein. How this surface is maintained and how other proteins are also maintained at the surface, is not completely understood. Recent advances have begun to characterise the major players and mechanisms involved, and new and maturing technologies are now available that allow a detailed dissection of this process in a more holistic manner.

I propose a system-wide approach to understanding the roles of surface molecules in trypanosomes and how the surface is maintained. By exploiting methods that allow sampling of the entire trypanosome cell, this will allow an integrated, unbiased and comprehensive understanding of the roles of various proteins in maintaining surface composition. The combined outcomes will identify mechanisms that are unique to the parasite, those that represent vulnerable processes and also insights into therapeutic mechanisms.

Dr Paul Flicek

Regulatory potential of repeat elements in the evolution of tissue-specific transcription

The human genome, like all mammalian genomes, is in large part composed of decayed – but once active – repeat elements, many of which carry tissue-specific regulatory information.

We hypothesise that repurposing of repeat elements has been critical for creating tissue-specific transcriptional regulation. Our research plan involves an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across recent radiations in placental mammals.

Professor David Glover

University of Cambridge

Duplication and cellular functions of Drosophila centrioles

A wide range of diseases and inherited abnormalities are associated with the malfunctioning of centrioles, the nine-fold symmetrical structures that lie at the core of centrosomes. Centrosomes organise a network of microtubules that serve as railway tracks to move various cargos around the non-dividing cell and to partition chromosomes between the cell as it divides. Centrioles also become the templates for building cilia and flagella, outgrowths from the cell that provide motility and act as signalling antennae. In the majority of proliferating cells, it is important that there are only two centrosomes per cell and that they have correctly inherited each cellular generation. 

This study aims to understand the mechanism whereby duplication of the centriole is precisely controlled and synchronised with cell division and how the newly duplicated centriole becomes competent to duplicate and nucleate cellular microtubules. We will also address the poorly understood properties of centrosomes. We will examine their ability to organise membranous vesicles that effectively form the digestion and defence system of the cell. We will also look at the way they interact with the cell's outer membrane to orchestrate formation of the signalling antennae.

Dr Trevor Graham and Dr Andrea Sottoriva

Queen Mary University of London and Institute of Cancer Research

Evolutionary Predictions In Colorectal Cancer (EPICC)

Being able to accurately determine the prognosis of a cancer enables doctors to choose appropriate treatment. Our proposal aims to make determining a cancer's prognosis as routine as forecasting the weather. Weather forecasting is possible because it combines detailed measurements of the current state of the atmosphere together with a mathematical model that describes how the atmosphere will change in the coming days. Feeding the detailed measurements about today's atmosphere into the model leads to accurate predictions about tomorrow's weather. In cancer, we are able measure the cells in the cancer in great detail, but we lack the mathematical model to predict how the cancer will change over time. Our research will address this problem.

We will take accurate measurements in the laboratory of how individual tumours have evolved until today and we will then use this understanding to create mathematical ‘rules’ that describe future changes. We will then use these rules to construct new tools to forecast cancer evolution. Our research will focus on bowel cancer, the second most common cause of cancer-related death in the UK.

Dr Jonathan Grimes

University of Oxford

A mechanistic understanding of the replication of influenza virus

Influenza infects about 3 to 5 million people every year, leading to between 250,000 to 500,000 deaths around the world. Key to viral replication is the polymerase that copies the viral genome and produces viral messenger RNA which is then used to make building blocks for new virus particles. The polymerase of influenza has to perform a number of chemical steps in order for the virus to replicate. It is increasingly clear that being highly dynamic is key to its ability to function.

We will aim to understand the structural changes that occur in the polymerase at various stages during replication and transcription.

These insights will be crucial for our understanding of the key molecular events that take place during infection and could support the development of drugs that prevent it from functioning by ‘disarming’ the virus and making it unable to spread.

Professor Iain Hagan

University of Manchester

Spatial and temporal control of mitotic commitment

In a typical eukaryotic mitotic cell-division cycle, there are key steps that must be sequentially completed for successful division (G1 gap phase precedes DNA replication in S phase, and then a second gap phase, G2, precedes genome segregation in mitosis, M). Growth, development and environmental cues regulate the G1/S and G2/M transitions to control the rate of cell proliferation. Failure of such events can result in forms of cancer.

I aim to dissect the fundamental mechanisms that regulate mitotic commitment using the model organism fission yeast. The focus of his research will be on the precise spatial and temporal controls that are co-ordinated by the centrosome, where the cell microtubules are organised. In addition, I will define how mitotic commitment is reconfigured under specific environmental conditions, such as oxidative stress. Using a combination of genetics, biochemistry, phosphor-proteomics and fluorescence imaging, I will increase the understanding of the eukaryotic cell cycle in health and disease.

Professor Grahame Hardie

University of Dundee

Role of AMPK in nutrient sensing and cancer

I have shown that the protein AMPK senses the energy state of living cells, much like the system in a mobile phone that monitors battery charge, and adjusts cellular metabolism accordingly. For example, it senses energy shortage in muscles during exercise and is responsible for many of the short- and long-term adaptations that occur after exercise, many of which have health benefits. Several chronic human conditions, such as obesity or type 2 diabetes, can be regarded as disorders of energy balance and AMPK is also crucial here, which is why some existing diabetes drugs work partly by switching it on. I have been investigating  how AMPK senses availability of carbohydrate independently of cellular energy, whether it senses other cellular metabolites that bind in the so-called ’ADaM’ site on the protein, if it senses availability of glycogen, the main intracellular reserve of carbohydrate, and why some genes encode AMPK subunits amplified in human cancers. 

The findings will yield insights relevant to major human diseases and could suggest that AMPK inhibitors would enhance the effect of drugs currently used for chemotherapy in cancer, reducing unwanted side effects.

Professor Stephen High

University of Manchester

The quality control of mislocalised membrane and secretory proteins

Proteins are essential to life, providing important building blocks and performing complex roles that maintain health and fight disease. Making proteins is complicated, so we have systems to recognise and remove any misfolded proteins that arise when things go wrong. The ability to control the quality of our proteins is important, since faulty proteins often clump together into potentially dangerous aggregates that are linked to diseases like Alzheimer’s and Huntington’s. Rogue membrane and secretory proteins that reach the wrong destination in our cells, collectively termed muscle LIM proteins (MLPs), also have a strong tendency to aggregate. However, a specialised quality control process recognises and removes these MLPs thereby avoiding potential problems.

We have identified important cellular factors that deal with MLPs by controlling their aggregation and fast-tracking their destruction. It is now vital to understand exactly how these different components work together to deal with MLPs so effectively.

By discovering how MLP quality control works and learning how cells cope when it does not, we will find out why cells can deal with certain kinds of misfolded proteins so effectively and discover how important efficient MLP quality control is for keeping our cells healthy.

Professor Tracy Hussell

University of Manchester

Pathogenic airway macrophage adaptation in the chronically inflamed lung

Macrophages are specialised cells that patrol the lungs, clearing harmless debris as well as dangerous microbes that enter the air spaces. Some people with asthma and chronic obstructive pulmonary disease (COPD) fail to clear microbes which can lead to exaggerated disease, entry of microbes to the bloodstream (sepsis), hospitalisation, a reduction in life quality and, in a lot of cases, death. COPD is one of the most prevalent diseases in the world and accounts for a large amount of the overall health cost. Little progress has been made in its treatment and it is mainly managed by tackling symptoms.

We have identified that macrophages adapt depending on the needs of the lung and they are affected by past experiences. In most people this adaptation is beneficial. However, in patients with COPD or asthma, the ongoing attempt to repair the lung prevents normal macrophage activity. We aim to understand the processes leading to this adaptation so we can develop strategies to restore the normal status quo.

This study will help with strategies to treat patients with COPD and asthma.

Dr Leo James

University of Cambridge

Host physiology of the intracellular humoral immune response

Antibodies are a key molecule of the immune response. It was previously thought that they only work extracellularly, but we have shown that antibodies also prevent infection intracellularly.

We want to understand how intracellular antibody immunity works and is regulated. We will investigate TRIM21, the receptor for antibodies carried into the cell by viruses during infection. TRIM21 is widely expressed but in an inactive form. We will combine biophysics with cellular and organismal infection models to understand how TRIM21 is activated. TRIM21 has a unique ability to target viruses inside the cell and strip them of their protective shell. We will investigate whether this makes viruses more susceptible to other immune sensors, such as RIG-I and cGAS. We recently found that complement C3 also prevents infection from inside the cell but in a different way to antibodies. We will identify the receptor that detects C3 and compare its activity with TRIM21. We will also determine which other serum proteins have intracellular functions.

Understanding how these newly identified immune processes work may reveal new therapeutic possibilities and help in the development of future vaccines.

Dr Meriem El Karoui

University of Edinburgh

DNA repair and genetic stability: elucidating the effects of cell physiology in Escherichia coli

In all domains of life, cells rely on the correct replication and repair of their chromosomes to transmit genetic information. In bacteria, the importance of these processes is highlighted by the many clinically relevant antibiotics that cause DNA damage resulting in cell death but also in mutations leading to antibiotic resistance. Bacteria can proliferate at very different speeds depending on their environment; some infections are very rapid while others will take much more time to develop. The speed at which bacteria grow affects all the molecular processes necessary for life, yet the connection between bacterial growth and sensitivity to DNA-damaging agents has so far been overlooked. It has been observed that slow growing bacteria are less sensitive to DNA-damaging antibiotics, but the reasons underlying this observation are not known.

By combining experimental and theoretical methods, I aim to elucidate the molecular mechanisms that explain this important phenomenon and to quantify how it affects the acquisition of drug resistance.

My ultimate goal is to discover new ways of manipulating bacterial growth for novel applications in antibiotic therapies.

Professor Julian Knight

Nuffield Department of Medicine, University of Oxford

Characterising extreme innate immune response phenotypes informative for disease using a functional genomics approach

This research aims to identify people who show extreme responses to lipopolysaccharide (a component of bacterial cell walls) or interferon-gamma (a chemical signalling molecule associated with infection and inflammation) when used to activate white blood cells called monocytes.

The hypothesis is that genetic factors determine such differences between people. We hope to identify specific genes that are affected by having particular genetic variants and the functional consequences. Such information is very helpful for drug discovery. It provides information about the likely consequences of using a particular drug before large financial investments are made. We will analyse data from large existing cohorts of healthy volunteers who have donated blood samples. We will use a model system based on stem cells to generate the cell types of interest and then use new tools for editing the genome using an accurate cut and paste method so that we can test the effects of making a genetic change.

We will work with experts in drug discovery to make sure that our results aid drug development. The work will help patients with different diseases associated with dysregulated immune function including sepsis.

Professor Zoe Kourtzi

University of Cambridge

Adaptive decision templates in the human brain

When immersed in a new environment, such as navigating a new city or being surrounded by speakers of an unknown language, we are challenged to make sense of an initially incomprehensible stream of events. At first, it seems like a befuddling cacophony that leaves us completely unprepared for what will happen next. And yet, quite rapidly, the brain finds structure and meaning in the incoming signals, helping us to predict and prepare ourselves for future actions. We have little understanding of how the brain achieves this.

I propose to study participants’ ability to learn different types of structure, such as regular patterns in clutter or sequences. Using sophisticated algorithms, we will track participants’ ability to extract structure during training. Our goal is to test how these changes in behaviour relate to underlying brain changes. We will use brain imaging to provide complementary evidence for the brain mechanisms that support structure learning. We will test how different brain circuits specialise to support learning of spatial vs. temporal structures and interact to support our ability to generalise knowledge about structure to new contexts.

Harnessing the brain’s capacity to extract structure during training  has potential implications for boosting lifelong training.

Dr Jan Löwe

MRC Laboratory of Molecular Biology, University of Cambridge

Actin-like cytoskeletal systems in bacteria and archaea

Bacteria contain proteins that form internal fibres. These proteins have counterparts in all other organisms but the functions of the fibres in bacteria are different. One type of fibre (FtsZ protein) facilitates multiplication of bacteria by dividing them into two daughter cells. Others organise the distinct shapes that bacteria adopt (MreB protein). Other types of fibres make sure that certain kinds of parasitic small DNAs (plasmids), are distributed to daughter cells during division (Tubz and ParM proteins), or organise small magnets that form inside certain bacteria so that they are able to swim guided by Earth’s magnetic field (MamK protein).

We propose to investigate some of these fibre systems by integrating information at various length scales, ranging from atoms to individual protein molecules and protein fibres, even to entire cells. Methods we will use include X-ray crystallography, electron microscopy and electron tomography. Combining them with methods that reveal information about the system's dynamics, such as light microscopy, and assembly from their components outside cells, we will be able to investigate how the systems do their work.

The study’s insights might make it possible to disrupt these processes using new drugs that kill harmful bacteria.

Professor Ben Luisi

University of Cambridge

The molecular machinery of RNA metabolism and riboregulation in bacteria

In response to stress and environmental changes, bacteria generate hundreds of small RNA molecules that have key roles in regulating gene expression. This process of riboregulation involves chaperone proteins that facilitate the actions of regulatory RNAs, and enzymes that affect RNA transcript lifetimes.

I aim to understand the molecular basis of riboregulation by taking a multidisciplinary approach. I will use biochemical and structural analyses, including cryoEM and cryoET, to visualise how RNA transcripts are captured and channelled to active sites, either for degradation or processing. I will also identify the RNA targets of chaperone proteins and the degradative machinery, and explore whether the patterns change with physiological state or during the cell cycle, and why.

These studies will help to explain how small RNAs enhance the speed and accuracy of bacterial genetic regulation, enriching the capacity of the simplest organisms to exhibit complex behaviour.

Professor Jane McKeating

University of Birmingham

Defining the role of hypoxia-inducible factors in viral replication and pathogenesis

Dr Rachel McLoughlin

Trinity College Dublin

Staphylococcus aureus-induced immunosuppressive memory: consequences for bug and for host

The World Health Organization highlights the epidemic of antibiotic resistance in Staphylococcus aureus (SA) (methicillin-resistant SA) as a particular threat to society, strongly advocating for the development of alternatives to antibiotics. Efforts are under way to develop vaccines against SA but progress is curtailed by a lack of sufficient understanding of the mechanisms by which this bacterium interacts with the host immune system. In addition to causing severe invasive disease, SA lives innocuously in the nasal passages of the majority of the population. We understand nothing about how exposure to SA in this context affects our immune system or how this exposure might affect our ability to respond to a vaccine against this organism.

We propose that to colonise the host for long periods, SA must have acquired mechanisms to suppress or avoid detection by the immune system. We believe that by doing this the bacterium has the capacity to train the immune system to be unable to respond to a vaccine administered to boost the immune response to SA upon infection. This research will identify if this is the case and will develop strategies to overcome or neutralise this ‘training’ and improve vaccine effectiveness.

Professor Peter McNaughton

Wolfson Centre for Age-Related Diseases, King's College London

Control of body temperature: molecular basis of sensory and effector mechanisms

The molecular basis of how we sense ambient warm temperatures was unknown until recently. Our group showed that an ion channel called TRPM2, which spans nerve cell membranes and so regulates electrical activity in sensory neurons, directly senses warmth. We now want to use a similar method to elucidate the mechanism responsible for detecting extreme cold and the mechanisms by which thermosensitive neurons in the brain respond to warmth and maintain body temperature.

We will try to find out how we expend or conserve heat so as to maintain bodily temperature in the face of thermal challenges. Surprisingly, both the TRPM2 warmth-sensitive mechanism and the unknown cold-sensitive mechanism are present in sympathetic neurons, which are known to regulate body temperature, but the function of these novel sensory mechanisms is not known. We will also investigate how thermosensitive mechanisms in the brain are modulated to cause fever by looking at the effect of factors known to cause fever to see if these act on the same warmth-sensitive mechanisms we use to maintain normal body temperature, or whether there are  different mechanisms involved.

Discovering the molecular mechanisms involved in fever may aid the development of drugs to control pathological fever states.

Dr Martin Meyer

Institute of Psychiatry, Psychology and Neuroscience, King's College London

Imaging visuomotor transformations in the brain

A fundamental goal of neuroscience is to understand how sensory information is represented in the brain, for example identifying the activity patterns in the brain that allow an animal to distinguish prey from predator. Recording activity in the brain during sensory perception and behaviour is difficult to do in most species due to the size and inaccessibility of the brain. We will use the larval zebrafish whose small size and translucency allows imaging of neural activity throughout the brain using fluorescent reporters of neural activity. This allows us to see how the zebrafish brain sees.

We will present visual stimuli to mimic prey or predator while recording neural activity. At the same time, we will monitor for movements of the eyes and tail that are characteristic of hunting and escape behaviours. This will reveal the patterns of activity in the brain that signal the presence of potential prey or predator and will show how this activity is used to drive behaviour.

We will use zebrafish as an experimental model but our project will generate knowledge on the basic rules that govern sensory perception, decision making and behaviour that occur in all animals, including humans.

Professor Jeremy Mottram

University of York

Kinome-wide functional analysis of Leishmania growth and differentiation

Leishmania species are parasitic protozoa that are the causative agents of a spectrum of diseases, the leishmaniases. Little is known about the signalling pathways that regulate key events in the parasites’ life cycles and which protein kinases are essential and therefore potentially amenable to chemotherapeutic modulation.

To address this, I will perform gain-of-function and loss-of-function screens in Leishmania mexicana to identify genes involved in signalling pathways regulating parasite differentiation during transition between animal and sandfly hosts. It is expected that some genes will also be identified that are essential for proliferation and survival of Leishmania once an infection is established in the mammalian host.

The expected output of the project will be novel insights into protein kinase function in Leishmania and a holistic overview of cell signalling pathways that will integrate into ongoing ‘omics’ analyses within the Leishmania community.

Dr Matthew Neale

University of Surrey

Spatial regulation of meiotic recombination

Meiosis is a specialised form of cell division essential for sexual reproduction: it leads to a halving of the genetic content of gametes (sperm and egg cells in humans), ensuring that they are haploid and ready to fuse at fertilisation. Genetic recombination takes place during meiosis. This involves the exchange and shuffling of genetic material across chromosomes generating genetic diversity. In many organisms, including humans, control of the initiation and spatial distribution of recombination is critical to both reproductive and evolutionary success.

I will test the role of the evolutionarily conserved DNA damage-response checkpoint protein Tel1 in this process. I will also investigate how higher-order chromosome structure shapes the spatial landscape of genetic recombination, and will employ a variety of genetic, biochemical, genomic, computational and imaging approaches to study meiosis in yeast cells.   

Professor Matthew Nolan

University of Edinburgh

Intra- and inter-layer entorhinal circuit mechanisms for estimating location

Neurons in a part of the brain called the medial entorhinal cortex (MEC) generate signals that are important for telling the rest of the brain where we are. Location signals are a good model for understanding cognitive processes at a cellular level because they are well characterised. Nevertheless, progress from observing location signals to understanding the mechanisms that generate them is hindered by the complexity of the layered organisation of the cortex, limited availability of tools for manipulating specific cell populations and difficulty in separating the influence of spatial and self-motion signals.

We propose experimental approaches to overcome these challenges. We will focus on two key populations of nerve cells in different layers of the MEC. Our goals are to delineate how these neurons interact with one another and to investigate their activity and roles in encoding locations and influencing behaviours.

Our results will advance understanding of the relationship between cellular signalling and neural computation in the MEC and in cognitive circuits in general. Our findings will also inform understanding of disorders that affect specific layers of the MEC, including Alzheimer’s, schizophrenia and epilepsy, and may also influence the design of devices for artificial navigation.

Dr Duncan Odom and Dr Paul Flicek

University of Cambridge and European Bioinformatics Institute

Regulatory potential of repeat elements in the evolution of tissue-specific transcription

A surprising fraction of the DNA that contains the information required to make a complex organism is composed of sequences that are repeated thousands to tens of thousands of times called repetitive or repeat elements. Every mammalian genome has a unique collection of repeats, which change in number and location during evolution. 

Our study tests the hypothesis that different types of repeats carry instructions that can alter when nearby genes are turned on and in which tissues. We will integrate experimental and computational analyses of the function and activity of newborn and ancient repeat sequences in four key tissues in ten species of mammals. We will then functionally test their activity using genetic engineering tools to disrupt or introduce candidate repeats that may influence how genes are expressed.

Understanding this is important as changes in gene expression can lead to diseases such as cancer and are thought to be a central mechanism of species divergence.

Professor Frances Platt

University of Oxford

The Niemann-Pick type C lysosomal pathway as a novel hub in host: pathogen interactions

Studying rare diseases can bring to light disease mechanisms that occur in more common diseases. For many years we have been studying a rare neurodegenerative disease called Niemann-Pick type C (NPC) disease. We have unexpectedly found that the faulty protein in this disease is targeted by the bacterium that cause tuberculosis (TB). TB inhibits the function of this protein so it can prevent itself being killed by the cell it infects. This unexpected link between NPC and TB now gives us new methods for treating TB based on treatments we have developed for NPC. The Ebola virus also uses this very same protein to infect cells which suggests that the pathway in NPC disease is a hub that is targeted by multiple infectious diseases.  

This study aims to understand how infectious agents manipulate this pathway and use this knowledge to develop a new generation of antibiotics and antiviral drugs.

Professor Sheena Radford

The Astbury Centre for Structural Molecular Biology, University of Leeds

Protein-protein interactions in the early stages of amyloid assembly mechanisms

Over 50 human disorders involve the aggregation of proteins into amyloid plaques. These disorders include type 2 diabetes, Alzheimer’s and Parkinson’s diseases, as well as a host of rarer disorders, which all have no cure. The need to develop successful therapies for amyloid disease is a major priority for human health today. Amyloid formation is of intense interest both to academics focused on how changes in the sequence of a protein causes amyloid formation, and to pharmaceutical companies who want to design drugs that can prevent these diseases.

We will focus on two amyloid diseases – type 2 diabetes and dialysis-related amyloidosis, which involve the formation of amyloid deposits in different sites in the body. By combining structural molecular biology and chemical biology we will map the early processes that initiate amyloid formation and use the knowledge gained to create molecules able to control assembly by targeting these sites.

By testing the effects of this toolkit of reagents in cells and in model organisms we hope to reveal new understandings of why proteins aggregate and to develop new strategies to control aggregation-induced cellular dysfunction and disease.

Dr Markus Ralser

The Francis Crick Institute

Metabolic co-operation in eukaryotes: when metabolic networks operate non-cell autonomously

Metabolism is vital for cell function. Recently, it was discovered that cells not only produce metabolites for themselves but can exchange them with others, sharing the metabolic workload.

I will study how and why cells exchange metabolites. I will define the panel of metabolites exchanged by cells growing together and what determines the flux of these metabolites between cells. It is thought that this metabolic exchange process will produce cellular heterogeneity which could influence cell survival, particularly in response to toxic challenges. This will be studied in the context of fungal infections and cancer to determine whether this system could be manipulated to help treat these diseases, for example to make cells more susceptible to antifungals. Yeast strains used in the biofuel, fermented beverage and food industries will also be studied to see whether modifications could be made to make these cells more productive.

Professor Sarah Reece

University of Edinburgh

Parasite offence or host defence? The roles of biological rhythms in malaria infection

For several centuries, the species of malaria parasite that infect a patient was diagnosed by the regularity of fever (every one, two, or three days). Fever results from the synchronous bursting of malaria parasites in the host’s blood when they release their progeny to infect new red blood cells and cause the symptoms of malaria. Despite this knowledge, it is unknown why parasites that exclusively live in the bodies of other organisms have a daily rhythm. I have shown that the survival and transmission of malaria parasites depends on the coordination of their developmental rhythm with the circadian rhythm of their host.

I will integrate evolutionary ecology, chronobiology and parasitology to explain how parasite rhythms are generated and why daily rhythms matter for parasite fitness. This will open up novel avenues for disease control which includes the development of drugs to disrupt parasite rhythms, harnessing circadian systems to enhance immune responses, or precisely timing drug administration to make treatment more effective.

Growing evidence that the daily rhythms of malaria parasites can confer tolerance to antimalarial drugs and that the use of bed nets is changing the biting time of the mosquitoes that transmit malaria, makes understanding how and why parasites exhibit daily rhythms increasingly urgent.

Professor Beatriz Rico

King’s College London

Assembly and organisation of inhibitory networks in the cerebral cortex

How do complex biological systems self-emerge from cells and molecules? In the cerebral cortex, the most complex and advanced region of our brain, there are neural networks that rely on the interaction between excitatory and inhibitory neurons, but the mechanisms controlling their wiring into specific circuits remain largely unknown. 

Our project aims to elucidate how specific classes of inhibitory neurons choose precise targets among excitatory cells. We will take a multidisciplinary approach to identify how genetic information present in excitatory and inhibitory cells determines their precise connectivity, and how experience shapes this process. 

Unravelling the mechanisms underlying the finest details in the formation of neuronal networks in the cortex has important implications for mental healthcare. Increasing evidence suggests that inhibitory neurons malfunction in many neurodevelopmental disorders, including autism and schizophrenia. Understanding how cortical networks assemble during development will help to produce new treatments for these disorders.

Professor Steven Riley

Imperial College London

The life course of human immune responses to influenza infection and vaccination

Humans experience repeated challenges by influenza A antigens over their lifetime via natural exposure and vaccinations, with the result of each challenge dependent on the history of previous challenges.

During this award, I will combine an existing serological cohort (FluScape) with mathematical methods to precisely describe this lifelong interaction of humans with an evolving virus. Samples collected from the FluScape cohort span multiple time points for the same individuals across two distinct antigenic clusters. Serological assays will be used to measure the antibody strength in these samples against a panel of historical strains of influenza, allowing extension of an existing antibody kinetics model. The model will give answers to key research questions around optimal repeat vaccination schedules for different age groups. I will also refine the model to incorporate data from novel assays that directly measure the frequency of specific clonal B cells.

Professor Antal Rot

University of York

Physiological and pathophysiological roles of DARC (ACKR1) in haematopoiesis

I will study how the expression of the atypical chemokine receptor ACKR1 by erythroid cells affects the steady-state haematopoiesis, including the molecular make-up and functional profiles of stem-, progenitor- and lineage-restricted cells. Furthermore, I will explore the contribution of ACKR1 to the pathomechanisms of experimental diseases that rely in their pathogeneses on haematopoietic cell outputs. Experimental findings in mouse models will be aligned with molecular and cellular parameters of haematopoiesis in individuals of West African origin who carry the hugely prevalent ACKR1 polymorphism FyB(ES) and thus selectively lack ACKR1 in the erythroid lineage.

FyB(ES) is the most predictive ancestry informative marker of African origin and individuals who carry it are recognised to have altered incidences and outcomes of several debilitating diseases, compared to other ACKR1 polymorphisms. I will seek to provide a causative explanation for these findings.

Professor Christiana Ruhrberg

University College London

Gating endothelial cell behaviours in vascular health and disease

Blood vessels consist of an outer protective coat, composed of muscle-like cells and fibrous substances, as well as an inner lining that is formed by endothelial cells (ECs). In healthy vessels, ECs provide a thin and smooth surface that facilitates the exchange of gases, molecules and cells between blood and tissues. However, ECs can also respond to signals from oxygen-starved tissues to expand the vessel network or promote inflammation for tissue repair and to help fight infections. These processes are perturbed in diseases such as atherosclerosis and diabetic eye disease.;

We will investigate how the cell surface molecule neuropilin 1 (NRP1) integrates signals from the environment to alter the expression of genes that balance EC behaviours important for vascular growth and at the same time prevents the poor function of ECs that is common to inflammatory diseases.

The findings will significantly advance our understanding of normal EC behaviour in the healthy body and uncover factors that can be targeted for therapeutic intervention in diseases with blood vessel dysfunction.

Professor David Sansom

Institute of Immunity and Transplantation, University College London

Unravelling the CTLA-4 immune checkpoint: from cell biology to clinical application

Our immune system acts like an army with powerful weapons which are used to fight off invading microbes like bacteria and viruses. However, in a number of diseases such as arthritis and diabetes, T cells in our immune system attack our own bodies, as if the weapon has been fired at the wrong target. Normally, special immune cells called Treg (regulatory T cells) prevent this from happening. Tregs carry a protein called CTLA-4 which hoovers up and destroys the signals that tell T cells to fire. Changes to hoovering efficiency can be critical and auto immune disease can develop when these cells do not work properly.

Despite being essential to our health, we know surprisingly little about how the CTLA-4 system works. In this study we will generate detailed new knowledge on how CTLA-4 behaves in different settings. This will allow us to understand precisely what happens when it goes wrong and will enable us to design and apply better treatments for diseases that affect a large number of people.

Professor David Sherratt

University of Oxford

Co-ordination of chromosome unlinking and segregation

I investigate the molecular mechanisms that control the organisation and processing of bacterial chromosomes throughout the cell cycle. My team’s research makes use of quantitative live-cell single-molecule imaging that enables the visualisation of the assembly and action of molecular machines such as MukBEF, the bacterial structural maintenance of chromosomes complex.

Combining this high-resolution imaging with mechanistic in vitro and in vivo biochemistry will advance our understanding of how bacteria and eukaryotes organise, segregate and repair their chromosomes.

Dr Rachel Simmonds

University of Surrey

Investigating the role of coagulation in the pathogenesis of Buruli ulcer

The neglected tropical disease Buruli ulcer is caused by a flesh-eating bacteria called Mycobacterium ulcerans. We have recently discovered that the bacteria causes a type of blood clot in patients’ skin with similar characteristics to those that cause deep vein thrombosis (DVT). We have already found an association with the loss of the anticoagulant gene thrombomodulin, but coagulation is a complex process resulting from a disturbance in the balance between procoagulant and anticoagulant forces. 

We will investigate what other coagulation components contribute to the clots and investigate the contribution of this process to overall disease progression. This will help us design improved treatments for Buruli ulcer because, like DVT, the clots may respond to anticoagulant medicines. 

This chronic debilitating disease affects mostly poor rural communities in West Africa. This research will help with the treatment of these patients who currently face permanent disfigurement and disability.

Professor Kenneth Smith

University of Cambridge

A new biology of clinical outcome in immune-mediated disease

The long-term outcome of inflammatory diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Crohn’s disease, asthma and multiple sclerosis, varies greatly between people even if they have the same diagnosis. For instance, a patient with SLE might respond to therapy never to relapse, while another with what appears to be an identical disease might suffer relapses, renal failure and death. This illustrates why long-term disease course is a far more important to people than the specific diagnosis they are given.

Medical science has largely neglected the factors that determine patient outcome in these diseases. We will redress that by investigating a ‘marker’ we have discovered by measuring gene expression in white blood cells of patients with various inflammatory diseases. This marker allows us to confidently predict long-term disease outcome, and has led to a test that can help doctors and patients decide on optimal treatment. We will use studies in human volunteers to understand the mechanism underlying this gene expression change.

Our study will provide information we believe will lead to better tests to predict outcome and the development of new drugs that can alter it.

Dr Andrea Sottoriva

Institute of Cancer Research

Evolutionary predictions in colorectal cancer (EPICC)

We aim to make prognosticating cancer like forecasting the weather. Weather forecasting combines detailed measurement of the current atmospheric state with a mechanistic understanding of atmospheric evolution that can be played forward using a mathematical model to give accurate predictions. In oncology, we have the capability to make detailed measurements of the current state of a cancer, but lack a mechanistic understanding about how tumours will evolve over time. The shortfall in knowledge presents a major hurdle to accurate prognostication and is the focus of our proposal.

We will perform a uniquely high-resolution molecular analysis of human colorectal cancers, and via mathematical modelling of these data, derive a quantitative understanding of the ‘evolutionary laws’ that underpin colorectal carcinogenesis. We will evaluate the prognostic value of these laws and use them to construct and test models that mechanistically forecast disease evolution. The proposal builds upon our previous work demonstrating the predictability of cancer genomic alterations as a direct consequence of physical constraints on tumour evolution.

This research will represent a major step towards the replacement of correlation-based prognostication with a new paradigm of accurate mechanistic forecasting.

Dr Anne Straube

University of Warwick

Self-organisation of acentrosomal microtubule arrays

Cells control and remodel their shape using protein filaments such as microtubules, which can act as both a skeleton providing mechanical stability and as transport highways delivering cargo to specific regions of the cell.

We will develop a mechanistic understanding of how active and passive microtubule crosslinkers cooperate in order to form highly ordered and functional microtubule arrays. We will use biochemistry, biophysics and in vitro imaging assays to investigate the formation of microtubule arrays in living cells to identify the principles and minimal requirements for microtubule self-organisation.

Dr Nicholas Timpson

University of Bristol

What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping

Body mass index (BMI) is a simplified measure of body composition/fatness based on your weight adjusted for height and there are clear correlations between BMI and health. However, it is extremely difficult to change BMI in many people and we still do not understand why BMI is a risk factor.The processes of our bodies leave behind chemical biproducts which can be measured easily and efficiently to provide a snapshot of health status. The relationships between these ‘metabolites’ and BMI can help understand the biological implications of different body sizes.

Using collections of metabolites measured in very different studies, I will characterise the effects of BMI on a broad range of biological processes. I will then use very large studies of the general population to bring together evidence and generate a list of metabolites which are affected by BMI. Once done, I will use publicly available genetic studies of disease to find out if BMI has an effect on metabolites and what this does to the risk of disease. 

This will inform future work that looks closely at metabolites that do alter disease risk, rather than attempting to change BMI alone.

Professor Martin Tobin

University of Leicester

Large-scale genomic epidemiology approaches to study the natural history of lung function and COPD

Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death worldwide. Smokers are not equally at risk of COPD and not all patients with COPD are smokers. Genetics also plays a role. We have discovered variants in the DNA that affect lung health, but understanding which genes and proteins to target with new drugs needs more investigation. 

In this project we will use more detailed DNA data from hundreds of thousands of people, together with data that inform us how DNA variants function in cells of the body. We will study how useful these DNA variants are in predicting risk of COPD and whether they affect the risk of other diseases. We also want to study why some patients develop rapid exacerbations of their disease on multiple occasions while others do not. We need to develop methods to study exacerbations and related problems using the electronic medical records of consenting study participants. Using these methods we can study these medical conditions alongside the DNA variations that we and others measured at UK Biobank. 

The findings will take us towards more effective treatment for COPD and possibly towards better prevention of this debilitating disease.

Dr Martin Turner

Babraham Institute

Regulation of B-cell activation and differentiation by AU-rich element RNA binding proteins

My work focuses on understanding how RNA binding proteins that interact with AU-rich elements in RNA regulate the activation of B cells and their participation in the germinal centre reaction.

By studying where in B lymphocytes the RNA binding proteins are located, their physical interactions with RNA and with other proteins, and how they are required for B lymphocyte function, understanding of the basic molecular biology of these cells will be gained.

This knowledge could promote approaches to altering B lymphocyte function in health and disease.

Dr Alessandro Vannini

Institute of Cancer Research

Architectural role of RNA polymerase III promoters and associated factors in shaping and organising the human genome

The human genome is highly compacted in the nucleus, and chromatin fibres – the basic organisational unit of eukaryotic genomes – are specifically organised in units that are brought together to form chromosomes. The three-dimensional organisation of the genome influences the way that the genetic information stored within can be decoded by cells.

I will use a combination of structural biology methods with in vitro functional studies to investigate the protein complex RNA polymerase III, which plays an important role in transcription, in order to determine what role it plays in controlling the topology of the genome.

Professor Steve Watson and Professor Robert Ariëns

Institute of Cardiovascular Sciences, University of Birmingham and Institute of Cardiovascular and Metabolic Medicine, University of Leeds

Fibrin at the interface of platelet activation and thrombus stabilisation

Platelets are small cells in the blood which clump together and form a blood clot at sites of injury. However, excessive clotting in diseased blood vessels, such as at sites of fatty plaques, can lead to blockage and precipitate a heart attack or stroke. Patients at risk of life-threatening clots are treated with drugs, such as aspirin, that block platelet activation. However, all current drugs carry a risk of bleeding which in some cases can be life threatening. We have made a discovery that rewrites our understanding of blood clotting. We have shown that fibrin which is known to form a mesh-like structure that supports the blood clot also drives platelet clumping. Thus fibrin not only strengthens the blood clot but it also causes it to grow.

We propose that drugs that block this action of fibrin represent new forms of treatment for patients at risk of thrombosis. We will study the molecular mechanisms underpinning this interaction and generate inhibitors including proteins that will allow this hypothesis to be tested in human blood and in mice.

Professor Hugh Willison

University of Glasgow

Pathophysiological factors in the diagnosis and treatment of the Guillain-Barré syndromes

Guillain-Barré syndrome (GBS) is characterised by severe paralysis due to inflammation in peripheral nerves. More than 100 years after it was first described in 1916, we still know very little about what causes it. We know the disease is precipitated by a wide range of infections that induce antibodies as part of the normal protective immune response. However, in GBS cases, rogue antibodies are made by the immune system due to a mistake in immune programming and they inadvertently attack the nerves. 

We aim to understand how the rogue antibodies attack the nerves in the GBS disease variants, and how this information can be used to diagnose and treat the syndrome. We have developed experimental methods for large-scale screening of human GBS blood for abnormal antibodies. We have also developed mouse models based on the screening data that can examine disease pathways in nerve tissues and also test new treatments. 

Our overall goal is to improve understanding and treatment of GBS for future patients, healthcare providers and researchers using this translational research.

Dr Hiro Yamano

Cancer Institute, University College London

Control and enzymatic activation of the APC/C ubiquitin ligase system

We study a cellular enzyme that plays a key role in selective protein destruction: the anaphase-promoting complex/cyclosome (APC/C). The APC/C controls many events including genome DNA duplication and segregation, cell growth, differentiation and death, DNA damage repair, brain and metabolic functions. Greater understanding of APC/C function will be of great benefit to human health. Although 20 years have passed since its discovery, our understanding of APC/C function and control is lamentably limited. This is partly due to the sheer size and complexity of the enzyme. The APC/C comprises 14 subunits, many of which are chemically modified at multiple sites by the addition and removal of phosphate groups. Very little is known about the control of these cycles of chemical modification.

We have developed an approach that can now be used to study these controls. We reconstitute the entire APC/C enzyme by making the subunits in a surrogate production system. We then study the function of these reconstituted APC/C complexes in extracts from frog eggs.

This programme will extend these studies to define more precisely how the APC/C is controlled by phosphorylation, identify new binding partners and map the changes in APC/C structure that accompany activity.

Professor Rose Zamoyska

Institute of Immunology and Infection Research, University of Edinburgh

Mechanisms and consequences of T-cell antigen receptor signalling for normal immune homeostasis and the development of autoimmune disease

The major cause of autoimmunity is when a type of white blood cell, called a T cell, makes an immune response against one or more organs or tissues in the body. T cells are very important for mounting immune responses that protect us against pathogens, such as bacteria and viruses, and there are a number of failsafe mechanisms that generally prevent them from attacking tissues in the body. Some people carry mutations in genes that put them at higher risk of developing autoimmunity. A number of these genes influence how T cells behave and these mutations increase the likelihood that T cells may attack the body’s tissues.

Our research is focused on trying to understand how and why these genetic mutations alter the behaviour of T cells. We will identify biochemical processes and pathways that become disregulated by these mutations.

The primary aim of our research is to pinpoint pathways that go wrong so that we can use this information to develop therapies that may be used to alleviate disease.

Dr Marta Zlatic

University of Cambridge

Circuit principles of memory-based behavioural choice

Animals often have to choose between combinations of good and bad outcomes. For example, a child might see a dog under a cherry tree. In order to make appropriate decisions the brain must learn which stimuli predict good or bad outcomes – cherries are tasty and dogs can be dangerous. They must then determine the overall value of each decision – going over to the tree could lead to eating cherries but could also risk a dog bite, but avoiding the tree leads to neither. They must then make one choice and suppress the others. The goal of my research is to explain how brains achieve these kinds of decisions, which are critical for normal life across the animal kingdom and are disrupted in many neuropsychiatric disorders.

Nervous systems are networks of interconnected neurons. Determining the patterns of connections between neurons is an essential first step in understanding how brains work, but this is only possible for relatively small brains. We have produced a connectivity map of a memory and decision-making centre in the brain of the fruit fly larva. We will use genetic tools available in the fruit fly to manipulate and monitor the activity of individual neurons in this network and elucidate general principles by which brains make decisions.



Professor Luke Alphey

Pirbright Institute

Developing methods for driving beneficial genetic traits into vector populations

Mosquito-borne diseases cause severe morbidity and mortality around the world. Dengue is relentlessly increasing in incidence and severity, and chikungunya and Zika viruses have recently invaded the Americas. Genetic control methods potentially offer new, sustainable, environmentally friendly control measures. One possibility is to modify the wild mosquito population so that it is less able to transmit specific diseases. This would leave the mosquito population intact and would be a minimalist intervention in the ecosystem; one aspect of which is that no ‘empty niche’ would be left open for another vector species. Professor Alphey aims to develop methods to make such changes to wild populations, which will require that most of the mosquitoes in the target population carry the disease-resistance gene and continue to do so for many generations. The aim is to develop genetic systems that will persist in target populations, but not invade adjacent, semi-isolated populations. This would allow local action to be taken in modifying selected vector mosquito populations. 

Professor David Beech

University of Leeds

Understanding vascular mechanical sensitivity

One of the most critical aspects of the endothelial cell is its sensitivity to mechanical forces, which arise because of the beating heart, tissue remodelling, external insults and other factors. Piezo1, a large multi-pass membrane protein, has been linked to calcium signalling and mechanical sensitivity, and was found to be required for one of the earliest responses to sheer stress: activation of non-selective cationic channels to allow calcium entry. Piezo1 is considered to be pivotal in both the detection of physical force and its transduction into appropriate vascular architecture. With this award, Professor Beech aims to uncover new mechanistic understanding of the Piezo1 protein and to uncover how vascular mechanical sensitivity works in physiology. This research will lead to a greater understanding of the endothelial cell, the primary architect and architecture of vasculature in the brain, heart and all other major organs.

Professor Robert Brownstone

University College London

Tuning spinal motoneurons for movement

In order to move, our muscles contract with precise forces and coordination. When these processes are disrupted by injury or disease, movements are impaired, resulting in decline in quality of life. To generate appropriate forces, the electrical activity of nerve cells in the spinal cord is finely tuned. Spinal motor neurons connect the central nervous system with muscles, and their activity causes muscles to contract with particular forces. Interestingly, the properties of each motor neuron match those of the type of muscle fibres it innervates. Professor Brownstone will investigate the mechanisms that govern the process of motor neuron tuning. In particular, he will focus on the role played by local spinal cord circuits in ensuring that motor neurons develop the electrical properties required for appropriate force generation. This knowledge will form the foundation of strategies aimed at correcting the neurological control of force production in diseases in which this is impaired.

Professor Antony Carr

University of Sussex

Replication arrest, restart and genome instability

A single human cell contains approximately 12,000,000,000 DNA bases, which must each be accurately copied uncountable times during development. To maintain an adult, this copying occurs billions of times daily. DNA replication is remarkably accurate, but errors do occur and the subsequent genetic alterations can result in genetic and somatic disorders such as cancer. Professor Carr aims to understand the specific mechanisms underlying replication-dependent genomic instability. With a major focus on restarted replication forks, he will combine classical and molecular genetics with super-resolution microscopy to explore new concepts in genome stability. He will establish new assays to understand replication dynamics and novel experimental systems, to explore the nature and consequences of restarted replication forks and how they merge with active replication forks.

Professor Daniel Davis

University of Manchester

The nanoscale organisation of immune cell surfaces in health and disease

Super-resolution microscopes, celebrated in the 2014 Nobel Prize for Chemistry, are one of the tools that allow us to study immune cells in unprecedented detail. Recently, Professor Davis’s research team has used these microscopes to study the changing arrangements of molecules on the surface of immune cells as they survey other cells for signs of disease. They will now compare how the surface organisation of specific immune cells, called natural killer cells and macrophages, varies in health and disease, as well as in individuals with variations in immune system genes. The team will test how the structure of cell surfaces impacts the thresholds at which immune responses are turned on and off. As well as understanding how immune cells work, the aim is to uncover new ways in which medicines can nudge their activity up or down.

Professor Ulrike Eggert
Credit: Credit: David Tett

King's College London

Manipulating membranes: how do lipids interact with the cytoskeleton?

Lipids are important molecules with many essential functions. They are major constituents of all membrane compartments and are key determinants of their interactions with other cellular structures. Cells produce thousands of different lipids and hundreds of proteins to synthesise and transport these lipids. Lipid dysfunction is associated with numerous diseases, but the importance of lipids has been under-appreciated in cell biology. Professor Eggert will use this award to investigate the role of lipids, and particularly their side chains, in processes controlled by the cytoskeleton, such as cell division, movement and cell-cell interactions. Initially focusing on cell division, which requires the participation of lipids and membranes, she will combine multiple methods from chemical biology, cell biology and biophysics to elucidate the specific roles of lipids in modulating the functions of membrane-associated proteins that play different, yet essential, roles in cytokinesis.

Dr Denise Fitzgerald

Queen's University Belfast

Harnessing T cells to remyelinate the central nervous system

Myelin, the supportive insulation that wraps around nerve axons in the central nervous system (CNS) is produced by oligodendrocytes. When myelin is damaged in conditions like Multiple Sclerosis (MS), a repair response can be activated. This should result in the maturation of oligodendrocyte progenitor cells into myelin-regenerating oligodendrocytes that re-ensheath axons (remyelination) and restore neurological function. However, when remyelination fails, as is common in MS, patients can develop permanent disability. Recently, immune cells have been implicated in regulation of this regenerative process. However, little is known about the role of T cells in remyelination, despite decades of research into T-cell-mediated myelin damage (demyelination). By combining neuroscience, immunology and regenerative biology, Dr Fitzgerald will determine how different types of T cells influence remyelination, and examine whether the progression of demyelinating diseases like MS alters these fundamental functions of T cells in CNS regeneration.

Professor Greg Hannon

University of Cambridge

A small RNA-based innate immune system guards germ cell genomes

One of the most fundamental biological imperatives is faithful transmission of the genome from parent to progeny. Transposons - parasitic mobile genetic elements - threaten this process and represent one of the most pervasive embodiments of the host-parasite relationship. Their drive is to propagate in germ cells; failure to control these elements can lead to sterility. Professor Hannon discovered the piRNA pathway, a small RNA-based innate immune system that recognises and silences transposons in germ cells. He will use this award to study the action mechanism of piRNAs. Specifically, he will investigate how maternally-inherited piRNA populations in drosophila influence transposon silencing in germ and somatic cells, how piRNAs are processed, and establish how they bring about long-term transcriptional repression.

Professor Richard Hartley and Dr Michael Murphy 

University of Glasgow and University of Cambridge

Exploring mitochondrial metabolism in health and disease using targeted biological chemistry

Mitochondrial dysfunction contributes to pathologies ranging from the acute, such as cardiac ischaemia-reperfusion injury, to chronic, such as the metabolic syndrome and the degenerative diseases that occur with ageing. Pathology is often associated with increased levels of reactive species such as superoxide and hydrogen peroxide. However, the molecular mechanisms by which elevated mitochondrial reactive species and disruption to redox signalling contribute to pathology are unclear and disputed. This is largely because reactive species and redox changes are difficult to assess in vivo and therapeutic options are limited. Professor Hartley and Dr Murphy aim to determine the molecular mechanisms by which disruption to mitochondrial reactive species and redox signalling networks contribute to acute pathologies and chronic degenerative disorders. This will help to develop new classes of rational therapies for these disorders.

Professor Rita Horvath

Newcastle University

Exploring novel molecular targets in mitochondrial protein synthesis to develop treatments in mitochondrial disease

Professor Karl Kadler

University of Manchester

What are the mechanisms by which cells establish and maintain collagen fibril-rich tissues?

Collagen is the most abundant structural protein in vertebrates. It occurs as centimetre-long fibrils in connective tissues such as skin, tendon, ligament, cartilage and blood vessels. A primary function of the fibrils is to 'stress shield' cells from the potentially damaging forces imposed on tissues by everyday activities like walking. A good analogy is the buildings in which we live and work – there are thousands of tons of concrete above our heads, but the walls protect us by a phenomenon called stress shielding. Collagen fibrils are made during early adulthood and last for our entire lives. This raises an important question about how cells protect the fibrils and if failure of a protective mechanism underlies chronic diseases such as tendinopathies, osteoarthritis and heart disease. Professor Kadler hypothesises that the circadian clock regulates the synthesis and removal of a mechano-protective matrix whose job it is to protect the precious collagen fibrils from being damaged by wear and tear. Using genetic manipulation, mechanical testing and by studying the protein secretory pathway in cells, Professor Kadler aims to understand the role of the circadian clock in tissue maintenance. The work could lead to new ways of preventing chronic diseases of tendons, ligaments, cartilage, skin and blood vessels.

Professor Achillefs Kapanidis

University of Oxford

Molecular mechanisms and regulation of bacterial transcription in vivo

Transcription is a fundamental process for all organisms, constituting the first step in gene expression, and controlling the ability of living systems to develop, differentiate, sense their environment and adapt. Tight regulation mechanisms are required to ensure that the correct genes are expressed at the correct time and place and at the levels required. The timing of transcription is controlled during transcription initiation; a complicated process with many transitions involving transient, dynamic complexes formed through protein and DNA conformational changes. Professor Kapanidis will use cutting-edge single molecule approaches to elucidate the molecular mechanisms that living cells employ to regulate the transcription of genes in a precise spatial and temporal manner by direct, real-time visualisation of transcription on single genes inside single living cells.

Professor James Kaufman

University of Cambridge

Comparative studies to understand the role of class II molecules expressed in epithelial cells

The major histocompatibility complex (MHC) encodes molecules that play crucial roles in the immune responses of vertebrates, including classical MHC class I and class II molecules presenting peptides from the inside of cells to T lymphocytes. Chickens have a much simpler MHC compared to mammals, which has allowed the discovery of phenomena that are difficult to discern in the more complex mammalian MHC, most recently the expression of particular MHC class II molecules primarily in epithelial cells of the chicken intestine. Such specific expression of class II molecules is unprecedented and particularly interesting as the intestine is filled with both beneficial commensal organisms and potential pathogens, and decisions about whether to mount an immune response are complex. Perhaps as a result, the intestine is a site of many infectious, autoimmune and inflammatory diseases. Professor Kaufman wishes to understand the mechanisms and functions associated with these novel class II molecules, first in chickens, and then in mammals.

Professor Paul Klenerman

University of Oxford

Function of novel human T-cell subsets in host defence

The immune system of the gut and the liver are finely tuned to respond rapidly to dangerous infections, but to tolerate normal commensals and food. Among the lymphocyte populations involved in such host defence in humans are newly defined subsets of T cells with unconventional functions. The focus of Professor Klenerman’s studies are two subsets of related CD8+ T cells which both express the cell surface receptor CD161, including a group of cells with antibacterial responsiveness designated mucosal-associated invariant T cells. The aim of this work is to define what the functionality of these cells is in normal tissues, and to what extent it may be modulated in infectious and inflammatory disease, including viral infections such as chronic hepatitis. Since these cell types are a dominant tissue-resident population, these studies look to define their role in normal host defence and in disease pathogenesis, offering routes for intervention.

Professor Peter Latham

University College London

Learning as Bayesian inference

Professor Matthias Marti

University of Glasgow

Elucidating mechanisms of extracellular vesicle-mediated cellular communication and stage conversion in malaria parasites

Malaria parasites cycle between an asexual proliferative and a sexual transmission stage during human infection. To enable efficient transmission to the mosquito, vector parasites need to finely tune the balance between asexual reproduction and sexual development. It has been demonstrated that extracellular vesicles can be transferred between parasite-infected red blood cells (iRBCs) and impact the rate of sexual stage activation, or sexual conversion rate. Professor Marti’s group will define the mechanistic basis of vesicle-mediated cellular communication between iRBCs and its link to the regulation of sexual stage formation. This work has the potential to generate new paradigms in our understanding of Plasmodium biology and interactions with the host environment, and possibly in related Apicomplexan parasites. Understanding the mechanistic basis for Plasmodium’s capability to communicate and regulate the rate of reproduction versus transmission also provides a powerful opportunity for novel interventions.

Professor Anthony Maxwell

John Innes Centre

Understanding and exploiting the role of type II DNA topoisomerases in DNA replication and recombination

DNA topoisomerases perform vital roles in all organisms, regulating DNA topology (supercoiling, catenation, knotting), during replication, recombination and transcription. These enzymes have also emerged as valuable drug targets for both antibiotics and anti-cancer drugs. Professor Maxwell will use structural, biochemical and biophysical approaches to further investigate the role of DNA topoisomerases in DNA replication and recombination, and to understand how the DNA cleavage/religation reaction is regulated in relation to cellular function. He will address long-standing questions in the field, such as the role of ATP hydrolysis in type II topoisomerase reactions, how type II topoisomerases carry out illegitimate replication, and the physiological role of topoisomerase VI in DNA replication.

Professor Thomas Meier

Imperial College London

Molecular mechanism of rotary ATPases and their role as new targets in infectious diseases

ATP is the universal energy storage molecule living cells use to power biochemical reactions. A human being needs approximately their own body weight of ATP per day. ATP is produced by the enzyme ATP synthase; it converts the energy stored in an electro-chemical gradient of protons or sodium ions into ATP and operates by a unique rotary mechanism. Professor Meier aims to understand the structure and operation principles of this molecular machine, and to decipher its mechanism using structural and biophysical methods, including cryo-EM and X-ray crystallography. Specifically, he will investigate how rotary ATPases dynamically couple ion translocation with ATP synthesis and how new types of drugs and inhibitors, such as the class of diarylquinolines, attack and inhibit rotary ATPases on a molecular level. 

Professor Conrad Nieduszynski

University of Oxford

How does a cell complete genome replication?

Accurate and complete genome replication is essential for all life. A single DNA replication error in a single cell division can give rise to genomic disorders, including cancer. Professor Nieduszynski’s research aims to determine how cells faithfully complete genome replication before cell division. Errors in DNA replication occur on single molecules in individual cells. However, these errors can be hidden from view in genomic approaches that look at data from populations of several million cells, causing the pattern of DNA replication in single cells to be hidden by the population average. Consequently, rare problems during DNA replication, including delays in completing replication, cannot currently be readily detected. During this award, Professor Nieduszynski will develop novel single-molecule methods to directly measure DNA replication in single molecules and determine the dynamics of genome replication at the DNA sequence level, and investigate the consequences of insufficient replication origin activity.

Professor Luke O'Neill

Trinity College Dublin

Metabolic reprogramming in innate immunity

Professor O’Neill will investigate metabolic changes occurring in macrophages upon activation of innate immune signalling pathways. Metabolic reprogramming of cells of the immune system has been the focus of recent work by immunologists, with complex alterations occurring in metabolic pathways that govern the function of the immune cell being activated. Specific metabolites accumulate, that then signal to gene expression programmes, enhancing immunity and inflammation. Firstly, the role of the metabolite succinate in generating reactive oxygen species from complex I in reverse electron transport will be investigated. Citrate accumulation leading to the production of malonyl-CoA and malonylation of the enzyme GAPDH will then be examined in detail. This process might lead to GAPDH dissociating from target mRNAs for critical inflammatory mediators, leading to enhanced translation. Finally, the role of glutathionylation and its regulation by the enzyme glutathione transferase omega will be further analysed, as this appears to be another determining event in macrophage activation. This project may point to new therapeutic approaches to limit macrophages in inflammatory and immune diseases.

Professor Tracy Palmer

University of Dundee

Identification of substrates and roles in virulence of the Staphylococcus aureus Ess protein secretion system


Professor Andreas Schaefer

University College London

Behavioural role and neural representation of temporal dynamics in sensory stimuli

The world is a dynamic place. This is particularly true for the sense of smell. Air turbulences impose a rich temporal structure onto smells, as can be appreciated from watching smoke meandering, for example. Professor Schaefer will explore what this temporal structure is, what information it contains, how it is represented in the brain and how it is used to extract critical insight about the world, such as the location of odour sources. Through electrical recordings, images of brain activity and perturbation of specific neuronal types, he will investigate how stimulus dynamics govern behaviour, and thus unravel mechanisms of how information about the external world is represented and processed in neural circuits.

Professor Peter Stockley and Professor Reidun Twarock

University of Leeds and University of York

New perspectives for antiviral therapy: the regulatory roles of genomic RNA in virus assembly, infection and evolution


Professor Guy Thwaites

Oxford University Clinical Research Unit, Vietnam

Personalised adjunctive anti-inflammatory therapy to reduce deaths from tuberculosis

Professor Daan van Aalten

University of Dundee

Mechanisms of O-GlcNAc signalling

Glycosylation of serines/threonines, with O-GlcNAc on nucleocytoplasmic proteins in higher eukaryotes, is an abundant and dynamic intracellular post-translational modification that is essential for metazoan life. Dysregulation of this O-GlcNAcylation has been linked to a diverse set of human diseases, including neurodegeneration, cancer and diabetes. While O-GlcNAc has been identified on over 1000 proteins, it’s not clear how only two enzymes, O-GlcNAc transferase and O-GlcNAcase, can produce this dynamic signalling system. Professor Van Aalten will use Drosophila as a model system to understand how the O-GlcNAc transferase recognises specific proteins as substrates. He is also planning to use a combination of crystallography and chemistry to identify the molecular mechanisms that underpin O-GlcNAc signalling.

Professors Graham Williams and J. H. Duncan Bassett

Imperial College London

Cellular thyroid hormone availability: regulation of development and tissue repair, and pathogenesis of degenerative disease

The basic cellular and molecular programmes that drive growth and development are also essential for tissue maintenance and response to injury. These fundamental mechanisms have been evolutionarily optimised for reproductive fitness, but not for healthy ageing. Dynamic regulation of intracellular thyroid hormone availability is an evolutionary conserved development switch that controls cell proliferation and differentiation, organ maturation and growth. Reversion to this critical developmental programme has recently been implicated in injury and tissue repair. During this award, Professors Williams and Bassett intend to provide a comprehensive understanding that can be exploited for therapeutic benefit in the prevention and treatment of degenerative disease and tissue injury. They have developed unique resources required to manipulate the developmental switch in a conditional and cell-specific manner. They hypothesise a fundamental role for regulated thyroid hormone availability in the coordination of tissue development and function, but its dysregulation in ageing and chronic disease.

Professors Anne Willis and Kathryn Lilley

University of Leicester and University of Cambridge

Transcription, Trafficking, Translation: dissecting the spatiotemporal mechanisms underlying localised protein synthesis

Proteins are central to all processes that take place inside cells and reside at defined intracellular locations tailored to their function. DNA in the nucleus is transcribed into mRNA that migrates from the nucleus into the cytoplasm, where it is translated into proteins, which are trafficked to the location in the cell where they are required to perform their defined function. Little is known about the spatial organisation of the translation of proteins that are synthesised in the cytosol, or peripherally-associated membrane proteins. Many diseases are known to be associated with protein mislocalisation. Professors Lilley and Willis will use their award to define the spatial relationship of the transcriptome, proteome, and the processes that control this relationship, by creating global subcellular maps of proteins and mRNA following specific cellular stimulation. They will combine genomic, proteomic, quantitative cell biological and biochemical approaches, in conjunction with large-scale informatics, and will develop new methodologies and pipelines to understand the control of localised protein synthesis globally.



Professor Benjamin Berks

University of Oxford

Moving folded proteins across membranes

All bacteria produce proteins that operate on the outside of the cell. To reach their correct location these proteins must be exported across the normally impermeable cell membrane by specific transporter systems. The twin arginine translocation (Tat) system is a protein exporter with the highly unusual ability to transport folded proteins. It is required for the virulence of many common pathogens. Tat transport involves the formation of a transient transporter complex. Professor Berks has recently identified ways of following the behaviour of the Tat transporter complex in real time in living cells, of stalling the transporter complex in the assembled state, and of solubilising the transporter complex from its native membrane environment. Professor Berks will exploit these advances to address fundamental questions about the structure and mechanism of the Tat apparatus.

Professor Sir Adrian Bird

University of Edinburgh

Towards understanding and treatment of MECP2-related disorders

Mutations in the MECP2 gene are responsible for two autism spectrum disorders: a loss of function causes Rett syndrome, while over-expression causes MECP2 duplication syndrome. As either too little or too much MECP2 protein leads to profound intellectual disability, understanding how this protein contributes to brain function is a priority. One hypothesis is that is that MECP2 is a multifunctional hub protein implicated in diverse cellular pathways, while a simpler alternative is that MECP2 is primarily a transcriptional repressor that binds methylated DNA and recruits a co-repressor complex. Professor Bird will investigate these hypotheses with experiments that will identify both the determinants of MECP2 binding to chromatin and how varying levels of MECP2 affect gene expression.

Professor Marina Botto

Imperial College London

Complement C1q and CD8+ T-cell immunity – implications for autoimmunity

Patients with the autoimmune condition systemic lupus erythematosus (SLE) develop antibodies that react with molecules found in all the cells of the body, known as autoantibodies. When autoantibodies bind to 'self' molecules, they may cause disease by inducing inflammation in the kidney, skin and other organs. A group of blood proteins called the complement system play a key role in preventing the development of SLE by facilitating the disposal of dying cells and regulating the immune response. During this award Professor Botto’s group will investigate whether and how the deficiency of one component of the complement system, C1q, alters the function of a specific type of immune cell (CD8+ T cells). Ultimately these studies will help to define a new molecular framework for addressing the role of virus infections as potential triggers of autoimmunity.

Professor Frances Brodsky

University College London

The physiological role of clathrin light-chain diversity in vertebrates

Clathrin-coated vesicles are responsible for cell-cell interactions in eukaryotic organisms by mediating membrane traffic pathways that control receptor expression and organelle formation. This process regulates cellular metabolism, cell growth, and immune and nerve cell function. Using cell biology, protein chemistry and mouse genetics, Professor Brodsky will investigate how the light-chain subunits of clathrin coat influence the physiological function of clathrin in vertebrates and how clathrin light-chain diversity enables tissue-specific clathrin functions.

Professor Clare Bryant

University of Cambridge

Inflammasome formation in infectious and inflammatory diseases

Upon infection or injury the host mounts an innate immune-driven inflammatory response to control infections and repair damaged tissue. Dysregulation of innate immunity, however, is associated with many diseases such as cardiovascular disease, diabetes, cancer and autoimmunity in humans and animals. Receptors present inside the cell (NOD-like receptors) sense bacteria and viruses, or non-infectious danger-associated molecules produced endogenously, to form a macromolecular inflammasome-signalling complex which drives protective immunity against pathogens and optimises the development of adaptive immunity. Professor Bryant’s research programme will investigate how inflammsome-signalling complexes self-assemble within cells in response to different pathogens or ligands and the consequent functional impact on the host immune response to infection. The impact of within- and between-species diversity in inflammasome genes on inflammasome self-assembly and host innate immune responses will also be investigated.

Professor George Christophides

Imperial College London

Anopheles-Plasmodium interactions: mosquito immune response and parasite immune evasion strategies

Professors Nicholas Franks and William Wisden

Imperial College London

Capturing the neuronal ensembles underlying sleep and sedation

Why we spend one third of our lives in a state of vulnerable inactivity – sleep – is an enduring mystery. Like hunger and thirst, the urge to sleep is a primal biological drive. It builds during waking and then dissipates during sleep. But the question of what exactly the drive to sleep is remains unsolved. In fact the drive to sleep after prolonged sleep deprivation seems so strong that it is similar to taking a sedative drug. During this award, Professors Franks and Wisden will investigate the mechanisms underlying the sleep drive and ask whether certain sedatives produce unconsciousness by activating the same neuronal pathways. Using a genetic approach that 'tags' the neurons involved, they aim to find out how these circuits function. A deeper knowledge of how sedatives work could lead to drugs that have fewer side effects and might even give the restorative benefits of natural sleep.

Dr Clare Jolly

University College London

Virus-host interactions regulating HIV-1 replication in T cells

To successfully infect human cells and cause AIDS, HIV must navigate a complex environment, hijacking the essential cellular machinery it needs to replicate and spread, while avoiding innate and adaptive immune defences. The aim of Dr Jolly’s research is to understand the molecular cell biology of HIV infection and how this shapes pathogenesis. HIV exploits direct cell-to-cell spread to rapidly disseminate at immune cell contacts. During this award, Dr Jolly will explore exactly how HIV co-opts cellular signalling pathways to drive successful infection and spread in T cells, and determine the biological consequences for the virus and the host. These studies seek to provide greater insight into virus infection of immune cells. This will advance understanding of HIV pathogenesis and contribute fundamental knowledge about T-cell function in health and disease, potentially informing future antiviral strategies.

Professor Kim Nasmyth

University of Oxford

How are chromosomes held together by cohesin?

Each chromosome must be replicated to produce sister DNAs, which segregate to opposite sides of the cell during mitosis. Chromosomes metamorphose into threads largely segregated from their sisters but attached along an inter-chromatid axis through sister chromatid cohesion. This ensures that sister DNAs are pulled in opposite directions. Professor Nasmyth has identified proteins that mediate sister chromatid cohesion and shown that they form a multi-subunit ring-shaped complex called cohesin. He has proposed that cohesin holds sister DNAs together by trapping them within its ring structure. Professor Nasmyth aims to establish the universality of this 'ring model' to elucidate how DNAs enter and exit cohesin. He will also apply insights derived from cohesin to understanding how a related complex called condensin holds the DNA within individual chromatids together. This work will enrich chromosome biology and yield insights into tumours and age-related infertility in females.

Professor Nicholas Proudfoot

University of Oxford

Molecular mechanism and regulatory function of protein coding gene transcriptional termination in mammalian genomes

The enormous facility with which mammalian genomes can be sequenced has outstripped our understanding of gene function in a genomic context. This disconnect between genomics and gene mechanism is especially evident in understanding how gene transcription units are defined. Professor Proudfoot investigates transcription termination – both its basic mechanism and how it acts to regulate gene output. He will combine genomic analysis of nascent transcription with mechanistic studies, and aims to define the class of termination mechanism for each gene in the human genome and understand why termination is defective in cancer. This information will be important to better understand how specific genes are regulated and could ultimately aid more effective cancer therapy.

Professor Daniel Raleigh

University College London

The molecular basis of islet amyloid induced beta-cell death and the inhibition of islet amyloid induced toxicity

Amyloid formation plays a central role in a wide range of devastating diseases such as Alzheimer's and Huntington's disease, but the mechanism of amyloid formation has yet to be defined in detail for any protein. The nature of the toxic species produced during amyloid formation is controversial and past efforts at drug development that target amyloid for therapeutic benefit have been disappointing. Professor Raleigh's work will focus on islet amyloidosis by the neuropancreatic hormone islet amyloid polypeptide and its role in type 2 diabetes and pancreatic beta-cell death. His lab is aiming to determine how islet amyloid polypeptide forms and why it forms both toxic and non-toxic oligomers.

Professors David Ray and Andrew Loudon

University of Manchester

Clock control of inflammation in the lung

Circadian rhythms dominate virtually all aspects of human physiology. It is now established that disruption of the circadian clock has a profound impact on inflammation in both humans and in animal models. During this award, Professors Loudon and Ray intend to address the fundamental question of how the clock controls host defence. To do this, they will focus on pulmonary inflammation and specifically aim to elucidate how time-keeping and inflammatory cells communicate to shape pulmonary immune response, how the molecular clocks control pro- and anti-inflammatory signalling within the lung, and how clock regulation of epigenetic structure mediates inflammatory set point. The aim of this award is to further our understanding of how local tissue environment and the immune system interact to dictate the magnitude, direction and responsiveness to treatment at sites of immune challenge.

Professor Angela Roberts

University of Cambridge

Fractionating the functions of primate ventromedial prefrontal cortex of relevance to depression

Depression has a lifetime prevalence of 16 per cent and is the single most important contributor to the total European disease burden. Unfortunately, the current range of treatments is relatively restricted and their success is limited and variable because of the marked individual differences in symptoms and the varied reasons why someone may become depressed. Depressed patients have marked changes in activity in a brain area called the ventromedial prefrontal cortex, but whether these alterations are a cause of depression or a compensatory change is unclear. Thus, the goal of Professor Roberts's research is to identify the different functions of distinct regions within the ventromedial prefrontal cortex and associated brain circuitry and determine how they relate to different symptoms of depression, and how they are modulated by existing drug therapies. Not only will this allow existing therapies to be targeted more effectively, but it will also help discover new therapies and guide personalised treatment strategies.

Professor Philippe Schyns

University of Glasgow

Brain algorithmics: reverse engineering dynamic information processing in brain networks from MEG time series

The ultimate goal of cognitive neuroscience is to understand the brain as an organ of information processing. This will remain difficult unless we understand more directly what information the brain processes when it categorises the external world. For example, our brain can extract from a face (a powerful social communication tool) information to categorise identity, age, gender, ethnicity, emotion, personality and even health. Though our brain knows what information to use for each task, as information receivers we typically do not have direct access to this knowledge. The current state of cognitive neuroscience is similar – we aim to understand the brain as an information processor, but we do not know what stimulus information it processes. Professor Schyns will address this fundamental problem by developing brain algorithmics, a framework that first isolates what specific information underlies a given face categorisation, then examines where, when and how the brain processes this information.

Dr Christian Speck

Imperial College London

Assembly, function and molecular architecture of the eukaryotic replicative helicase

Perhaps the most fundamental property of all living things is the ability to replicate their DNA, which allows cells to pass on their genetic material from parent to progeny. Accurate DNA replication is essential for genomic stability and organismal wellbeing. Errors in DNA replication are strongly associated with ageing and cancer. The ring-shaped replicative helicase complex MCM2-7 plays a vital role in DNA replication. Dr Speck is investigating the molecular basis of MCM2-7 ring opening using structural, genetic and biochemical techniques to understand how this fundamental molecular machine functions during DNA replication. Understanding the underlying mechanism of how the replicative helicase gains access to DNA, is regulated on DNA and is released from DNA will also aid the development of novel DNA replication inhibitors with therapeutic value.

Dr Jonathan Stoye and Dr Ian Taylor

The Francis Crick Institute

Lentiviral accessory proteins Vpx and Vpr, viral countermeasures to host cell defences

Vpr and Vpx are essential lentiviral accessory proteins required for optimal infection of immune cells by HIV-1 and HIV-2, the causative agents of AIDS. The function of Vpr and Vpx is to implement the destruction of host-cell defence proteins that would otherwise inhibit virus replication and so render the host permissive to infection. Both Vpx and Vpr exert their effects through interaction with DCAF1, a host-cell adaptor protein that directs proteins to the cell's E3 ligase ubiquitination machinery. Using their combined strengths in structural biology, retrovirology and cell biology, Dr Stoye and Dr Taylor propose to investigate how Vpx and Vpr interact with their cellular targets and examine the consequences for HIV-1 infection upon modification or disruption of these interactions. Such studies are prerequisites to the development of drug molecule ‘disruptors’ of this host-pathogen interaction that target viral countermeasures and expose the virus to the full effects of cellular defences.

Dr Brian Stramer

King's College London

Dissecting the cellular mechanics of contact inhibition of locomotion

Contact inhibition of locomotion (CIL), a process whereby migrating cells collide and repel each other, is critical during embryogenesis and is hypothesised to play a role in pathologies such as cancer. This phenomenon can be observed in vivo during the dispersal of embryonic Drosophila immune cells (macrophages), which require CIL for their developmental migrations in living embryos. The precise patterning of macrophage movement in Drosophila embryos is controlled by CIL. Dr Stramer aims to elucidate both the molecular and mechanical mechanisms regulating this process by exploiting a wide array of techniques available in this model system, such as live imaging and genetic manipulation.Knowledge and analytical techniques developed from these studies will be extrapolated to mammalian models of immune cell interactions to investigate the wider role of CIL in animal physiology.

Dr Nicolas Tapon

The Francis Crick Institute

Tissue growth control and mechanics during development

How each cell in a developing animal ‘knows’ to stop growing and dividing when the correct body size and shape has been reached is of fundamental importance to our understanding of diseases such as cancer. Systemic cues acting at the organism level, such as nutrient availability, strongly influence final organ size, as do signalling molecules involved in patterning, which couple tissue growth control with pattern formation. Recently, it has been shown that as the tissue grows, changes in physical forces might act as a developmental timer that specifies the onset of growth arrest. The conserved Hippo pathway, discovered in Drosophila genetic screens for tumour suppressors, is a good candidate to mediate the effect of mechanical forces on size control. Dr Tapon will investigate when and how the Hippo pathway is regulated during development and the mechanisms by which the cellular mechanical environment influences developmental growth arrest via Hippo signalling.

Professor Philip Taylor

Cardiff University

Understanding the molecular controls of tissue resident macrophages

Dr Steven West

University of Sheffield

Control, specificity and function of RNA polymerase II modification in human messenger RNA maturation

Messenger RNA (mRNA) processing by capping, splicing and cleavage and polyadenylation generates protein-coding information from primary transcripts. The maturation of mRNA is coordinated with transcription via phosphorylation of the C-terminal domain of the large subunit of RNA polymerase II. This modification is thought to constitute a code that orchestrates transcriptional and mRNA maturation events. Dr West will make use of a combination of biochemistry, genome editing and proteomics in order to investigate both how this C-terminal domain modification is co-transcriptionally regulated and whether there are other interacting proteins that are essential for the biological effects of this phosphorylation.


Professor Judith Allen

University of Edinburgh

Chitinase-like proteins: host protection through molecular multi-tasking

Helminth infection results in a host-protective type 2 immune response that is important for both parasite control and tissue repair. Chitinase-like proteins (CLPs) are induced during type 2 immunity, and are strongly associated with helminth infection, tissue injury and a variety of chronic diseases. CLPs unexpectedly induce the pro-inflammatory cytokine IL-17, leading to a response that limits parasite numbers but at a cost of enhanced tissue injury. As infection progresses, CLPs contribute both to the induction of a protective type 2 immune response and to repair of the damaged tissue. Professor Allen will use a tissue-migrating helminth model to investigate how CLPs perform such diverse tasks and reveal why they are so strongly associated with numerous pathological conditions. More fundamentally, the studies will provide key insight into how IL-17 pushes the type 2 response into a more pathological state, which will be relevant to a range of chronic conditions.

Professor Peter Brophy

University of Edinburgh

Identifying how membrane proteins required for saltatory conduction are trafficked and stabilised in PNS axonal domains

Rapid nerve impulse conduction in vertebrate nerves depends on the clustering of voltage-gated sodium channels at nodes of Ranvier, which are gaps between the successive myelinated segments of axons. If nerves lose their myelin sheath, such as in multiple sclerosis or Charcot-Marie-Tooth disease, nodes are disrupted, leading to loss of nervous system function, blindness, paralysis or even death. Professor Brophy’s team have discovered that a protein called neurofascin plays an essential role in clustering these channel proteins at nodes in response to myelination, but there is currently little understanding of how it does this. The objective during this award is to directly visualise how neurofascin accomplishes this crucial task by using conventional and super-resolution light microscopy to track the targeting and fate of fluorescently-tagged nodal proteins in living nerves. This information will then be used to probe the mechanisms of node assembly and stabilisation.

Professor Andres Floto

University of Cambridge

The host response to Staphylococcus aureus infection

Professor Floto's team are focused on understanding how the innate immune system interacts with Staphylococcus aureus. Specifically, they will examine how this bacterium can disrupt macrophage function to avoid intracellular killing, how autophagy is activated and may be subverted, and how cellular invasion is sensed and signalled to the wider immune system. They are particularly interested in how signalling through nerve growth factor beta coordinates effector immune responses during infection and may potentially be therapeutically stimulated to enhance bacterial clearance.

Professor Gad Frankel

Imperial College London

Deconstructing Citrobacter rodentium pathogenesis

The control of bacterial infections is arguably the most important achievement of modern medicine. However, the rapid emergence and spread of antibiotic resistance emphasises the constant need to develop new antimicrobial therapies and vaccines. The development of effective control measures requires a systematic understanding of the biology of the disease in the context of the complex interactions between bacterial pathogens and their hosts. The human intestinal pathogens enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) use a type III secretion system to inject effectors into infected cells, where they reprogram cell signalling. The global aim of this project is to study the function of the effectors, including the identification of their partner proteins in infected enterocytes, in vivo. The programme will focus on Citrobacter rodentium as a well-established and tractable murine system that serves as the model to study EPEC and EHEC pathogenesis and mucosal immune responses to infection.

Dr Elena Gheorghiu

University of Stirling

Towards a better understanding of mirror-symmetry coding in human vision

Mirror symmetry is a ubiquitous feature in natural images, in both biological and man-made objects. Symmetry provides insight into the ways in which human vision solves fundamental perceptual problems. It plays an important role in object recognition and figure-ground segmentation. During this award, Dr Gheorghiu will investigate neural mechanisms responsible for mirror-symmetry perception in human vision with the aim of elucidating how these mechanisms interact with those involved in colour, stereoscopic depth and motion processing. She will use a combination of approaches: appearance-based and performance-based psychophysical methods, event-related potential methods, and computational modelling. This research programme will advance our understanding of how mirror-symmetry mechanisms operate in individuals with normal vision and will provide insight into the spatiotemporal flexibility and limitations of these mechanisms. A better understanding of mirror-symmetry coding in human vision will enable the prediction of how these mechanisms will be affected in an ageing visual system and in individuals with abnormal processing of mirror-symmetric form.

Professor Jonathan Higgins

Newcastle University

The function of histone modifications in mitosis

For productive division, cells must accurately segregate their chromosomes and pass lineage-specific gene expression patterns to their daughters. These events involve the recruitment to chromatin of proteins required for chromosome segregation, the displacement of transcription factors to downregulate or reprogram transcription, and the retention of specific bookmarks that allow memory of the transcription program to be inherited through mitosis. Histone modifications, which regulate the association and dissociation of mitotic regulators and transcription factors from chromosomes, are critical for these events. Professor Higgins will address fundamental questions that remain about these mechanisms of regulation during cell division.

Professor Jay Hinton

University of Liverpool

Novel virulence properties of non-typhoidal Salmonella associated with epidemics in bloodstream infection

Invasive non-typhoidal Salmonella disease is causing a global epidemic of bloodstream infection. Salmonella bacteria are targeting HIV-infected adults and immune-suppressed children, killing 388,000 people each year across Sub-Saharan Africa. Although the clinical picture is well established, there has been a lack of basic research into this neglected disease. Professor Hinton’s research will identify the specific properties of the new types of Salmonella that are responsible for the African clinical syndrome. Using a multidisciplinary approach involving functional genomics and comparative transcriptomics, this project will contribute to our understanding of the evolution of virulence in bacterial pathogens.

Dr Peter Lawrence

University of Cambridge

Novel approaches to the cell biology of planar cell polarity

Cells in epithelial sheets are polarised in the plane of the sheet, as shown by the patterned orientation of mammalian hairs and insect bristles. This fundamental phenomenon, known as planar cell polarity (PCP), is essential during development, and failures in PCP have been implicated in common human birth defects, such as cleft palate, spina bifida, hearing defects and polycystic kidney disease. Dr Lawrence studies PCP in the fruit fly Drosophila and has recently discovered that single epithelial cells can be multipolar - polarised in different directions - suggesting that the mechanisms of PCP are subcellular. During this award, Dr Lawrence aims to understand the molecular mechanisms by which cells read and interpret their environment to determine their orientation and communicate this information to neighbouring cells, by using a combination of Drosophila genetics, cell biology and in vivo imaging.

Professor Boris Lenhard and Professor Ferenc Mueller

Imperial College London and University of Birmingham

The core promoter: an unexplored regulatory level of transcription during vertebrate development

Critical transitions in animal development are determined by a succession of transcriptional regulatory events mediated by a large number of cis-regulatory modules, which are integrated into transcription initiation at RNA polymerase II core promoters – the DNA sequences at which transcription to RNA is initiated. The type of the core promoter is the regulatory point that critically determines the activity profiles of genes. However, different types of promoters are defined tentatively, and the role of the differences is often overlooked. The principal reason for this is our current lack of understanding of promoter regulatory codes and their functional diversity, which can provide key insights into their underlying biology. Professors Lenhard and Mueller are planning to address this issue by investigating the systematic use of distinct promoter types for specific regulatory purposes, to discover unknown classes and subclasses genome-wide, define their fundamental properties, and uncover their functions in regulating transcription in the developing embryo.

Professor Bradley Love

University College London

Neural and computational mechanisms of categorisation

Judging a person as a friend or foe, or a tumour as cancerous or benign are examples of categorisation tasks. Category knowledge provides a necessary basis for almost every cognitive act, ranging from assessing the value of an object to problem solving. This project evaluates a novel theory about how people learn and use category information to make critical decisions. The theory emphasises how people sample their external world (e.g. eye movements) and their internal world (e.g. memory retrieval) when learning and making decisions. A computer model is used to simulate how people learn and categorise novel objects. The psychological and neural plausibility of this model will be evaluated in a series of brain-imaging studies. The outcomes of this project should inform best practices for treating people who have difficulties in the mental processes supporting categorisation, including those related to learning, memory retrieval and attention.

Dr Goedele Maertens

Imperial College London

Characterisation of a novel human T-cell lymphotropic virus integrase binding partner: from structure to function

The delta-retrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the cause of an aggressive T-cell leukaemia and a debilitating neurological disease. To date, there are no effective treatments. One unique and essential step in the life cycle of retroviruses such as HTLV-1 is the integration of a DNA copy of the viral RNA into the host genome. This process is catalysed by the viral enzyme integrase. Target site selection is not random, but appears to be determined by the interaction between integrase and a host factor. Recent findings suggest a correlation between integration into active transcription units, increased proviral expression and development of disease. Using a proteomics screen Dr Maertens's group has identified a set of HTLV-1 integrase binding partners, of which one candidate also significantly stimulates the HTLV-1 integrase biologically relevant activity. During this award the group’s main aims are to define the mechanism for modulation of IN activity by this novel host factor, to characterise the role of the integrase binding partners in HTLV-1 infection, and to structurally characterise the delta-retroviral integration machinery. This study will also inform the design and development of drugs to treat HTLV-1-infected patients.

Professor Gero Miesenboeck

University of Oxford

Time to decide

Many behaviours, including movement, navigation, communication and decision making, unfold over time. These behaviours must therefore be based on orderly sequences of nerve cell activity. How the brain generates such sequences is largely unknown. Professor Miesenboeck will explore this fundamental problem in fruit flies, which (like humans and higher animals) take time before committing to a choice. The amount of time taken varies with the difficulty of the decision and is heavily influenced by a small group of approximately 200 nerve cells in the fly’s central brain. These 200 cells are distinguished by the presence of FoxP, a genetic regulator molecule whose human versions are important determinants of cognitive ability. Professor Miesenboeck’s group will study how the activity of the FoxP-containing nerve cells in the fly changes as a decision progresses toward commitment, identify the biophysical principles and neuronal connections that support these evolving activity patterns, and investigate the molecular and cellular mechanisms through which FoxP acts.

Professor Chris Ponting

University of Oxford

CEROX-miRNA control of mitochondrial OXPHOS activities in health and disease

Low mitochondrial enzymatic activity is a shared feature of many neurological disorders, such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington’s disease and certain forms of brain cancer. Professor Ponting aims to explore the role of long non-coding RNA and micro-RNA in mitochondrial enzymatic activity, and will focus on a novel class of RNAs, termed competitive endogenous RNAs, which he has shown to affect oxidative phosphorylation. A diverse range of experimental and computational approaches will be used, as well as newly generated animal models. The ultimate goal is to ameliorate oxidative stress in iPS cell lines from patients with a variety of neurodegenerative or neuropsychiatric diseases including Alzheimer's and Parkinson's.

Dr Caetano Reis e Sousa

The Francis Crick Institute

Actin exposure as a universal trigger of inflammation

Inflammation is a response to microbial invasion or tissue damage designed to eliminate the offending stimulus, clear debris and stimulate tissue repair. Although much is known about the pathways that trigger inflammation in response to pathogen invasion, the induction of sterile inflammation following tissue injury remains poorly understood. This is an important area because dysregulated and/or chronic inflammation, often of sterile origin, is increasingly recognised to be a contributing factor to a vast range of human diseases, from cancer to neurodegeneration. During this award Dr Reis e Sousa will explore whether exposure of the actin cytoskeleton following cell damage contributes to sterile inflammation across species, and will investigate underlying mechanisms.

Professor Giampietro Schiavo

University College London

The mechanism controlling sorting and axonal retrograde transport in neurons

Neurodegenerative diseases carry a significant global health burden and are currently incurable. We have only incomplete knowledge about their pathological mechanisms and which physiological processes are key for disease onset and progression. Professor Schiavo's findings indicate that long-range transport pathways, such as fast axonal transport, are essential for maintenance and survival of neurons. Accordingly, deficits in axonal transport are associated with the onset of several neurodegenerative diseases, suggesting a causal role for dysfunctions in this pathway in these pathologies. Given the limited knowledge of the mechanisms controlling long-range axonal transport, the goal during this award is to address the mechanisms controlling the progression of cellular organelles along the axonal transport route. Professor Schiavo's lab will pursue this aim by investigating the journey of tetanus toxin, a potent neurotoxin causing tetanus in humans and animals, into the nervous system, and the role of components of its receptor complex in axonal transport and neuronal survival.

Professor Claudio Stern

University College London

Mechanisms that position the embryonic axis and the causes of identical twins

In humans, identical (as well as conjoined) twins can arise by spontaneous splitting of the embryo relatively late in development, right up to the time when the primitive streak forms, when the embryo already contains many cells. This suggests that the mechanisms that determine the position of the embryonic axis remain plastic for a long time, and that in normal development something must inhibit formation of multiple embryos. Almost nothing is known about the mechanisms involved in this embryonic regulation, which is likely to be responsible for the generation of monozygotic and conjoined twins in humans and other amniotes. Professor Stern plans to take a multidisciplinary approach, using chick embryos and the genetics of human populations systematically to identify inducers and inhibitors of axis formation and generate a comprehensive model of the cell and gene interactions controlling polarity, regulation and twinning.

Professor Rajesh Thakker

University of Oxford

Calcium-sensing receptor – a G-protein-coupled receptor – signalling pathways in health and disease

The calcium-sensing receptor (CaSR), a G-protein-coupled receptor that is widely expressed, is critical for calcium homeostasis and also has non-calcitropic roles (development of neurons and lungs, cell fate, tumorigenesis and gastro-entero-pancreatic physiology). Mutations of the CaSR and associated proteins cause approximately 75 per cent of hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, and CaSR abnormalities may also affect glucose homeostasis. However, precise molecular mechanisms of CaSR signalling and trafficking, and their calcitropic and non-calcitropic roles, remain to be elucidated. During this award, Professor Thakker aims to characterise CaSR signalling and trafficking pathways and facilitate translational research. These studies also aim to provide diagnostic and therapeutic advances for patients with calcitropic disorders (eg renal and metabolic diseases associated with kidney stones) and non-calcitropic disorders (eg diabetes mellitus).

Professor Brian Walker

University of Edinburgh

Tissue-specific control of cortisol versus corticosterone in humans

Human adrenal glands secrete both cortisol and corticosterone. High cortisol levels in blood cause Cushing's syndrome, with obesity and accelerated cardiovascular disease, while low levels cause Addison's disease. Professor Walker's research has shown that cardiometabolic risk factors in the population are associated with more subtle elevation in cortisol levels in both blood and tissue. However, any contribution of corticosterone in humans has been neglected to date. During this award, using the experimental medicine toolkit that his group has developed to study steroid physiology in vivo in humans, Professor Walker will extend recent discoveries that blood and tissue levels of cortisol and corticosterone are controlled independently, and establish the consequences for steroid signalling in adipose tissue in obesity. The programme will include proof of concept for a new therapeutic approach to improve metabolic control in patients with adrenal insufficiency.



Dr Tal Arnon

University of Oxford

Regulation of splenic B-cell responses by tissue resident macrophages

The spleen provides a critical immune defence against pathogens that have reached the blood recirculation. Dr Arnon will study how immune responses are organised within the spleen, focusing on the roles of tissue-resident macrophages in regulating B-cell migration and activation. This research will use a combination of approaches, including novel mouse models and advanced imaging techniques, to determine the functional specification of distinct macrophage populations, and to define their roles in regulating humoral immune responses. These studies will advance our understanding of immunity against blood-borne antigens and the way by which tissue macrophages have evolved to address the specific requirements of their niche.

Professors David Baker and Michael Blackman

London School of Hygiene and Tropical Medicine and The Francis Crick Institute

Functional analysis of the cGMP signalling pathway in malaria parasites: a master regulator of life-cycle progression

Cyclic GMP (cGMP) is an intracellular messenger molecule that plays important roles in most cell types. Levels of cGMP in the cell are controlled by the opposing action of two enzymes called guanylyl cyclases and phosphodiesterases. When an environmental signal triggers this pathway, it brings about intracellular changes, often via the activation of a cGMP-dependent protein kinase. The cGMP signalling pathway has numerous roles in mammals, including perception of light by the eye, smooth muscle contraction, and heart function. The malaria parasite, Plasmodium, also has a functional cGMP signalling pathway which has been shown in recent years to regulate several important events during its life cycle in both the human host and mosquito vector. Professors Blackman and Baker will investigate the function and regulation of the pathway using biochemical and genetic approaches. Significant differences between the parasite and mammalian systems will present opportunities to develop novel antimalarial drugs.

Professor Imre Berger

University of Bristol

Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription

An essential first step in biogenesis is gene transcription. In humans, this process is regulated by complexes often comprising ten or more subunits, which arrange in superstructures that cooperate at the interface of chromatin, fine-tuned by activating and repressing modalities. Professor Berger's research aims to understand the cellular mechanisms of these protein machines, their assembly process from gene to functional complex, their interdependence in gene regulation and the factors that control them. He will study an archetypal general transcription factor complex (TFIID), a multiprotein coactivator (SAGA) and a multiprotein corepressor (NuRD), using a combination of macromolecular crystallography, electron microscopy, proteomics, cell biology and genetics.

Dr John Diffley

The Francis Crick Institute

How the eukaryotic replicative DNA helicase is loaded and activated

We each synthesise roughly 500 million km of DNA every day – more than the distance from the earth to the sun and back. Despite this scale, and the large number of tumour suppressor genes and potential oncogenes in our genomes, two-thirds of the UK population will live cancer-free lives. Thus, DNA replication and the quality control mechanisms associated with it are remarkably efficient. Dr Diffley is investigating how the minichromosome maintenance helicase is loaded onto replication origins and subsequently activated no more than once per cell cycle. Gaining a detailed understanding of how DNA replication initiates will help us to understand how high-fidelity DNA replication is ensured in normal cells, and is a prerequisite for understanding and exploiting the subversion of this process to potentially treat cancer.

Professor Changjiang Dong

University of East Anglia

From structural and functional studies of essential and novel lipopolysaccharide transport and assembly membrane proteins to novel drug discoveries combating emerging multidrug-resistant pathogenic bacteria

Antibiotics are the most successful medicines for controlling bacterial infections. However, bacteria adopt different mechanisms to gain drug resistance, which is becoming a huge global health problem. Multidrug-resistant Gram-negative bacterial infections are more difficult to control than those of Gram-positive bacteria, as the Gram-negative bacteria have an additional membrane, the outer membrane, protecting the bacteria from the antibiotics. Lipopolysaccharide is a main component of the outer membrane of Gram-negative bacteria, and is essential for the vitality of most Gram-negative bacteria and plays an essential role in drug resistance. Professor Dong will be using multidisciplinary approaches to investigate the molecular mechanisms of how membrane protein complexes of Gram-negative bacteria build up the outer membrane, with the goal of the development of novel antibiotics against multidrug-resistant bacterial infections.

Dr Shah Faruque

International Centre for Diarrhoeal Disease Research, Bangladesh

Multidisciplinary studies in the ecology and epidemiology of cholera to predict epidemics

Epidemics of cholera due to toxigenic strains of the bacterium Vibrio cholerae cause approximately 120,000 deaths and millions of cases annually, with major economic impact in developing countries. The pathogen naturally exists in an aquatic ecosystem and infects humans to cause the devastating diarrhoeal disease. The proposed research will involve a multidisciplinary approach to better understand the ecological interactions, epidemiology, and the intricate genetic regulations that allow the pathogen to survive under both environmental and host conditions, and factors which lead to periodic outbreaks of cholera. Dr Faruque has an outstanding track record of research in the ecology, epidemiology and evolution of V. cholerae and its bacteriophages. The planned studies using cholera as a model system are expected to provide important thematic insights which may be useful, not only in controlling cholera, but subsequently in a variety of other waterborne enteric diseases which affect populations in developing countries.

Professor Russell Foster

University of Oxford

The melanopsin signalling pathway in ocular, circadian and sleep physiology: mechanisms to clinical application

A major focus of Professor Foster's research has been to understand how light influences circadian rhythms – the daily cycle of biological processes that impact upon sleep and wakefulness. He is particularly interested in how photoreceptors in retinal ganglion cells of the eye detect and signal light information to regulate circadian rhythms. During this award, Professor Foster will use animal models to elucidate the neurobiological machinery that sets, maintains and tunes the internal clocks of mammals. He will also develop new pharmacological agents to adjust circadian rhythms in human subjects with abnormal sleep/wake timing. This work will significantly increase our understanding of the cellular and molecular determinants of sleep and wakefulness, while applying this knowledge to the task of improving human health across a broad range of conditions from eye disease to mental illness.

Professor Stephen F Goodwin

University of Oxford

Genetic dissection of sexual behaviour

Professor Goodwin uses the fruit fly, Drosophila melanogaster, to study the genetic determinants of sex-specific neural circuits and behaviours. He is particularly interested in the transcription factors fruitless and doublesex, which act together to specify and configure the anatomy and physiology of sex-specific neural circuitry. During this award, Professor Goodwin will use cutting-edge genetic, molecular and behavioural techniques to determine the principles that govern how fruitless and doublesex direct the assembly of neural circuits. He also plans to elucidate the neural circuits in the fly that encode sex-specific behaviours such as their distinctive courtship ritual. The research will significantly increase our understanding of how 'maleness' and 'femaleness' develop.

Dr Francois Guillemot

The Francis Crick Institute

Regulation of adult hippocampal stem cells by niche signals

Hippocampal stem-cell activity decreases with age, contributing to the degradation of spatial memory and affective behaviours in older rodents. New neurons are also added to the hippocampus in adult humans and these adult-born neurons are thought to contribute to hippocampal functions. It is thought that a reduction in stem-cell activity might therefore contribute to the cognitive impairments associated with human ageing, neurodegenerative pathologies and mood disorders. Dr Guillemot aims to better understand the mechanisms responsible for the vulnerability of these adult hippocampal stem cells to pathologies and old age, and in particular whether different subsets of stem cells are differentially affected by ageing. Better understanding of these mechanisms will serve as a foundation for further research into treatments against cognitive decline in patients and will also help develop strategies to improve the capacity of the brain to self-repair.

Professor Adrian Hayday

King's College London

Intraepithelial lymphocytes: lessons in immunoregulation from 'landlocked' T cells

During his award Professor Hayday will seek to update the current 'textbook' definition of the roles and actions of T cells. This research will place new emphasis on the fact that many tissues are constitutively replete with 'landlocked' T cells that Professor Hayday's laboratory has shown to respond very rapidly to tissue perturbation by infection and/or non-microbial stress such as physico-chemical insults. Pursuing the observation that the composition of the T-cell compartments differs from one anatomical site to another, Professor Hayday's hypothesis is that there are organ-specific epithelial molecules that ‘select for’ their cognate T-cell compartments. In support of this, the research group has identified a novel molecule, Skint1, expressed uniquely in thymic epithelium and in epidermal keratinocytes, that is required specifically for the development of the epidermal skin T-cell compartment. This research will test whether this is a generalisable phenomenon by tracking the identity of novel intestinal epithelial determinants of the gut T-cell repertoire. Such molecules may offer new insight into gut inflammation and interactions with the microbiome, and set a foundation for understanding T-cell compartments at other body surfaces.

Professor Glyn Humphreys

University of Oxford

I-brain: a neuropsychological analysis of social attention and cognitive control

Professor Arthur Kaser

University of Cambridge

Can gene-environment interaction in Paneth cells trigger Crohn's disease?

Crohn's disease is a debilitating disease diagnosed at two peaks of age – in early adulthood, and in the sixth to seventh decade of life. It causes profound, life-long suffering and remains a major unmet medical need. Amongst immune-related diseases, Crohn's disease is special in that very few risk genes account for a huge fraction of its heritability. During his award, Professor Kaser will test the hypothesis that a genetically affected, relatively coherent biological mechanism operative in Paneth cells might determine the characteristic features of Crohn's disease involving the ileum. This mechanism would interact with more 'generic' genetically affected pathways, associated with increased immune reactivity and/or decreased tolerance, shared with other immune diseases. Delineation of such a mechanism will allow the predicting and testing of which environmental triggers set off ileal Crohn’s disease in genetically susceptible individuals. Together with studies in genetically stratified patient samples, Professor Kaser believes this affords an unparalleled opportunity to gain fundamental insights into Crohn’s disease, with the aim of informing a precise therapeutic intervention.

Professor Richard Maizels

University of Edinburgh

Helminths and the immune system: regulation, regulators and immunity

Helminths are intestinal and tissue parasites which have evolved sophisticated means of blocking the host immune system. Even today they infect over two billion people around the globe, but as yet no vaccines are available. Helminths are also associated with down-regulating 'bystander' reactions such as allergies, and other inflammatory diseases associated with modern lifestyles. By taking a molecular approach, Professor Maizels is identifying individual products from helminths which are able to suppress these inflammatory diseases, as potential new 'drugs from bugs'. Such defined molecules may offer the immuno-regulatory benefits of helminths while causing none of the harm of live infections. This research will also design new ways of building host immunity against infection, using these same molecules as targets for vaccines, and defining how to stimulate key types of immune-system cells to eliminate the parasites.

Professor Michael Malim

King's College London

Interferon and MX2-mediated control of HIV-1

Human cells are laden with genes and proteins that have evolved to inhibit viral infections. Many of these are rapidly mobilised in direct response to viral exposure and can collectively be called the mediators of innate immunity. The effectiveness of these fast-acting innate factors and mechanisms, together with later-developing adaptive immune responses, as well as the capacity of a virus to evade or counteract immunity, determines the outcome of infection in terms of health or disease, resolution or persistence. Professor Malim's research team will seek to discover innate immune mechanisms and pathways that can control infection by HIV, the virus that causes AIDS, and to define and understand the molecular underpinnings of viral suppression and evasion. This information can be leveraged in the future to develop or improve antiretroviral therapies, HIV vaccination strategies, and, potentially, approaches for HIV cure.

Professor Andrew McAinsh

University of Warwick

Kinetochores as force-sensing and -generating machines

During mitosis chromosomes undergo an exquisite series of four-dimensional manoeuvres that result in each daughter cell receiving an exact complement of the genetic material. At the heart of this process lie kinetochores, which assemble on each chromosome and form dynamic connections to spindle microtubules. There is an extensive parts list for the kinetochore, but we still lack an understanding of how the kinetochore moves and makes force. Professor McAinsh's research aims to understand the mechanisms by which kinetochore-microtubule complexes work as multi-component force-generating machines: how specific protein modules within the kinetochore complex collaborate to generate, exert and sense force. To achieve this, Professor McAinsh will be combining new microscope-based live-cell imaging assays with computational and biophysical tools. This work will provide key insight into how cells avoid errors in chromosome segregation, an event associated with developmental syndromes and cancer.

Professor Brian McStay

NUI Galway

The genomic architecture of human nucleolar organiser regions and its role in nucleolar biology

The nucleolus is the largest nuclear body and its primary role is ribosomal synthesis and assembly, though it also contributes to the cellular response to stress. The human genome contains approximately 300 ribosomal gene repeats, which are organised in tandem arrays at nucleolar organiser regions situated on the short p-arms of each of the five human acrocentric chromosomes. Professor McStay's research aims to determine how nucleolar organiser regions are arranged at a chromosomal level, how they direct formation of the nucleolus and how they regulate the function of nucleoli in human cells. He also plans to extend our understanding of the genomic architecture of the short arms of acrocentric chromosomes, as they are absent from the current human genome assembly.

Professor Shona Murphy

University of Oxford

The point of no return: a novel poly(A)-associated elongation checkpoint controlling gene expression

Professor Murphy aims to investigate a potential CDK9-regulated transcription-elongation checkpoint that is associated with polyadenylation signals at the end of protein-coding genes. This functions in addition to the well-known CDK9-dependent early-elongation checkpoint at the beginning of genes, and the failure of RNA polymerase II to negotiate this polyadenylation-associated checkpoint aborts transcription elongation prematurely. This checkpoint may provide a final quality-control step for mRNAs at the point of no return, after which a potentially functional mRNA is produced. Polyadenylation-associated checkpoints could therefore provide a powerful and rapid mechanism for the control of transcription in response to a range of signals, such as during development, where synchronous activation and repression of gene expression is required.

Professor Dónal O'Carroll

MRC Centre for Regenerative Medicine, University of Edinburgh

RNA regulation and modification in tissue development and homeostasis

The regulation of genomic output is of fundamental importance in the coordination of the complex processes that underpin stem-cell function and cellular differentiation essential for tissue development and homeostasis. Furthermore, understanding of the molecular mechanisms by which RNA modification and RBPs regulate gene expression is directly relevant to the comprehension of basic biological processes underlying development, stem-cell biology, and disease mechanisms. Professor O’Carroll will explore these regulatory mechanisms in the mouse germ line. His work will concentrate on the importance of the ubiquitous post-transcriptional RNA modifications of transcript uridylation, as well as the direct methylation of cytosine and adenosine bases within cellular RNA. In addition, he will explore the role of RNA-binding proteins in stem-cell function.

Dr Ketan Patel

MRC Laboratory of Molecular Biology, Cambridge

The origin and catabolism of genotoxic aldehydes and their impact on stem cell maintenance

Professors Sir Peter Ratcliffe and Christopher Schofield

University of Oxford

Defining the physiology and therapeutic potential of oxygenases as signalling enzymes

The joint programme aims to link biochemical, physiological and medical perspectives to better define the potential of human 2-oxoglutarate-dependent (2-OG) dioxygenases as therapeutic targets. Both scientists have established track records in relevant fields: Professor Ratcliffe in the discovery and elucidation of physiological pathways that control gene expression in accordance with cellular oxygen levels, and Professor Schofield in the biochemistry and structural analysis of 2-OG oxygenases that catalyse diverse biological oxidations. Their work came together with their joint discovery of a set of 2-OG oxygenases that transduce oxygen-sensitive signals through oxygen-dependent hydroxylation of the transcription factor, hypoxia-inducible factor. From these discoveries, their joint goal is to continue to explore the wider potential of the 2-OG oxygenases as signalling vectors. This will include studying how they react under hypoxic, metabolic and related stresses, and defining the potential for therapeutic targeting in the many human diseases that are characterised by hypoxia and dysregulated metabolism.

Dr Frank Reimann and Professor Fiona Gribble

University of Cambridge

Physiology of the enteroendocrine system

The diffuse enteroendocrine system comprises more endocrine cells than any other endocrine organ in the body, and plays a central role in the coordination of metabolism. Its location within the intestinal epithelium enables it to sample and respond to the availability of nutrients in the external (luminal) environment. The potential for exploiting the enteroendocrine system therapeutically is increasingly recognised. Dr Reimann and Professor Gribble have worked towards characterising signalling pathways in enteroendocrine cells (EEC), but recognise that there are still gaps in the knowledge of how the enteroendocrine axis operates in a physiological setting. They propose to identify diversity in the EEC population influencing the effectiveness of dietary and pharmacological stimuli, and to explore the biology of a newly identified orexigenic gut hormone. Defining the basis for the variability of gut hormone responses in humans and establishing methodology to monitor activity of primary human EEC will open new avenues for studies.

Professor Helen Saibil

Birkbeck, University of London

Molecular and cellular mechanisms of protein aggregation and toxicity in models of neurodegeneration

Protein quality-control systems normally prevent the accumulation of toxic, misfolded species that cause degenerative diseases. Through genetic and biochemical changes of unclear origin, protein quality control becomes less effective with ageing, eventually resulting in late-onset neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. A better understanding of the mechanisms of protein disaggregation would enable new approaches to understanding toxic gain of function, how cells handle aggregates, and the failure of protein quality control in ageing individuals. Professor Saibil plans to investigate the cellular machinery for processing amyloid and related aggregates of misfolded proteins using a combination of molecular and cellular electron microscopy with mechanistic studies.

Professor Mark Woolrich

University of Oxford

Exploring the mechanisms of distributed spontaneous brain activity


Professor Jean Beggs

University of Edinburgh

Regulation of splicing and functional links between splicing and transcription

In most eukaryotic genes the information in the DNA sequence is interrupted by noncoding regions called introns. An RNA copy of the gene has to be cut and then spliced back together to remove the introns and produce a continuous message with the correct information to produce a protein. An unexpectedly high proportion of genetic diseases and cancers are caused by splicing defects, and one-third of disease-causing single nucleotide polymorphisms have the potential to disrupt splicing. Professor Beggs will investigate the mechanistic links between pre-mRNA transcription and splicing, including the potential role of splicing-dependent transcriptional checkpoints as a cellular system of RNA quality control.

Dr Ariel Blocker

University of Bristol

Molecular mechanisms powering a bacterial toxin injection device

Type III secretion systems (T3SSs) are essential devices in the virulence of many Gram-negative bacterial pathogens. They translocate protein effectors of virulence into eukaryotic host cells to manipulate the cells during infection. In order to enter the narrow channel at the centre of the T3SS injection needle, substrates must carry a targeting motif and become unfolded. However, the architecture of the cytoplasmic and inner-membrane export apparatus is not well defined. In addition, it is unclear how energy from ATP hydrolysis and the proton motive force is utilised to drive substrate export. Dr Blocker plans to use a combination of genetic and biochemical studies focused around in vitro reconstitution, as well as high-resolution structural approaches, such as electron microscopy and mass spectrometry, in order to investigate these aspects of T3SSs.

Dr Simon Boulton

The Francis Crick Institute

Mechanisms of double-strand break repair pathway choice

DNA double-strand breaks (DSBs) are a major threat to genome stability, as failure to repair them correctly can give rise to chromosome translocations and genome amplification events and is the underlying cause of a number of hereditary cancer predisposition syndromes, such as Fanconi anaemia. The two main pathways for the repair of DSBs are non-homologous end joining and homologous recombination. Dr Boulton will be investigating the role of the protein 53BP1 in the regulation of DSB repair, with the goal of gaining a molecular understanding of how 53BP1 and its cofactors bind and protect DNA ends.

Professor Ian Collinson

University of Bristol

Understanding mitochondrial protein import and membrane insertion

Mitochondria require the import of proteins produced by the host genome in order to carry out their biological function of adenosine triphosphate generation and the exertion and regulation of metabolism. This import is achieved by a collection of complexes located in the mitochondrial membranes, such as the translocon of the outer membrane (TOM) and translocon of the inner membrane (TIM). Professor Collinson aims to undertake a comprehensive analysis of the TOM and TIM complexes in order to determine their 3D structures using cryo-electron microscopy. He is also planning to develop a range of in vitro biochemical and biophysical assays that will enable him to dissect the molecular details of the mitochondrial import process.

Professor Peter Cullen

University of Bristol

Defining the role of retromer in endosomal sorting in health and disease

Retromer, a highly conserved protein complex, is a master regulator of endosomal sorting, with defects in its function increasingly being linked to human disease. The observation of lower levels of retromer expression in the brains of Alzheimer's and Parkinson's disease patients, and the segregation of mutations in retromer and retromer-associated pathway components with Parkinson's disease, have further focused attention on this complex, and, more broadly, on the endocytic network's role in neuroprotection. However, little is known about how retromer works. During his award, Professor Cullen aims to define the inner workings of this machine, reveal fundamental information on cargo-sorting events conserved across eukaryotic phylogeny, and provide an insight into retromer's many roles in development and cell and organism physiology. Applying acquired knowledge to retromer's role in Parkinson's disease will provide unique insight into the cell biology of this disease.

Dr Marcus Dorner

Imperial College London

Determinants of hepatitis B virus interspecies restriction factors

Hepatitis B virus (HBV) affects over 350 million people worldwide and, due to the current inability to cure the infection, requires lifelong treatment. Its narrow host tropism, restricting infection to humans and chimpanzees, has greatly limited our ability to develop new and improved treatment strategies. A better understanding of the HBV life cycle in human and non-human cells could lead to the development of small-animal models to be used in the preclinical evaluation of novel drug candidates. Dr Dorner's research focuses on the identification of non-redundant host factors that are essential for HBV infection in non-human cells, with the aim of creating an immunocompetent small-animal model for HBV.

Professor Charles ffrench-Constant

University of Edinburgh

What are the mechanisms by which myelination in the central nervous system is established and refined?

Dr Alex Gould

The Francis Crick Institute

Mechanisms underlying the developmental origins of adult metabolism and lifespan

There is substantial evidence from human and rodent studies that fetal malnutrition is a major risk factor for developing metabolic diseases, such as type 2 diabetes, during adult life. The identification of the mechanisms by which early-life nutrition can have long-term or programming effects upon adult health is likely to have an impact upon dietary guidelines and other approaches for preventing and treating metabolic disease. Dr Gould will harness the genetic advantages of a newly developed Drosophila model to investigate the nutritional programming of metabolism and lifespan. His aims are to identify new molecular mechanisms responsible for nutritional programming and to define the complex interactions between early-life and adult diets during this process. He will also test the degree to which nutritional programming mechanisms are conserved between Drosophila and mammals.

Professor Philip Goulder

University of Oxford

Mechanisms of HIV disease limitation and cure revealed in paediatric infection

Professor Goulder aims to address the research question of whether a cure can be achieved in an HIV-infected individual. Professor Goulder's lab has identified three groups of children in whom it believes a cure is most likely to arise. These studies are linked by the hypothesis that a cure is possible where there are obstacles to HIV establishing a latent reservoir in long-lived resting T cells. The first group in the study is HIV-infected newborns in whom antiretroviral therapy (ART) is initiated at birth. The second group is HIV-infected children in whom ART was initiated in infancy, now leaving no trace of infection or HIV antibody response. The third group is HIV-infected children over five years old who are entirely healthy and indistinguishable from HIV-uninfected age-matched children, except for high levels of HIV in their blood. This group is key to understanding how disease from HIV can be avoided – and, despite their high levels of HIV, these children may also have cure potential.

Professor Anthony Green

University of Cambridge

CALR mutations and human myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies predominantly affecting older individuals and are associated with an increased risk of thrombosis and acute leukaemia. They provide a powerful approach to studying mechanisms whereby stem and progenitor cells, which are inaccessible in other malignancies, are subverted in the earliest stages of tumorigenesis. Professor Green has identified that somatic calreticulin (CALR) mutations reveal a novel biological pathway that modulates haematopoiesis, and that CALR is a target for tumorigenic mutations. During his award Professor Green intends to explore the function of CALR mutations in order to shed new light on normal haematopoiesis (particularly haematopoietic stem cell behaviour and megakaryopoiesis), MPN pathogenesis and calreticulin function.

Professor Keith Gull

University of Oxford

Cell morphogenesis, development and pathogenicity in trypanosomes

The kinetoplastid parasites that cause trypanosomiasis and leishmaniasis represent major threats to world health and agricultural development. Sustained diagnostic and control efforts have lowered the number of new cases from earlier epidemic proportions. However, this improving picture relies on often-fragile infrastructure for complex diagnosis and treatment. Significant challenges remain for improving trypanocide use for livestock disease, which is still inhibitory to agricultural development. Professor Gull's primary aim is to understand the molecular cell biology of cell form and shape in Trypanosoma brucei and other kinetoplastids in relation to their pathogenicity, life cycle and evolution. This research will provide an integrated view of the trypanosome cytoskeleton, from component proteins to complexes, and the mechanisms of building the high-order organisation of the main structures. It offers a route to understanding dependency relationships in the construction of these structures and how they influence major membrane domains associated with receptor and sensory functions.

Professor Adrian Hill

University of Oxford

A multicomponent high-efficacy malaria vaccine

Exceptionally potent immune responses targeted at key antigens have been required to achieve even partial vaccine efficacy against malaria. A number of advances in recent years have provided the prospect of greatly improved antibody-inducing vaccine components, through the use of both transgenic parasite technology and mass-spectrometry-based sequencing of parasite antigen screening. Professor Hill aims to build on these exciting advances to design and develop an effective multicomponent vaccine against Plasmodium falciparum, the parasite that causes malaria. He aims to do this by: investigating whether a more protective liver-stage vaccine against P. falciparum malaria can be identified by assessing antigens using transgenic parasite technology combined with sequencing of parasite peptides; investigating whether this liver-stage vaccine can be improved by combining it with a new anti-sporozoite vaccine; and investigating whether these components can be efficiently integrated with anti-blood-stage and anti-sexual-stage vaccine components to develop a highly effective multicomponent malaria vaccine.

Professor Paul Kaye

University of York

Host determinants of infectiousness in visceral leishmaniasis

Leishmaniasis is one of the major neglected diseases of poverty, affecting over a million people worldwide, with the most severe form – visceral leishmaniasis, or kala azar – responsible for tens of thousands of deaths every year. This parasitic disease is spread through the bite of a female sandfly that has become infected by biting someone who is either sick from the disease or carrying the parasite without knowing it. To develop tools that will help break the cycle of disease transmission, more needs to be known about how these parasites spread around the body, how they are acquired by sandflies and how variations in host immune responses affect these processes. Professor Kaye's research addresses these questions using new animal models of leishmaniasis transmission, state-of-the-art techniques in cellular immunology and molecular pathology, and computational modelling. The research will provide new knowledge directly applicable to the fight to eliminate this devastating disease.

Dr Jean Langhorne

The Francis Crick Institute

The pir gene family: chronic infection, immunity and virulence

Multigene families are present on most of the chromosomes of the malaria parasite Plasmodium. One gene family, pir (Plasmodium interspersed repeat), is present in all Plasmodium genomes sequenced so far. Despite their discovery more than ten years ago, the function of pir genes is not understood. Recent results from Dr Langhorne's laboratory suggest that they may be virulence factors. Dr Langhorne plans to use a well-defined animal model to discover the interactions of pirs with the mammalian host, which could explain their role in virulence or in other host-parasite interactions. An investigation of the biology of this gene family and its interactions with the host may be key to understanding malaria pathogenesis, and could change our ideas about the relationship between the immune response and virulence. The knowledge gained will promote new research directions and aid new approaches to intervention.

Professor Eric Miska

University of Cambridge

Transgenerational epigenetic inheritance: adaptation, genome stability and evolution

Professor Chris Newbold

University of Oxford

Multigene families in malaria

It has been known for some time that proteins encoded by the var multigene family in human malaria that are expressed on the surface of the infected red cell are extremely important in both pathogenesis and the development of host immunity. More recently, evidence from a rodent malaria model has implicated a second, larger multigene family known as pir (Plasmodium interspersed repeat), common to all species of malaria and an important determinant of virulence. Both families are extremely polymorphic. Professor Newbold's group have developed algorithms that allow accurate assembly of these gene families from next-generation sequencing of large numbers of field isolates. These studies have revealed an unexpected level of sequence sharing both within and between continents. Using analysis of these data, Professor Newbold's group will investigate how this sequence sharing relates to the development of cross-reactive antibodies and immunity, and whether the pir family is also important in the virulence of human malaria.

Professor Anna Christina Nobre

University of Oxford

'Premembering' perception in the human brain

Professor Nobre studies the neural systems that support cognitive functions in the human brain. She is particularly interested in the influence of memory on perception. Memories are essential for bringing together fragments of past experiences, but they are equally important for guiding predictions that help create new sensory experiences. Professor Nobre has dubbed this process 'premembering'. During her award she plans to examine how memory-based expectations combine with current task goals to shape neural activity in anticipation of perceptual events unfolding in dynamic environments. She plans to elucidate the psychological and neural mechanisms of premembering using a range of experimental techniques, including psychophysics, magnetoencephalography, functional magnetic resonance imaging and transcranial magnetic stimulation.

Dr Luca Pellegrini

University of Cambridge

Macromolecular mechanisms of genome duplication and stability

Each time a cell divides, it needs to duplicate its DNA in order to transmit a complete set of genetic instructions to each daughter cell. Inside the cell, dedicated collections of protein molecules cooperate in space and time to execute the biochemical process of DNA replication, upon which genetic inheritance depends. Research in Dr Pellegrini's laboratory aims to understand, at the atomic level, how the proteins and enzymes of DNA replication carry out their vital task. Ultimately, the lab's work will provide a detailed description of the molecular mechanisms by which the cell achieves the remarkable feat of genomic duplication. In addition to its biological importance, this knowledge is of great medical relevance as faults in DNA replication are a major predisposing cause of disease. Dr Pellegrini plans to exploit the knowledge of the three-dimensional structures of replication proteins to identify potential inhibitors that could be developed as novel treatments for cancer.

Professor Jordan Raff

University of Oxford

A molecular analysis of centriole, centrosome and cilium assembly and function

Centrioles organise the assembly of two important eukaryotic cell organelles: the centrosome and the cilium. Centrosomes are the major microtubule-organising centres in many animal cells, and play an important role in cell division, in establishing and maintaining cell polarity, and in positioning and transporting molecules and organelles within the cell. Most cells in the human body form a single, immotile, primary cilium, which can play a vital role in cell signalling and in mechano- and chemo-sensation. There is increasing evidence linking the dysfunction of centrosomes and cilia to a plethora of human diseases, including cancer, kidney disorders, obesity and macular degeneration. Using Drosophila as a model organism, Professor Raff aims to understand how centrioles, centrosomes and cilia assemble and function at the molecular level, the main challenge being to understand how these proteins interact and how their assembly is regulated.

Dr Felix Randow

MRC Laboratory of Molecular Biology

How pathogenic cytosol-dwelling bacteria escape from autophagy

Dr Randow is interested in how individual cells defend themselves against infection. Bacteria that colonise the host cytosol encounter specific anti-microbial defences, and therefore have developed specific adaptations to antagonise these cell defences. Over the last few years autophagy has emerged as a major defence system for the host cytosol. To improve our understanding of anti-bacterial autophagy and to develop novel strategies against professional cytosol-dwelling bacterial pathogens, Dr Randow will investigate how cytosol-dwelling bacteria escape from autophagy, whether we can artificially enforce anti-bacterial autophagy against professional cytosol-dwellers, and which additional cell-autonomous defences are deployed in activated cells to detect and destroy professional cytosol-dwelling bacteria. This research will be crucial for future attempts to manipulate pathogen recognition and vaccine-mediated immunity.

Professor Trevor Robbins

University of Cambridge

Frontostriatal systems in impulsive-compulsive disorders

Professor Robbins studies the relationship between dysfunction in discrete neural systems and the impulsive and compulsive behaviour that accompanies some psychiatric disorders such as obsessive-compulsive disorder, attention-deficit hyperactivity disorder and stimulant drug addiction. An overarching goal of his work is to increase our understanding of the neural mechanisms governing cognitive control. As part of his award, Professor Robbins plans to test whether abnormal compulsions are a result of aberrant stimulus-response habit learning that is potentially exacerbated by impaired anxiety and cognitive control. To do this, he will use state-of-the-art experimental techniques such as DREADDs (designer receptors exclusively activated by designer drugs), optogenetics and neuroimaging to study and compare animal models of impulsivity and compulsivity with key patient populations.

Professor Dame Carol Robinson

University of Oxford

The effects of drug and lipid binding on the structure and function of membrane proteins in health and disease

Membrane-spanning proteins lie at the heart of many human diseases and constitute important drug targets, but little is currently known about the importance of their interactions with the lipid bilayer to their normal function. Professor Robinson plans to use mass spectrometry to investigate whether specific lipid-binding sites exist on membrane proteins and whether they have a major effect on the behaviour and stability of membrane proteins. Professor Robinson also aims to study the potential role of post-translational modifications of membrane proteins in regulating their function and interactions with the lipid bilayer.

Dr Luiz Pedro Sorio de Carvalho

The Francis Crick Institute

Uncovering nutrient acquisition and metabolism in Mycobacterium tuberculosis

Human tuberculosis still claims over a million lives annually, and the spread of multidrug-resistant strains increases the global health impact of the disease. Despite over 100 years of research since its identification we still do not know much about what Mycobacterium tuberculosis 'eats' during infection. In addition, we do not know how host-imposed stresses affect nutrient acquisition. Using virulent M. tuberculosis and a multidisciplinary approach centred on the use of metabolomics, Dr Carvalho aims to identify nutrients that are important during infection, define their transporter systems, map downstream metabolic pathways and pinpoint the nutrients' functions in cellular physiology during infection. This knowledge will significantly increase our understanding of the core processes required for M. tuberculosis survival and pathogenesis. A number of these identified pathways and proteins might represent ideal targets for the development of novel antitubercular agents, which are urgently needed to treat increasingly prevalent antibiotic-resistant infections.

Dr Tony Southall

Imperial College London

Reprogramming neurons for nervous system repair

The brain is one of the most complex biological systems and consists of billions of neurons that possess very diverse morphologies, neurotransmitter identities, electrical properties and preferences for synaptic partners. Understanding how neuronal fates are specified is important to our understanding of neuronal development and neural dysfunction. Dr Southall aims to identify the transcription factors that attribute neurons with particular neurotransmitter identities, and to study whether these transcription factors are able to reprogramme neurotransmitter identity in vivo. Using Drosophila as a model organism, Dr Southall will use a novel technique that allows specific neuronal populations to be profiled with ease, with the aim of identifying the major transcription factors involved in specifying different neuronal properties and reprogramming properties in vivo.

Professor Stephen Wilson

University College London

How is brain asymmetry established and what is it good for?

Nervous system asymmetries influence cognition and behaviour and usually arise during development under the influence of both genetics and environment. Asymmetries may confer advantages through increasing neural capacity and by reducing conflict between hemispheres, and it is likely that the nervous systems of all bilaterally symmetric animals are left-right asymmetric with respect to the processing of information and control of behaviour. In addition to asymmetry being a feature of normally functioning nervous systems, laterality defects are observed in some neurological conditions. Although an important feature of the nervous system, the developmental and genetic bases of brain asymmetries remain obscure. Professor Wilson will use developmental, genetic, imaging and behavioural approaches in zebrafish to address how asymmetries arise in development, how they are encoded in circuits and what their importance is for nervous system function, in order to gain a better understanding of the brain in health and disease states.


Professors John Aggleton and Shane O'Mara

Cardiff University and Trinity College Dublin

The cognitive thalamus: more than a relay

Research on the biological basis of episodic memory has traditionally focused on the functioning of the hippocampus, a brain structure in the medial temporal lobe. Professors Aggleton and O'Mara are interested in studying how other brain areas play important roles in the formation, maintenance and recall of episodic memories. They are particularly interested in the thalamus, a structure in the middle of the brain. Their recent research has shown that neurons in the thalamus signal multiple types of spatial information, providing new insight into why this area might be so critical for memory. Professors Aggleton and O'Mara plan to elucidate the path that spatial information travels to reach the thalamus and to determine the impact of thalamic neurons on spatial memories. This work could help explain how networks of brain areas beyond the medial temporal lobes work with the hippocampus to shape memory.

Dr Becca Asquith

Imperial College London

Inhibitory killer immunoglobulin receptors and virus-specific adaptive immunity in humans

Killer immunoglobulin receptors (KIRs) are known to be associated with innate immunity, but the role of KIRs in adaptive immunity is virtually unknown. Dr Asquith has evidence that KIRs can modulate the adaptive response, with direct consequences for human health. She will now investigate the mechanisms underlying this modulation in viral infection using a combination of theory and experimental methods. She has three main aims: to investigate whether KIR2DL2 enhances T-cell survival in vivo during HTLV-1 and HCV infections; to determine new models to distinguish causality from correlation between KIRDL2 and lymphocyte survival; and to identify genes involved in KIRDL2-mediated enhancement. Dr Asquith will also assess whether inhibitory KIRs enhance adaptive immunity in two globally important virus infections. Specifically, she will examine whether KIRDL2 could be a predictor of the outcome of HIV-1 infection, and the impact of KIR genotype on the longevity of CD8 T-cell responses to yellow fever vaccine.

Professor Andrew Biankin

University of Glasgow

Defining platinum- and PARP-inhibitor-responsive molecular phenotypes of pancreatic cancer

The overall aim of Dr Biankin's research is to advance innovative approaches in cancer genomics for therapeutic development, with the aim of defining, understanding, testing and implementing personalised therapeutic strategies for pancreatic cancer. This research will focus on identifying patients who will respond to platinum-based therapies (which are emerging as the standard of care) and to PARP inhibitors that target similar mechanisms, so that only those who are likely to benefit receive these drugs. This also allows those who are unlikely to respond to avoid the toxicity of ineffective therapies and to receive treatments that are more likely to benefit them as individuals.

Professor Andrea Brand

University of Cambridge

Nutritional control of neural stem-cell quiescence and reactivation

The systemic regulation of stem cells ensures that they meet the needs of the organism during its growth and in response to injury. Stem cell populations in varied tissues spend much of their time in a mitotically dormant (quiescent) state; a key element of regulation is the decision between quiescence and proliferation. Using Drosophila as a model organism, Professor Brand aims to uncover how the environment, both systemic and local, influences neural stem-cell behaviour and the molecular mechanisms that control neural stem-cell quiescence and reactivation, in order to gain insights into tissue regeneration under normal and pathological conditions and in response to ageing.

Professor Neil Bulleid

University of Glasgow

Protein folding and thiol modification in the mammalian endoplasmic reticulum

The correct folding and assembly of proteins is the final stage in cellular protein synthesis. Protein folding requires a group of proteins that can either catalyse folding reactions or function as molecular chaperones to prevent non-productive protein aggregation. The lack of correct folding can lead to stress responses that ultimately cause diseases such as diabetes and cancer. Professor Bulleid will be investigating the molecular mechanisms that cells use to ensure that the chemical environment inside the endoplasmic reticulum enables the correct folding and assembly of secretory proteins. He will also study the regulation of protein folding by the modification of thiol chemical groups.

Dr Marco Catani

King's College London

Lateralisation of human brain networks: implications for stroke recovery

A distinctive feature of the human brain is that certain cognitive functions, such as our ability to use language, tend to be lateralised to one side of the brain or the other. This phenomenon has been extensively studied, but little is known about whether the networks of neurons that connect distinct areas in the brain are similarly lateralised. Dr Catani will use advanced neuroimaging techniques to map patterns of neural network lateralisation in the brain and relate these patterns to cognitive function. Specifically, he will examine lateralisation of neural networks related to language function and visuo-spatial attention in both healthy participants and patients who have stroke-related brain damage. This work could significantly increase our understanding of the complex relationship between brain structure, behaviour, and recovery following stroke. 

Professor Paul Crocker

University of Dundee

Molecular dissection of siglec-mediated regulation of neutrophil inflammatory responses

Neutrophils play crucial roles in host defence against bacterial and fungal pathogens. The regulation of neutrophil-endothelial cell interactions is important to prevent damage, especially in the lungs, where there is a vast network of narrow capillaries. Professor Crocker has focused for the majority of his career on the discovery and characterisation of the siglec family of sialic acid-binding Ig-like lectins. He has recently identified a new siglec inhibitory pathway that controls β2-integrin-dependent neutrophil recruitment following exposure to lipopolysaccharide His goal is to understand the molecular mechanisms of how neutrophil-expressed siglecs in mice (siglec-E) and humans (siglec-9 and siglecs-5 and -14) regulate neutrophil functions during inflammation. Professor Crocker will undertake detailed proteomic and glycomic analysis of siglec signalling complexes and siglec counter-receptors and ligands on endothelial cells in order to provide new opportunities for the treatment of diseases such as acute lung injury.

Professor Robert Cross

University of Warwick

How kinesins generate directional force and movement

Kinesin molecular motors are walking machines that transport cargo along microtubules in cells. Kinesin-driven transport is a core organising principle of eukaryotic life, driving a variety of self-organisation processes, for example mitosis, meiosis and axonal transport. Professor Cross's research asks how kinesin motors work at the molecular level. To answer this fundamental question, he will use a variety of protein engineering, microscopic and computational approaches, including single-molecule optical trapping microscopy.

Professor Alun Davies

Cardiff University 

Tumour necrosis factor superfamily forward and reverse signalling in neural development

Professor Davies studies the molecular mechanisms that govern the survival of neurons and the growth of neuronal processes (axons and dendrites) during development. His team has recently discovered that members of the tumour necrosis factor (TNF) family of extracellular signalling proteins play important roles in regulating axon growth. Professor Davies plans to study how different TNF proteins orchestrate the establishment of patterns of neural connectivity during development, and to unravel the molecular mechanisms underlying this. The results of Professor Davies's work will further our understanding of how the nervous system is wired up, and may shed light on what goes awry in certain neurodevelopmental disorders.    

Professor Julian Downward

Institute of Cancer Research

Investigation of circulating tumour DNA in the early detection of KRAS and EGFR mutant cancers

In common solid tumours where RAS or EGFR mutations are frequent, early surgical intervention is the most effective therapeutic approach. The most important limitation to the use of curative surgery is that patients present with cancers that have already spread beyond their primary site. Improved ability to detect cancers at a very early stage would allow greater usage of surgical intervention. While advances in the early detection of cancer are occurring on many fronts, developments in recent years have come from the ability to analyse tumour-derived DNA in circulating blood, either as circulating free-tumour DNA fragments or in circulating tumour cells. Professor Downward aims to investigate the potential of circulating free-tumour DNA to enable the early detection and characterisation of cancers, and to determine whether circulating free-tumour DNA is likely to have a utility as a tool for detection of cancers in the clinic.

Dr Sherif El-Khamisy

University of Sheffield

The repair of oxidative and topoisomerase-induced chromosomal breaks: mechanisms and implications for human health

Breakage of a single strand of DNA is the most abundant DNA lesion in cells. It arises from oxidative damage or the actions of DNA ligases or topoisomerases. If these DNA breaks are not rapidly repaired then transcription can be impaired and double-strand DNA breaks can become more likely to occur during cellular replication. Dr El-Khamisy's research focuses on understanding the molecular mechanisms for the repair of oxidative and protein-linked DNA breaks in health and disease.  

Dr Thomas Ezard

University of Southampton

How does natural and anthropogenic disturbance change short- and long-term human population growth?

Dr Ezard is an evolutionary ecologist interested in the dynamic consequences of how the structure of populations and communities interacts with environmental change. He is examining this through developing the interfaces between mathematical and statistical models. He will address his research question by constructing a database of momentum in human populations and using it to dissect the demographic, environmental and social drivers of human transient dynamics, from city to global scales. This research will provide insights into the drivers of short- and long-term population growth, elucidating how world wars, global pandemics, revolutions, catastrophic floods, political acts and social change shape societal responses to contemporary events. Dr Ezard's work will contribute to the much-needed evidence base on the dangers and benefits that momentum poses for population health in the 21st century.

Professor Kate Jeffery

University College London

Neural encoding of complex space

Humans and animals are remarkably good at moving through a complex and ever-changing world. Professor Jeffery explores how the brain integrates different forms of sensory information to make spatial navigation possible. Professor Jeffery aims to investigate how neurons in the brain represent large areas of previously explored space. Prior work has shown that several classes of neurons communicate and store information about our immediate surroundings. Professor Jeffery will test the hypothesis that these local representations of space are connected in the brain to form a master map of our world, utilised for navigation beyond local environments. The work could significantly increase our understanding of the neural basis of spatial navigation, while also providing insight into disorders of orientation and spatial memory.

Professors Nicholas Luscombe and Jernej Ule

University College London

The role of 3' untranslated region variation in the molecular pathogenesis of motor neurone disease

3' untranslated regions (3' UTRs) play critical roles in the control of mRNA translation and stability by presenting sequence motifs and secondary structural elements that mediate interactions between the mRNA and other factors such as proteins or miRNAs. Recent studies have demonstrated that human genetic variations in UTRs and variations in promoter sequences impact upon gene expression to a similar degree. Professors Luscombe and Ule hypothesise that 3' UTR sequence variation disrupts mRNA stability and translation, which can contribute to the pathogenesis of diseases such as cancer or neurodegeneration. They will use genetic and biochemical investigations in differentiated human motor neurones combined with computational modelling to study the impact of alternative 3' UTRs on health and disease.

Professor Keith Matthews

University of Edinburgh

Environmental sensing and cell-cell communication in African trypanosomes

Professor Matthews proposes a global approach to understanding the molecular mechanisms that control infection by the African trypanosome, the parasite responsible for sleeping sickness in humans and related diseases in cattle. Sensing of the environment by trypanosomes is central to both autoregulation of growth in the bloodstream and the cellular differentiation necessary for transmission by the tsetse fly vector. Professor Matthews's aims are: to develop a further understanding of the control of population density and growth regulation in infected mammals; to investigate interspecies competition; and to determine the molecular mechanisms underlying the perception, transmission and execution of signals for the differentiation that follows the transfer to a tsetse fly. This work could lead to a better understanding of the processes by which the pathogenic bloodstream forms limit infection while maximising transmissibility to the insect vector, and how the parasites respond to environmental signals upon ingestion by the tsetse fly.

Professor Oscar Marín

King's College London 

General principles underlying the assembly of cortical inhibitory circuits

Dr Marín is a neuroscientist studying the growth, movement and wiring of interneurons in the cerebral cortex, the outermost layer of the brain. He will explore how the development of inhibitory interneurons influences the structure and function of the cerebral cortex. Specifically, he hopes to elucidate the genetic and molecular factors in the brain that influence interneuron lineage, location and wiring. He also plans to investigate the mechanisms that emerge within populations of neurons to drive the identity, distribution and number of cortical interneurons. Dr Marín's work could shed light on the pathophysiology of disorders such as epilepsy, autism and schizophrenia, while also bringing us a step closer to understanding how brain function might arise from the assembly of neural circuits. 

Professor David Newby

University of Edinburgh

Identification and prediction of coronary artery plaque rupture using 18F-fluoride positron emission tomography

There are approximately 150,000 myocardial infarctions per annum in the UK, but patients are not stratified to identify those who would most likely benefit from currently available treatments. Professor Newby believes that a better understanding of the biology of atherosclerotic plaque and the classification of necrotic and inflamed coronary atherosclerotic plaques will help clinicians identify those at a high risk of recurrent cardiac events. Professor Newby will use a non-invasive imaging technique to investigate whether the identification and quantification of plaque inflammation and rupture could enable a more focused, effective and efficient method of tailoring therapy. This approach could prevent unnecessary and potentially harmful invasive investigations (invasive coronary angiography) and treatments (percutaneous coronary intervention and coronary artery bypass graft surgery), as well as lead to better targeting of secondary preventative drug therapies, avoiding harmful side effects.

Dr Snezhana Oliferenko

King's College London

A comparative approach to understanding nuclear division

Mitotic division ensures the faithful inheritance of genetic material in proliferating eukaryotic cells. Errors in this process often lead to developmental defects and disease. The cellular genome is enclosed within the nucleus, which is bounded by a double membrane termed the 'nuclear envelope'. To facilitate the inheritance of genetic material, eukaryotic cells use a diverse set of cell type-specific and organism-specific mechanisms, which range from fully 'open' to fully 'closed' mitosis with varying degrees of nuclear envelope breakdown. Dr Oliferenko will investigate the mechanisms that cells use to dynamically restructure the nuclear envelope during mitosis to allow chromosome segregation and the formation of daughter nuclei.

Professor Antonella Riccio

University College London

Epigenetic regulation of neuronal development

Professor Riccio is a neuroscientist studying chromatin – the mix of DNA and proteins that makes up the nuclei of cells. She is particularly interested in how physiological stimuli, such as neurotrophins, neurotransmitters and synaptic activity, induce dynamic changes in chromatin and associated gene expression. Professor Riccio plans to explore the molecular mechanisms that allow the neurotransmitter nitric oxide to modify chromatin in developing neurons. Her research will help elucidate how external stimuli drive heritable changes in neurons. This work could also further our understanding of neurodegenerative disorders caused by mutations in the proteins that regulate chromatin.

Dr William Schafer

University of Cambridge 

Identifying novel sensory molecules and mechanisms in nematodes and mammals

Our senses of taste, touch and hearing depend on ion channels embedded in sensory receptors. External sensory stimuli trigger these channels, causing their associated sensory receptors to fire. The molecular mechanisms that govern these types of sensory receptors and their ion channels are still poorly understood. Dr Schafer plans to examine a family of genes – the transmembrane channel-like (TMC) family – that may encode channels important for our senses of hearing, taste and touch. To do this, he will study the properties, functions and genetics of TMC proteins in mammalian cells and genetically modified Caenorhabditis elegans, or roundworms. The work will increase our understanding of how the nervous system transforms sensory stimuli into neural signals. It could also provide new insight into the nature and treatment of sensory disorders, such as deafness and chronic pain.

Professor Andrew Sharrocks

University of Manchester

Shaping transient transcriptional responses

Cell signalling often results in transient transcriptional responses in which genes are initially activated before being turned off again and reset in readiness to respond to the next wave of signal. This type of transcriptional response is associated with many biological processes where timing is essential, such as cell cycle regulation, differentiation, development, neuronal cell activation and immune responses. We know a lot about the activation phases but very little about the 'off' phases. Professor Sharrocks will redress this balance by studying the mechanisms by which transcription is terminated and held in a refractory state, and how the transcriptional machinery is then reset from this refractory state so that it is ready to be reactivated.

Professor Peter Simmonds

University of Edinburgh

The role of genome composition and the structure of mammalian RNA viruses on their host interactions, pathogenesis and transmission

RNA viruses, which form the majority of emerging pathogens affecting humans and animals, are remarkably adapted to evade and inhibit powerful host cellular and systemic immune responses to infection. In addition to encoding specific immune-evasion proteins, RNA virus genomes display several compositional features, such as skewed dinucleotide frequencies, that profoundly modify interactions with cellular defence mechanisms. Professor Simmonds is launching a new area of research to understand recognition mechanisms and the role of these global configurations in the pathogenesis, evolutionary fitness and transmission of RNA viruses. His approach is to investigate why and how certain sequence motifs in the genome are selected over evolutionary time and what fitness trade-offs are involved from a virus point of view. Newly discovered methods to accelerate or attenuate RNA virus replication can be exploited in vaccine or transgene technology.

Dr Katharina Simon

University of Oxford

The role of autophagy in quiescence of healthy hematopoietic cells

Autophagy is the major pathway for degradation of macromolecules in cells. However, the contribution of autophagy to the maintenance of healthy long-lived cells has not been investigated in normal physiological settings. Dr Simon has obtained preliminary data showing that the quiescent status of long-lived cells, such as hematopoietic stem cells (HSCs) and memory T cells, is autophagy-dependent. Dr Simon has two key aims to address in her work: to determine whether autophagy is required for HSC quiescence and to assess the molecular mechanism regulating this process; and to understand the role of autophagy in memory CD8 T-cell formation. The molecular mediators and mechanisms identified by Dr Simon's work have the potential to highlight new targets for improving regenerative medicine approaches, and could shed light on mechanisms of immune ageing and new avenues for cancer therapy, as well as contributing to improved vaccine development.

Dr Shankar Srinivas

University of Oxford

Control of epithelial cell migration

Many functions associated with epithelia during development, growth, disease and repair require them to be highly dynamic while maintaining robust structural integrity. Although extensive remodelling of epithelial sheets underpins key morphogenetic events during embryonic development, relatively little is known about how this remodelling is coordinated across the various scales of molecules, cells and tissues, or how it is modulated to achieve diverse epithelial forms. A major focus of Dr Srinivas's research is on understanding the cellular and molecular basis for the directional and coordinated migration of a group of embryonic epithelial cells called the anterior visceral endoderm, whose movement is essential for the correct orientation of the head-tail axis. Insight from this research, in addition to illuminating fundamental processes in embryogenesis, will also inform our understanding of core aspects of cell biology, such as the regulation of cell movement, a process often subverted in pathological situations.

Professors Paul Williams and Morgan Alexander

University of Nottingham

Bacterial surface sensing – to stick or not to stick?

Reducing the risk of infection associated with in-dwelling medical devices has huge public health significance. Professors Williams and Alexander propose to build on their discovery of bacteria resistant polymers (BRPs) and their use in in-dwelling medical devices. The mechanism by which these BRPs resist attachment is, however, not understood. The key mysteries are how bacteria respond dynamically to polymer surfaces, and what intra- and intercellular signalling mechanisms bacteria employ to sense and respond to these surfaces. Professors Williams and Alexander propose an interdisciplinary approach, combining materials science and molecular microbiology, in conjunction with high-resolution state-of-the-art imaging, exploiting the extensive material chemistry and attachment phenotypes. A closer understanding of the mechanisms used by bacteria to interact with polymer surfaces could inform the rational design of improved BRPs in the future and achieve a transformative change in preventing device-centred infections.

Dr Douglas Winton

University of Cambridge

Fundamental and applied biology of intestinal stem cells

The critical dynamics that underpin most of the cell and tissue biology of any renewing tissue are the relative capacities of cells to generate and support clonal progeny. However, the repertoire of behaviours by which stem cells achieve, maintain and alter their self-renewing function is still not well understood. A major focus of Dr Winton's research is to understand the relationship between the small number of equipotent stem cells and the extensive heterogeneity in the expression of stem-cell markers that associate with stem-cell function. In addition, Dr Winton aims to understand the dynamics of human stem-cell renewal that determine the number and replacement rate of stem cells in the human intestine, and how these dynamics change in intestinal pathologies.



Professor Gordon Brown

University of Aberdeen

C-type lectins in antifungal immunity

Professor Brown's work has established that C-type lectin receptors are critical for protective antifungal immunity. However, there is still much to discover in terms of the roles of these receptors and their therapeutic potential. During his award, Professor Brown will build on his exciting recent observations to investigate in detail how C-type lectins facilitate immune recognition and responses to fungi and how these responses can be both beneficial and detrimental to the host.

Professor Jonathan Clarke

King's College London

Cellular and molecular regulation of early brain development

The remodelling of cell shape and cell-cell junctions is of fundamental importance during the morphogenesis of many body organs. As well as being critical to building an embryo, misregulation of these processes may underlie serious disease states such as cancer, where cell behaviour is remodelled with potentially disastrous consequences. Professor Clarke aims to understand the cell biology of individual cells in the relatively complex environment of a living embryo's brain. Specifically, he will address how progenitor-cell shape and connectivity are remodelled during the morphogenesis and neurogenesis of the brain. The development of neuron morphology is of fundamental importance as it is one of the major factors that can contribute to neuronal connectivity and hence brain function.

Professors Anne Dell and Brendan Wren

Imperial College London and London School of Hygiene and Tropical Medicine

Deciphering the bacterial glycocode

Glycoproteins are ubiquitous biomolecules involved in many biological processes ranging from immunity recognition to cancer development. In eukaryotes, glycosylation is known to impart novel biological and physical roles by providing labels for cell-cell communication and assisting in protein stabilisation. However, the role of glycosylation in bacteria and pathogenesis remains poorly understood. Recent evidence for protein glycosylation being central to the survival and pathogenesis of many bacteria suggests it is an ideal target for disabling them. Professors Dell and Wren will investigate the molecular, structural and functional basis of glycosylation in pathogenic bacteria, which will provide new avenues for antibiotic and vaccine design.

Professor Antony Galione

University of Oxford

Two-pore channels and NAADP-mediated endolysosomal Ca2+ signalling in health and disease

Calcium ions are important signalling molecules regulating a multitude of processes, from fertilisation to cell death. Different stimuli and their combinations generate specific spatiotemporal calcium signals, which are decoded into distinct cellular responses. Cracking this code requires a detailed understanding of the spatial and temporal choreography of the messengers, proteins and organelles that generate these calcium signatures. Nicotinic acid adenine dinucleotide phosphate (NAADP) is unique in evoking calcium release from acidic endolysosomes, and recent work suggests that two-pore channels (TPCs) – a novel family of endolysosomal channels – are the target calcium channels for NAADP. Professor Galione's research aims to clarify fundamental aspects of NAADP signalling, particularly mechanisms by which cellular stimuli induce changes in NAADP levels, how NAADP mobilises calcium from the endolysosomal stores (particularly the precise roles of the TPCs), and the specific roles of endolysosomal calcium stores in (patho)physiological processes.

Dr Mark Isalan

Imperial College London

Gene network engineering: quantifying emergent gene expression in cancer and antibiotic resistance

Dr Isalan aims to understand and build gene networks that behave predictably, consistently and robustly in the context of solving medically relevant problems. Specifically, his research will explore the emergence of gene expression in response to need in the context of antibiotic-resistance genes in bacteria and multidrug-resistance genes in cancer cells. The main concept at the centre of his research is that natural selection occurs not only at the level of the gene (on genetic variation), but also at the level of gene expression, influencing heritable phenotypic variation. By combining laboratory experiments and computational modelling, he aims to develop a new theoretical basis for understanding emergent gene expression.

Dr George Kassiotis

The Francis Crick Institute

Mechanisms of endogenous retrovirus activation by microbial exposure

Co-infections can compromise key aspects of the immune control of endogenous retroviruses (ERVs). Dr Kassiotis will take a broad but coherent approach to the question of how ERVs are regulated by the immune system and microbial infection. His overall aim is to understand the regulation of ERV expression and its interplay with gut microflora, using a combination of approaches that include mouse models and surveys of human samples. Results could lead to important discoveries that will transform our understanding of ERVs and human disease.

Dr Claudia Kemper

King's College London

Complement receptor signalling in Th-1 immunity

Complement is critically important in human health and disease. Dr Kemper's research seeks to define the function of complement in the regulation of adaptive Th1-mediated inflammation and autoimmune diseases, such as rheumatoid arthritis and scleroderma. She will investigate how the autocrine-activated receptor-signalling network regulates Th1 immunity, how dysregulation of these pathways contributes to Th1-driven autoimmune diseases, and how druggable targets in these pathways can be exploited to have a therapeutic impact upon autoimmunity.

Professor Karim Labib

University of Dundee

Functional dissection of the eukaryotic replisome

One of the most important challenges for proliferating cells is to make a single and precise copy of each chromosome before cell division. This is achieved by a complex molecular machine called the replisome. Professor Labib aims to identify and understand the unique features of the eukaryotic replisome that are critical for the duplication and stable inheritance of eukaryotic chromosomes, but which are not shared with the much better characterised replisome of E. coli. A stronger understanding of chromosome replication is important: defects in chromosome replication are an early feature in the pathogenesis of cancer, and so may provide a target for the future development of new therapies to selectively target cancer cells.

Professor Leon Lagnado

University of Sussex

Synaptic computation in the visual system

Professor Lagnado will be using his Investigator Award to study how the retina and visual cortex carry out computations that are important for our sense of vision, such as detecting changes in contrast or estimating the orientation of an object. He will ask how these computations are modified in response to changes in visual input that lead to adaptive changes in processing, and in response to neuromodulators that alter circuit function on longer timescales. He is particularly interested in defining the roles of excitatory and inhibitory synaptic connections during these processing tasks. A feature of his approach is the imaging of activity across large populations of synapses and neurons. His guiding hypothesis is that the plasticity of neurotransmission plays a major part in altering the input-output relation of sensory circuits. The insight provided by this research will help us understand fundamental mechanisms by which neural circuits process information from a changing world.

Dr Kevin Maloy

University of Oxford

Regulation of intestinal immune homeostasis by NOD-like receptors

Professor Walter Marcotti

University of Sheffield

The development and function of the mammalian auditory circuitry

Professor Marcotti is studying how the auditory system develops and operates normally, and how defects at the molecular level can lead to deafness. He is doing this by investigating the physiological properties of the individual sensory hair cells of the mammalian cochlea, using electrophysiological, calcium-imaging and molecular-biology techniques. He will apply these techniques to unravel the physiological and genetic mechanisms that lead to the assembly of the proteins required for sound encoding, and, in so doing, aims to discover how inner hair cell synapses control the transfer of sound information to auditory fibres in vitro and in vivo.

Professor Juan Martin-Serrano

King's College London

Exploring the final events in eukaryotic cell division

Professor Martin-Serrano's research is focused on understanding how the last events in eukaryotic cell division are coordinated so as to prevent damage to any lagging chromosomes. The physical separation of daughter cells, termed abscission, is a fundamental process in biology that occurs as the final cytokinetic event, as it results in the physical cleavage of the midbody that forms between daughter cells. Professor Martin-Serrano is studying the mechanism that promotes midbody abscission, and how this process is regulated by a checkpoint process called NoCut, which can delay abscission where necessary to prevent genetic damage. His overall aim is to identify the molecular mechanisms underlying this process.

Dr Elizabeth Murchison

University of Cambridge

Genome diversity and evolution in transmissible cancers in dogs and Tasmanian devils

Tasmanian devil facial tumour disease (DFTD) and canine transmissible venereal tumour (CTVT) are the only known examples of naturally occurring clonally transmissible cancers. They are clonal cell lineages that have survived beyond the deaths of the individual hosts that spawned them by acquiring adaptations for the transfer of living cancer cells between hosts. Dr Murchison will catalogue genetic and phenotypic diversity in hundreds of DFTD and CTVT tumours found in geographically dispersed locations. She will use genetic data to explore how these two infectious diseases first arose and subsequently spread through their host populations, and she will investigate how tumour phenotypic diversity may be influenced by genetic and environmental change. She will analyse patterns of selection operating on the two lineages in order to understand factors that have influenced transmissible cancer evolution. In addition, she will investigate the frequency of horizontal DNA transfer in clonally transmissible cancers.

Dr Simon Newstead

University of Oxford

Mammalian peptide transporters as targets for advanced drug design and delivery

Dr Newstead will be investigating at the molecular level the structure and function of the mammalian proton-coupled peptide transporters PepT1 and PepT2, which are important for the uptake of dietary protein and provide a major route for the absorption of drugs. Currently, there is no clear molecular understanding of how PepT1 or PepT2 recognise and transport peptides or drug molecules. The binding sites of PepT1 and PepT2 have to accommodate peptides that vary significantly in size, charge and hydrophobicity, which means that they can also transport chemically diverse drug molecules. The results of Dr Newstead's work should enable the rational design of drugs with improved oral bioavailabilty, through insights gained from the use of sophisticated structural, biochemical and functional studies.

Professor D James Nokes

University of Warwick

Defining pathways of respiratory virus transmission leading to improved intervention strategies

The transmission dynamics of human respiratory viruses are fundamentally linked to the organisational structure of person-to-person contact throughout a population, whether at the household, school, local community or national level. Professor Nokes aims to uncover potential pathways of transmission determined by contact structures, so as to gain greater insight into the emergence, spread, persistence and control of major viral causes of respiratory disease, including influenza, respiratory syncytial virus, coronaviruses and rhinoviruses. Using a framework for surveillance of respiratory infection at all organisational levels throughout the population of Kenya, for the first time temporal-spatial data on four respiratory viruses or virus groups will be coupled to whole-virus genome-sequencing data and data on social contact networks. The aim of this is to predict the most probable transmission routes in the population and to drive mathematical models to be used in exploring the effectiveness of targeted interventions, eg household- or school-based.

Professor Ewan Pearson

University of Dundee

Stratified medicine in type 2 diabetes: insights from the study of drug response

Type 2 diabetes is a major chronic disease that presents a considerable burden to patients and healthcare systems globally. There has been some progress made on understanding the causes of the disease, particularly in unravelling its genetic aetiology, with this knowledge being applied in clinical practice in monogenic diabetes. The field of stratified medicine in diabetes is currently limited to relatively rare forms of monogenic diabetes. Professor Pearson aims to identify new ways to stratify the disease by developing an understanding (clinical, biochemical and genomic) of why some drugs work well in some people with type 2 diabetes but not others. He will also investigate the mechanisms for variation that explain why some patients respond to diabetes drugs and others experience adverse reactions.

Dr Christopher Petkov

Newcastle University

Neuronal mechanisms for extracting communication signals and signalling sequences: from animal models to humans

There is a great need for better treatments for language disorders and more accurate prognosis of language recovery following stroke. To achieve this, an understanding of the cognitive abilities underpinning language and the critical neuronal circuits and pathways involved is required. Dr Petkov's work harnesses the exciting recent development of first-of-their-kind models for understanding two key aspects of human communication: how the brain extracts voice-identity or meaning-related information; and the grammar of communicative sequences. Dr Petkov's group aims to clarify the evolutionarily conserved cognitive abilities that underpin human language, and to bridge the gap between studies in animals, typical humans and language-impaired individuals. This could provide unprecedented scientific insight into the brain pathways and neuronal circuit mechanisms supporting language-related cognitive abilities.

Professor Alison Simmons

University of Oxford

The function of NOD2 in health and Crohn's disease

The intracellular pattern-recognition receptor NOD2 is essential for defence against intracellular microbes, and polymorphisms in NOD2 are associated with the development of the inflammatory bowel disease Crohn's. Professor Simmons has shown that NOD2 activates autophagy to destroy intracellular microbes in a pathway that is defective in Crohn's disease, via the mitochondrial fission protein Drp1. She has three major aims in investigating aspects of NOD2 function: to define signalling to Drp1 with a view to understanding the mechanism of NOD2-mediated Drp1 activation, and to define targets for enhancement of this activity in Crohn's; to understand the influence of NOD2 on antigen presentation and the differences in T-cell responses to different commensal microflora in Crohn's; and to understand the role of NOD2 function in intestinal epithelial cells and how Crohn's-variant NOD2 affects intestinal barrier health.

Professor Kate Storey

University of Dundee

Cellular and molecular mechanisms regulating neuronal differentiation in embryos and adults

Professor Storey is interested in the regulation of neuronal differentiation. She has recently discovered a novel form of cell subdivision, which involves local actin-myosin-mediated abscission of the apical cell membrane in cells poised to undergo neuronal differentiation in chick and mouse embryos. This process also involves the separation of apically positioned centrosome and cilium, and underlies the abrupt loss of apico-basal polarity and cell signalling at the onset of neuronal differentiation. Professor Storey plans to investigate how apical abscission is controlled, how centrosome and cilium separation is regulated and how these processes impacts upon cell signalling. A better understanding of the underlying mechanisms of neuronal differentiation and how these can be manipulated will inform strategies for treatment of neuronal injury and disease.

Professor Christoph Tang

University of Oxford

Bacterial immune evasion

Neisseria meningitidis continues to be a serious pathogen and is the leading cause of meningitis in children. The main aims of Professor Tang's research are to understand the mechanisms that enable Neisseria meningitidis to evade host immunity, the implications of this important pathogen surviving in the human nasopharynx, and subsequent disease in individuals. Professor Tang's approach is to dissect the molecular mechanisms underlying the virulence of this important human pathogen and to analyse the dynamics of carriage of meningococcus and other members of the flora of the human nasopharynx.

Dr Barry Thompson

The Francis Crick Institute

Planar polarity and tissue morphogenesis

How tissue shape is determined during animal development is a major unanswered question in biology. Failure to correctly shape tissues during development can lead to birth defects. The Dachsous-Fat cadherin system of planar cell polarity is essential for determining tissue shape in animals. This system forms long-range gradients across epithelial tissues, which are then interpreted by cells, leading to the orientation of cell movement and division along a particular axis. Dr Thompson aims to identify novel molecules and mechanisms involved in the interpretation of these gradients and the orientation of planar polarity in Drosophila. In doing so he wishes to understand how genetic programmes can organise the shape of a developing tissue.

Dr Abigail Tucker

King's College London

Consequences of the dual origin of the middle ear epithelium on function

The mammalian middle ear is an air-filled space, lined with an epithelium, that houses three small bones called ossicles, which conduct sound from the eardrum to the inner ear. Previously, it was thought that the lining of the middle ear was entirely endoderm-derived. However, Dr Tucker's recent work shows that the lining has a dual origin, as part of the middle ear is lined with neural crest cells that undergo a mesenchymal-to-epithelial transformation. She now aims to understand the normal development of the middle ear – and how defects during development have an impact on the function of the ear – by identifying the signals involved in this mesenchymal-to-epithelial transformation. In addition, she wishes to understand the consequence of the dual origin of the epithelium on susceptibility to ear infection (otitis media) and the development of middle-ear cysts (cholesteatomas), both major problems in the middle ear.

Professor Andrew Wilkie

University of Oxford

Mutations in malformation and disease

Professor Wilkie's research focuses on the mutational processes that cause malformation and disease. By employing high-throughput DNA sequencing, it is now possible to obtain an unbiased inventory of mutations relevant to serious human diseases. Using this information, Professor Wilkie aims to investigate two different but complementary disease areas, in both of which the contributions of single gene mutations are well-established but the inventory of mutations is incomplete. These are craniosynostosis, which is the premature fusion of the cranial sutures, and mutations enriched in normal testes and sperm. One overall goal is to identify all monogenic causes of craniosynostosis, which cause the disease in about one quarter of affected individuals. In addition, pathogenic mutations in sperm will be explored through a novel disease process, termed selfish spermatogonial selection, which has been delineated in Professor Wilkie's laboratory. This will enable the identification of the molecular pathways in the testis that are vulnerable to this process.

Professor Nikolay Zenkin

Newcastle University

Transcription: from catalysis to cellular regulation

Transcription is a critical process in biology, but many of the details underlying key events of the transcription cycle, as well as its regulation, are yet to be uncovered. Professor Zenkin is studying enzymology and the regulation of RNA polymerase – the enzyme that produces the RNA transcript from a DNA template. This research draws on methods from classical biochemistry and molecular biology, as well as some novel and unique experimental systems. In the long term, an understanding of the mechanisms of bacterial transcription may provide the basis for the design of effective antimicrobial agents.


Professor Mohan Balasubramanian

University of Warwick

Using a permeabilised cell system and cell physiology to understand cytokinetic actomyosin ring constriction

Professor Balasubramanian's research focuses on understanding eukaryotic cytokinesis mechanisms. Cell division involves an actomyosin-based contractile ring – containing the contractile proteins actin and myosin – which constricts following chromosome segregation to divide one cell into two. However, very little is known about the mechanism of ring constriction and force generation. Professor Balasubramanian intends to research how the actomyosin ring constricts and generates force, and what role myosin II plays in this process. In addition, he aims to establish whether force-generation mechanisms independent of myosin II are involved in actomyosin ring constriction and cell division. Furthermore, he intends to investigate what mechanisms ensure that actomyosin ring constriction is initiated only after segregation of chromosomes. Because actomyosin contractility is central to numerous cellular processes, ranging from wound healing and cell migration to asymmetric cell division and stem cell development, this work will potentially have an impact on a broad range of fields.

Professor Michael Ferguson

University of Dundee

Protein glycosylation in trypanosomes: defining and exploiting a biological system

Professor Ferguson works on glycoprotein structure and biosynthesis in parasites, particularly Trypanosoma brucei, the causative agent of human African sleeping sickness. As part of their strategy to survive inside parasitised hosts, the trypanosomes depend on a coat of surface glycoproteins (proteins with sugar chains attached). Glycoproteins perform many vital functions for the parasites with respect to their infectivity and survival in hosts. These include nutrient uptake, endosome/lysosome function, flagellar adhesion and, above all, hiding themselves from the hosts' immune systems. Professor Ferguson plans to provide a complete understanding of the range of glycoprotein structures made by Trypanosoma brucei and to use the findings as a road map to define the biosynthetic machinery that allows the parasite to assemble them. This knowledge will help identify potential drug targets for translation into drug discovery for sleeping sickness and related parasitic infections.

Professor Frederic Geissmann

King's College London


Professor Geissmann will seek to understand the role that macrophages play in homeostasis, with a particular focus on their role in metabolic diseases such as type 2 diabetes, cardiovascular diseases and inflammatory diseases. The mechanisms underlying the role of macrophages are incompletely understood, in part due to the heterogeneity of macrophages in vivo. One of Professor Geissmann’s aims will be to understand the functional differences between the myb-dependent and myb-independent macrophage lineages, the latter having been described by him in 2012. He will analyse the contribution of these two lineages to inflammation and foam cell formation using mouse models, and undertake genetic analyses of macrophage responses to a lipid-rich diet using Drosophila.

Professor Neil Gow

University of Aberdeen

Making and breaking the cell walls of fungal pathogens

The cell wall of fungal pathogens determines their pathobiology and immunological signatures. It is a target for chemotherapies and immunotherapies because the major cell wall components are essential and fungal-specific. Professor Gow wishes to understand how the cell wall is assembled and how it is recognised by the immune system. He will investigate key assembly processes and functions of the extended gene families that articulate the cell wall, and deploy novel screens, phenotyping methods and in vitro synthetic biology approaches to dissect the functions of important genes. The programme will also define the chemical structure of cell wall molecules that stimulate, attenuate and imprint the innate and adaptive immune responses. Host and pathogen functional analysis tools will be used to study the immunologically relevant cell wall glycoconjugates. These complementary approaches should advance our understanding of therapeutically tractable targets of the cell wall and will inform the design of new therapeutics and diagnostics.

Professor Erhard Hohenester

Imperial College London

Molecular mechanisms of laminin function in health and disease

Laminins are the major cell-adhesive proteins of basement membranes, the archetypal form of extracellular matrix that is required for tissue formation. Genetic defects in laminins and their cellular receptors cause serious skin blistering diseases, muscular dystrophies and kidney disorders. Yet three decades after the discovery of laminins, we still lack a mechanistic understanding of their iconic functions: polymerisation and cell adhesion. Professor Hohenester’s research aims to address these important unresolved questions through a combination of structure determination and biochemical validation. A better understanding of the molecular mechanism of laminin binding to integrins should aid in the development of new reagents for tissue engineering and stem cell culturing.

Professor Vassilis Koronakis

University of Cambridge

Towards a high-definition view of cytoskeleton remodelling by the bacterial pathogen Salmonella

Professor Koronakis is fascinated with molecular events at biological cell membranes, encompassing the structure and function of bacterial multidrug efflux pumps, and the action of bacterial effectors that seize control of host cells to force pathogen invasion. He aims to study mammalian cell-membrane signalling pathways that are vital to the control of cytoskeleton remodelling in health and infectious disease. He will combine his innovative experimental approach to study membrane signalling platforms in vitro, with his work showing how effectors of the pathogen Salmonella subvert regulatory control of the host cell cytoskeleton. This will focus on the WAVE regulatory complex, one of the cell’s key regulators of actin assembly and cell shape, and how it is controlled by cooperating Arf and Rac GTPases. This fusion of biochemistry and cell biology promises a greater understanding of key signalling processes in our cells, and new insights into how bacteria establish infection.

Dr Peter Magill

University of Oxford

Functional dichotomy in the external globus pallidus

The external globus pallidus (GPe) is a key component of the basal ganglia, a network of brain regions critical for motor control and the learning of routine behaviours. It has long been thought that the neurons of the GPe are a relatively homogenous population, but recent evidence suggests that it is instead made up of dichotomous neuronal groups. Dr Magill will address the necessity for and nature of this dichotomy in the GPe. In elucidating the substrates for GPe neuron specialisation at different scales of function, he aims to provide explanations in the context of whole-brain function and behaviour.

Professor Mala Maini


Immunopathogenesis and immunotherapy of viral hepatitis

Hepatitis B virus (HBV) remains one of the most frequent causes of death worldwide, resulting in around 600,000 deaths annually from liver cirrhosis and hepatocellular carcinoma. Professor Maini has recently elucidated new pathways by which HBV exploits the tolerogenic hepatic environment to subvert antiviral immunity and promote liver disease. The objective is to build on this work by defining key molecular mechanisms that can be blocked in order to develop novel immunotherapeutic approaches to treat chronic HBV infection. Professor Maini has three interrelated aims: to investigate the capacity of hepatic antigen presenting cells to tolerise T cells; to explore the pathogenic and protective roles of NK cells in the liver; and to develop approaches to promote the survival and function of HBV-specific T cells generated by vaccination or immunotherapy. 

Professor Gilean McVean

University of Oxford

The genetic analysis of populations

Professor McVean's research uses patterns of genetic variation among individuals to answer questions about fundamental biological processes, the nature of evolutionary processes, and the link between genetic variation and an organism's observable characteristics or detectable traits. His research aims to develop statistical and computational tools to integrate de novo sequence assembly and multiple reference sequences to best characterise the genome sequence(s) of an individual or of diverse species (such as malarial parasites). These tools will also be used to define key genomic regions (such as the HLA region) from human sequencing data and to reliably identify diverse genome-changing events from whole-genome sequence data of individuals in extended pedigrees. The genetic structure of the HLA region in different populations will be assessed to explore how variation influences the immune response to, and risk of, infectious and autoimmune diseases.

Professor Markus Müschen

University of Cambridge

Negative feedback and oncogene signalling in leukaemia

Tyrosine kinase inhibitors (TKIs), used against cancer-promoting (oncogenic) tyrosine kinases, have created a new era of treatment for patients with leukaemia and solid tumours. Despite their clinical success in chronic myeloid leukaemia, TKI resistance is a common outcome in almost all other malignancies. Research has uncovered an unexpected dependence of tumour cells on negative feedback regulation of signalling pathways downstream of oncogenic tyrosine kinases. Professor Müschen aims to build a fundamental understanding of: why tyrosine-kinase-driven cancer cells are uniquely sensitive to loss of negative feedback; whether tyrosine-kinase-driven cancer cells can only thrive within the limits of a 'comfort zone' of oncogene signalling, with either attenuation (TKI) or hyperactivation (blockade of feedback) leading to cell death; and how ablation of negative feedback mechanistically leads to cell death. He then aims to leverage this information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and inhibitors of feedback.

Professors Richard Randall and Steve Goodbourn

University of St Andrews, St George's, University of London

The interaction of paramyxoviruses with the interferon system

The interferon (IFN) system is a major component of vertebrate innate antiviral immunity. It is so powerful that most (if not all) viruses have evolved IFN antagonists. Whilst there has been an explosion in our knowledge of this subject in the last 10–15 years, there are still many unanswered questions about how viruses interact with the system. Professors Goodbourn and Randall aim to build up a comprehensive understanding of this interaction by focusing on paramyxoviruses, an important group of human and animal viruses that includes measles, mumps, parainfluenza and Newcastle disease viruses. Their studies will investigate: how paramyxovirus infections trigger IFN production; whether overstimulation of the system (and other innate responses) exacerbates disease processes; how IFN controls paramyxovirus infections and influences virus host range, pathogenicity and persistence; and the potential application of their findings to improve the control of virus diseases.

Dr Jonathan Roiser


Neural and cognitive processes in depression

Depression is a debilitating illness and represents a major public health problem, with a heavy economic and social burden. Dr Roiser will use neurochemical, neuroimaging and behavioural techniques to understand the cognitive and neural mechanisms underlying depression, which his previous work suggests exist prior to the onset of symptoms and independent of medication effects. Dr Roiser aims to examine how abnormal processing of positive outcomes ('rewards') and negative outcomes (‘punishments’) contributes to particular depressive symptoms, whether this processing is also abnormal before and after an episode of depression, and how it is affected by levels of the brain chemical dopamine. His long-term goal is to provide a testable neuroscientific account of the brain mechanisms underlying depression. In the long term this approach has the potential to improve patient outcomes by moving away from a descriptive level of diagnosis towards a mechanistic approach to classification and treatment.

Professor Colin Taylor

University of Cambridge

Spatial dynamics of receptor-regulated calcium signalling

Professor Taylor's research will investigate calcium signalling, with a particular focus on the structure and behaviour of intracellular inositol trisphosphate receptors. The key question to be addressed is how dynamic organelles and proteins mediate communication between extracellular stimuli and the calcium signals that regulate many cellular activities. These signalling pathways must be specific and sensitive and respond with appropriate speed. A handful of diffusible messengers, including cAMP, calcium and inositol trisphosphate, selectively transmit information from G-protein-coupled receptors (GPCRs), which are activated by diverse extracellular stimuli, to numerous cellular responses. Inositol trisphosphate receptors respond to many of these messengers, generating calcium signals that regulate cellular activity. Defining the dynamic architecture of these signalling pathways is essential to understanding how specificity is maintained as information passes speedily from GPCRs to responses, and to identifying drug targets that might disrupt this communication.

Professor Anton van der Merwe

University of Oxford

Immune recognition by non-catalytic tyrosine-phosphorylated receptors

Professor van der Merwe's research aims to increase our understanding of the molecular and biophysical rules governing recognition by leukocyte receptors, a process that underpins immune responses. He has generated important biophysical data on the interactions that occur between T-cell antigen receptors (TCRs) and their surface-anchored ligands, and has demonstrated that the sizes of the molecules involved in the formation of the immunological synapse play a key role in the resulting signalling outcome. This has led him to propose a novel model of TCR triggering called the kinetic-segregation (K-S) model. Recently he has proposed that other leukocyte non-catalytic tyrosine-phosphorylated receptors (NTRs) are also triggered by the K-S mechanism. Professor van der Merwe will now address three main aims: to determine the mechanism of NTR triggering upon ligand binding; to explore how NTRs integrate their signals with each other and with other receptors; and to elucidate the mechanisms driving, and functional consequences of, NTR aggregation into clusters.

Professor César Victora

Federal University of Pelotas, Brazil

Global observatory of trends and inequalities in child health and nutrition

Expanding on his experience monitoring inequalities in reproductive, maternal, newborn and child health in low- and middle-income countries, Professor Victora will build up a global data platform on health inequalities to address important scientific questions with direct practical implications for country- and global-level decision makers. He aims to systematically analyse levels and trends in population subgroups, with a focus on maternal and child health and nutrition. Specifically, he will examine the monitoring of child health indicators, interpretation and evaluation of recent trends in health and nutrition, develop forecasting of long-term consequences on child health and nutrition, and investigate how findings can be rapidly and effectively disseminated to promote evidence-based decision-making.

Professor Waldemar Vollmer

Newcastle University

Bacterial cell wall synthesis and degradation

Professor Vollmer studies the structure and biosynthesis of the bacterial cell wall that protects the cell from bursting due to internal osmotic pressure, and that maintains the cell's specific shape (spherical, rod-shape, helical, etc). Bacterial cell wall synthesis is targeted by important classes of antibiotics, such as the beta-lactams and glycopeptides. Little is known about how bacteria enlarge their cell wall when they are growing and dividing. This research aims to decipher the molecular mechanisms of cell wall growth in Gram-negative bacteria, which have an outer membrane, including the model bacterium Escherichia coli and important pathogens like Pseudomonas aeruginosa and Helicobacter pylori. Professor Vollmer will study the interactions and activities of cell wall synthesising and degrading enzymes, which presumably form dynamic multi-enzyme complexes catalysing cell wall growth. This could lead to new strategies for interfering with bacterial cell wall synthesis, with the potential for the development of novel antibiotics.


Professor Luis Aragon

Imperial College London

Functional dissection of mitotic chromatin

The compaction of chromosomes as cells enter mitosis is probably the most iconic process of dividing cells and represents one of the most fundamental biological processes, yet it is poorly understood. Recent work from Professor Aragon demonstrated that minichromosomes in yeast cells undergo a change characterised by an overwinding of the DNA double helix that is mediated by the condensin complex as chromosomes are compacted. Since nucleosomes impose underwinding on DNA, the observation implies that the distribution and/or conformation of nucleosomes must be altered during mitosis. This realisation provides a radical departure from the view that mitotic nucleosomes are a passive factor during chromosome assembly. Professor Aragon is aiming to investigate the nature and functional role of the histone component of mitotic chromosomes and to uncover the mechanisms by which histones contribute to chromosome condensation.

Dr Jake Baum

Imperial College London

The cellular and molecular mechanics of malaria parasite invasion of the human erythrocyte

Dr Baum's programme of research aims to address key questions in understanding how malaria parasites (Plasmodium species) invade the red blood cell – a critical step in the pathogenesis of malaria disease. The focus of the programme is aimed at every level of investigation, from atomic resolution of the parasite motor and single-molecule biophysical dissection of parasite motor force, to fixed and live imaging of parasite cells on the move. Dr Baum will be combining each of these approaches with comparative Plasmodium biology and, critically, inclusion of the host erythrocyte cell biology, towards the ultimate goal of understanding key events in parasite invasion and the identification of weaknesses that can be targeted to stop it.

Professor Jorge Ferrer

Imperial College London

Understanding regulatory variation in human diabetes

It has recently become apparent that a major fraction of the human genome contains functional regulatory elements. Several studies have demonstrated that sequence variation in noncoding genomic elements can cause Mendelian disorders, and it is widely thought that these noncoding elements are critically important for susceptibility to common complex diseases. Professor Ferrer aims to provide tools to understand how noncoding variants disrupt regulatory functions that cause Mendelian diabetes or type 2 diabetes susceptibility. He will also aim to exploit human genetics to discover novel genome regulatory mechanisms, in analogy to how genetics has revealed unanticipated protein functions underlying beta-cell development and function.

Professor Matthew Freeman

University of Oxford

The control of signalling by members of the rhomboid-like superfamily

Professor Freeman plans to investigate how intercellular signalling is controlled in order to regulate nearly every facet of human physiology. Professor Freeman and his team have recently discovered that proteins of the rhomboid-like superfamily (polytopic membrane proteins related to rhomboid intramembrane proteases, most of which, however, lack protease active sites) act as regulatory adapters to control the fate of growth factors and cytokines, as they are trafficked through the cell. He will examine the molecular and cellular mechanisms by which rhomboid-like proteins determine the fate of signalling proteins, discover how rhomboid-like proteins are influenced by physiological cues, and determine their physiological significance and relevance to human disease. The further understanding of these rhomboid-like proteins may lead to the development of future therapeutic strategies.

Professor Sir John Gurdon

University of Cambridge

Mechanisms for the reprogramming of somatic cell nuclei by eggs and oocytes

Eggs have a remarkable ability to rejuvenate the nucleus of a differentiated (or adult) cell to provide a source of normal embryonic stem cells. Such cells have enormous potential for making disease-specific cultured cells for drug testing and possibly for cell replacement therapy. Nuclear transfer to eggs and transcription-factor-induced pluripotency are routes by which this rejuvenation of differentiated cells, and hence somatic cell reprogramming, can be achieved. Professor Gurdon will investigate which natural components of eggs and oocytes can achieve nuclear reprogramming and how differentiated cells resist reprogramming. It is hoped that examining the mechanisms by which differentiated cells are stable and resist reprogramming will help to explain the processes that, when defective, can lead to disease or cancer.

Dr Lindsay Hall

University of East Anglia

Role of early-life gut microbiota in colonisation resistance development

Complex microbial communities (microbiota) colonise the body after birth. These beneficial bacteria shape immune defence, limiting infection by gut pathogens through a process of colonisation resistance. However, disturbances such as caesarian sections and antibiotic exposure in early colonisation events can lead to increased susceptibility to pathogens, as well as allergic and chronic inflammatory diseases in later life. Dr Hall will work on building our knowledge of the contribution of specific bacterial species during early-life development, and how microbiota disturbances increase susceptibility to gut infection, focusing on bifidobacteria. The goals are to understand the effects of bifidobacteria on critical colonisation resistance, the impacts of antibiotic-induced disturbances, and the potential for restoring a disturbed early-life microbiota to control gut infection, for use in infectious-disease settings.

Dr Matthew Higgins

University of Oxford

Structural studies of host-parasite interactions at the heart of malaria pathogenicity

Proteins on the surface of the malaria parasite are at the front line of its battle with the host. Dr Higgins's project will use the latest tools to determine structures of protein-ligand complexes involved in red blood cell invasion and placental sequestration in pregnancy-associated malaria. Structural studies will allow mapping of polymorphisms onto molecular surfaces while identifying conserved binding sites and inhibitory epitopes on which to focus. An insight into the molecular structure of key malaria surface proteins will guide design of future vaccine components.

Dr Frederick Livesey

University of Cambridge

Human stem cell models of Alzheimer's disease

Dementia is a major healthcare challenge that currently affects about 36 million people worldwide. Alzheimer's disease (AD) is the most common form of dementia, accounting for over 60 per cent of cases, yet there are currently no licensed drugs that modify the course of the disease. Dr Livesey plans to build on his previous work, which led to the development of stem cell models of AD, to generate insights into AD initiation, progression and therapeutic intervention. Specifically, he will investigate how AD progresses and spreads through the human nervous system, and how AD affects neuronal function at the synapse and network level. He will also study AD-associated genetic variants and how these contribute to disease initiation and progression in sporadic, late-onset AD. By examining the causes and mechanisms of AD initiation and progression, it is hoped that these can be reversed and that new therapeutic interventions can be developed.

Dr Andrew McKenzie

University of Cambridge

Innate lymphoid cells in immunity and disease

Following the recent discovery of innate lymphoid cells (ILCs), it was determined that these cells are critical regulators of protective immunity against parasitic helminths and bacteria and also in autoimmune disorders. Dr McKenzie aims to investigate the biological roles of ILCs and to elucidate their developmental relationships within the lymphoid lineage and their functional roles in protective immunity and disease. The aim is to build on existing knowledge of type 1 and type 2 disease models, and their dissection using molecular genetics in mice, to provide new insight into these pathways and identify potential therapeutic targets.

Dr Jack Mellor

University of Bristol

The role of acetylcholine in hippocampal function

The mechanisms by which the neurotransmitter acetylcholine enhances cognition are not fully understood. Dr Mellor will be working towards defining the cellular, synaptic and network effects of acetylcholine in the hippocampus and determining its role in cognition. He will focus on which acetylcholine receptors regulate synaptic plasticity and neural network activity using a multidisciplinary approach. The aim is to define ways to pharmacologically modulate the hippocampal network.

Dr Nicholas Morton

University of Edinburgh

Functional characterisation of the novel adipocyte lean gene thiosulphate sulphurtransferase: developing next-generation obesity therapeutics

Obesity is a major global health problem. Its chronic disease complications (type 2 diabetes, hypertension, atherosclerosis and certain cancers) are the major causes of morbidity and mortality in developed and, increasingly, developing countries. Dr Morton’s vision is that genes promoting healthy leanness in the face of genetic and intense environmental obesity-causing pressures represent important biology and an untapped source for anti-obesity therapeutics. He has identified the enzyme thiosulphate sulphurtransferase (TST) as one possible candidate for driving healthy leanness. Dr Morton’s work will investigate the mechanism of action of TST. He will specifically test the hypothesis that TST augments mitochondrial function, reduces mitochondrial oxidative/metabolic stresses and thereby improves adipocyte function and release of anti-diabetic adipokines. It is hoped that by understanding the role of TST, it may be exploited to ultimately treat obesity and its related metabolic problems.

Professor Jeffrey Pollard

University of Edinburgh

The metastatic cascade: macrophages lead the way

In breast cancer, the survival rate of women with metastatic disease has not changed for 30 years, indicating the need for different treatment strategies. While research has largely focused on tumour cells, it has become apparent that, in tumour progression to malignancy, progressive modification of the stromal microenvironment is as important as the changes in the tumour cells themselves. The aim of Professor Pollard’s research is to define the molecular basis of how macrophages promote tumour progression to malignancy. Specifically, he will investigate how macrophages stimulate angiogenesis, promotion of tumour cell invasion and intravasation, suppression of anti-tumour immune responses, and promotion of extravasation at metastatic sites and their subsequent tumour cell establishment and persistent growth. It is hoped that this research will identify new pathways and targets for therapeutic intervention in human breast cancers.

Professor Barry Potter

University of Bath

Chemical biology of cellular signalling using polyphosphate messengers

Different cells can communicate via chemical messengers, such as hormones and neurotransmitters, and the malfunction of cell-signalling pathways often underlies disease. Such 'first messengers' generally interact with a cell surface receptor, and small-molecule 'second messengers' subsequently carry this signal to internal effector proteins to coordinate a response. Professor Potter will use the techniques of chemical biology, employing synthetic and biological chemistry, to explore the application of tailored synthetic signalling tools in investigative biology. His prime focus is on messengers possessing multiple phosphate groups that dynamically mobilise cellular calcium, such as the cyclitol polyphosphate IP3, and also on newer signalling nucleotides such as cADPR, NAADP and ADPR, and the enigmatic higher inositol polyphosphates. Designing chemical tools for the modulation of these polyphosphates by changing molecular structure, in concert with other interdisciplinary techniques and as part of a process informed by structural biology, will provide both targeted tools for the interrogation of cell-signalling mechanisms and early leads for potential drug candidates.

Dr Jan Rehwinkel

University of Oxford

Cytosolic DNA sensing in infection and autoimmunity

Dr Rehwinkel's programme of research aims to further our understanding of cytosolic DNA detection by the host immune system. Cytosolic DNA detection is important not only during many bacterial and viral infections, but also in autoimmune and autoinflammatory diseases and DNA vaccination. However, the signalling pathways that detect DNA in the cytosol and in particular the DNA sensors triggered by cytosolic DNA remain unknown or incompletely understood. Dr Rehwinkel plans to identify cytosolic DNA sensors and their downstream pathways, establish new models for studying DNA sensors, and define the role of cytosolic DNA sensing during autoinflammation and infection.

Professor Matthew Rushworth

University of Oxford

Neural mechanisms for foraging in an uncertain environment

Professor Rushworth's research is motivated by the idea that some aspects of human decision-making may best be understood using principles from animal foraging behaviour. To test this 'ecological' model, he will employ a range of novel tasks that seek to understand how humans identify what options are available in the environment and how their choices are guided by contextual factors (eg short- versus long-term goals). To understand which brain regions are involved in these processes, Professor Rushworth will combine computational modelling with functional magnetic resonance imaging (fMRI). He will also use transcranial magnetic stimulation to gain insight into how disrupting activity in parts of the decision-making network influences activity in other regions.

Professor Brigitta Stockinger

The Francis Crick Institute

Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor recently shown to play an important role in the immune system, although mechanistic insight is limited. Professor Stockinger plans to investigate the physiological functions of the AhR in the immune system. The programme of work includes: identifying protein interactions with AhR in different cell types and immunological conditions using AhR-FTAP mice; investigating the physiological regulation of AhR signalling via metabolic enzymes; analysing mice with cell-type-specific AhR deletions in order to identify cell-intrinsic consequences of defective AhR signalling; and testing the hypothesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barrier sites.

Dr Jessica Strid

Imperial College London

Lymphoid stress-surveillance – linking tumour immunesurveillance and atopy

The overarching aim of Dr Strid’s programme of work is to characterise and explore lymphoid stress-surveillance (LSS). Described by Dr Strid, this is the activation of local intraepithelial lymphocytes, by physico-chemical tissue damage, that in turn initiates local and systemic Th2 and IgE responses as well as anti-tumour immunity. Key goals of the research are to investigate fundamental aspects of LSS and to determine the role of early LSS-induced Th2 immunity and IgE antibodies in epithelial dysregulation and carcinogenesis. The results will shed new light on the afferent induction of Th2 immunity and will further our understanding of the biological relationship between allergy and cancer.

Professor Sivaramesh Wigneshweraraj

Imperial College London

Non-bacterial regulators of bacterial transcription

The widespread global emergence of bacteria resistant to antibiotics necessitates research into novel antibacterial drugs and drug targets. Bacteriophages, viruses that infect and destroy bacteria, have evolved numerous ways to arrest essential bacterial processes such as DNA transcription and replication, in order to successfully take over the bacterial host for bacteriophage reproduction. The methods employed by bacteriophages represent a new toolbox to inform and inspire novel antibacterial drug and drug target discovery. Professor Wigneshweraraj will focus on research into bacteriophage-derived inhibitors of bacterial RNA polymerase, the enzyme responsible for all RNA synthesis in bacteria.

Professor John Wood

University College London

Peripheral pain pathways

There is a clinical need for a better understanding of pain in order to develop new drugs. Professor Wood has shown previously that different sets of sensory neurons evoke distinct pain sensations. During this Award, he will use a genetic approach and employ novel transgenic mice to define the sets of peripheral sensory neurons responsible for distinct pain sensations and to investigate how these neurons transmit information to the central nervous system. His aim is to identify the mechanisms and molecules associated with distinct pain sensations, focusing on mechanical and cold allodynia and visceral pain. He will also investigate the contribution of sensory neurons, normally associated with innocuous sensations, to pain sensations in neuropathic pain states.



Professor Charles Bangham

Imperial College London

Regulation of retroviral latency in the human genome

Professor Bangham’s programme of research aims to understand the regulation of retroviral latency and expression - a problem of central importance in natural retrovirus infections such as HIV-1 and human T-lymphotropic virus type 1 (HTLV-1) and in gene therapy with retroviral vectors. The key goal is to identify the mechanisms by which HTLV-1 regulates its latency and so persists in the face of a strong host immune response, causing fatal and disabling diseases for which there is currently no effective treatment. Professor Bangham will exploit recent exciting discoveries by his team, and the unique advantages of HTLV-1 infection, to answer these fundamental questions in natural HTLV-1 infection and in humans treated with newly developed lentiviral gene therapy vectors. Using state-of-the-art techniques that his group has developed recently, comprising novel high-throughput mapping and quantification of proviral integration sites in vivo and mechanistic experiments in vitro, these studies will have both scientific and clinical significance in pathogenic human retroviral infections and in the rapidly developing field of gene therapy.

Dr Andrew Carter

MRC Laboratory for Molecular Biology, Cambridge

Transport of cargo by cytoplasmic dynein

The size of eukaryotic cells and the crowded nature of their cytoplasm mean that they rely on active transport by motor proteins to move components around. Dr Carter studies cytoplasmic dynein, a poorly-understood complex of proteins that carries out almost all the minus-end directed microtubule transport in cells. This includes the movement of membranous cargos, individual mRNAs and proteins. How dynein selects the correct cargo and transports it at the correct time and place and how viruses such as herpes and rabies hijack this process are currently unclear. Dr Carter aims to uncover the mechanism by which dynein can carry so many different cargos and how such transport is specifically regulated.

Professor Sir Philip Cohen

University of Dundee

Elucidation of molecular mechanisms that activate the MyD88 signalling network

Toll-like receptors (TLRs) are critical components of the innate immune system that are used for defence against bacteria, viruses and other pathogens. Their activation leads to the production of inflammatory mediators that mount responses to fight infection and promote tissue repair. Nearly all TLRs signal via the adaptor protein MyD88, and the goal of Professor Cohen’s research is to elucidate the MyD88 signalling network in molecular detail. This is critical for the development of our understanding of how the production of inflammatory mediators is regulated, why defects in this system lead to immunodeficiency, chronic inflammatory or autoimmune diseases, and to identify pathway components that are targets for therapeutic intervention.

Dr Mark Dillingham

University of Bristol

Double-stranded DNA break resection: from bacterial model systems to human cells

DNA breaks are highly toxic lesions, and failure to repair them correctly is associated with genomic instability leading to cell death, cancer or developmental defects. Repair of double-stranded DNA breaks by homologous recombination is initiated by resection to form a long 3(prime)-terminated ssDNA overhang. It is thought that resection is a two-step process involving structure-specific nucleases, which trim the ends in preparation for more extensive degradation by processive helicases and nucleases. Dr Dillingham is aiming to investigate how human resection factors cooperate to initiate the repair of double-stranded DNA breaks, to characterise the structure and mechanism of the minimal end resection machinery for simple DNA breaks, and to understand how the variety of nucleases involved in resection can process more complex DNA end structures such as ssDNA overhangs.

Professor Lars Fugger

Nuffield Department of Clinical Neurosciences, University of Oxford

Functional genomics in multiple sclerosis

Multiple sclerosis (MS) is a common chronic inflammatory and neurodegenerative disease of the central nervous system. Susceptibility to MS is inherited to a certain extent, but it is not clear which genes confer this risk and how they do so. Professor Fugger will employ a multidisciplinary approach to investigate the genetic association in MS. His goal is to validate candidate genes associated with the disease, clarify their functional roles, and assess how this knowledge can be translated into novel therapeutic approaches to treat MS.

Professor Nick Gay

University of Cambridge

Molecular mechanism of innate signalling in the immune and nervous system

Professor Gay has a long-standing research interest in the Toll-like receptors (TLRs) that alert the innate immune systems of all species, from fruit flies to humans, to the presence of microbial invasion. The novelty of his lab’s contribution has been in characterisation of supra-molecular complexes that are formed during signal transduction by the TLRs. Professor Gay proposes to pursue these studies with respect to the biophysical and structural analysis of the protein interactions within these complexes, as well as using imaging techniques to study the signalling process in vivo. In addition, novel studies will be conducted on the way in which the TLRs synergise with the modular kinase LRRK2 to generate neurotoxicity in the nervous system.

Professor Richard Grencis

University of Manchester

Immunity to whipworm: transforming the paradigm

Professor Grencis is hoping to answer the long-standing question of how gastrointestinal nematodes evade host immunity and survive for prolonged periods of time by studying the whipworm, Trichuris sp., a ubiquitous GI nematode. Previous progress has been hampered by paucity of genomic information, lack of appropriate immunological tools, and lack of tractable experimental murine systems that can readily be translated to human infection. The novel methodologies that are being developed, together with the emerging Trichuris genomic information, will help to identify novel intervention pathways and advance current understanding of the host-parasite relationship, ultimately leading to improvement in human and animal health. The key goals of Professor Grencis's work are to define the genes and their products in both parasite and host that determine successful parasite invasion and survival, to define the host immune dynamics that lead to either host protection or susceptibility, to identify and characterise the key parasite-derived immunomodulatory molecules, and to establish a functional and robust system to study human whipworm.

Dr Angelika Gründling

Imperial College London

Deciphering the nucleotide signalling network of the Gram-positive bacterial pathogen Staphylococcus aureus

Dr Gründling's main aim is to identify proteins and pathways regulated by the nucleotide c-di-AMP and to reveal the molecular bases for its requirement for bacterial growth. Nucleotides are important signalling molecules in all forms of life, and have important roles in bacterial physiology and pathogenesis, often through binding and controlling the function of a specific set of proteins. Current knowledge of their function remains rudimentary. Recent work by Dr Gründling’s team has revealed that c-di-AMP is required for the growth of Staphylococcus aureus and that this nucleotide has a role in the regulation of cell wall integrity in this organism. The plan is to investigate the function of c-di-AMP and additional nucleotides such as pApA, cAMP and ppGpp, with the aim to decipher the interconnections of nucleotide-controlled pathways. A deeper understanding of essential cellular processes in this S. aureus is of great importance, but it is anticipated that the findings will be applicable to a range of bacteria. Ultimately, this research has the potential to provide new targets for the development of alternative strategies to combat infections.

Professor William Harris

University of Cambridge

How to build a retina

Professor Harris is fascinated by how an organ as complex and refined as the brain is made during development. His laboratory focuses on the retina, perhaps the most experimentally tractable part of the brain. The key basic and interrelated questions that form the core of his proposed work are: (1) What mechanisms regulate the appropriate number of neurons generated from a population of retinal progenitor cells that themselves produce variable numbers of descendant neurons? (2) In all vertebrates, retinal cells consist of six main types and more than 50 subtypes. How are these types and subtypes generated in the correct proportions? (3) A conserved feature of retinal development is histogenesis, the relationship between cell birth, cell type and tissue architecture. How is this achieved?

Professor David Horn

University of Dundee

High-throughput decoding of virulence mechanisms in African trypanosomes

Professor Horn works on the African trypanosome, Trypanosoma brucei, which is transmitted among mammalian hosts by the tsetse fly, causing human African trypanosomiasis, or sleeping sickness, and the livestock disease nagana. The molecular mechanisms affecting virulence, antigenic variation, transmission, drug susceptibility and human serum susceptibility have remained largely unknown. Professor Horn’s team have developed RNA interference (RNAi) library screening for exploitation of T. brucei genome sequence data. He wants to exploit the power of the RNAi target sequencing approach to decode the genetic basis of fundamental aspects of T. brucei biology and pathogenesis. The key goals are to characterise the machineries that underpin parasite-drug interactions, evasion from host defence and survival within the mammalian host. The studies promise major advances in our understanding of these key virulence mechanisms.

Professor Susan Lea

University of Oxford

Molecular mechanisms in complement regulation and evasion

Professor Richard Marais

The Paterson Institute for Cancer Research, University of Manchester

Developing personalised medicine for malignant melanoma

Professor Stephen Matthews

Imperial College London

Understanding molecular control of functional amyloidogenesis

Under stress, bacteria switch to a lifestyle that is optimised towards survival, in which they form a community of cells usually attached to a surface, known as a biofilm. By collaborating in a biofilm, bacteria form a safe haven where they are protected from immune system detection and chemical onslaught from antibiotics. Biofilms also cause complications in the provision of clean drinking water, food processing and fouling of manufacturing processes. The formation of a viable biofilm is a highly regulated, complex process in which bacteria secrete a polymeric extracellular matrix. Amyloid fibrils are abundant in bacterial matrix, where they confer structural and organisational integrity due to their unique mechanical properties. Despite the usefulness of amyloids, they are often toxic to a cell when formed at the wrong time or place. Bacteria have devised elegant solutions to control inappropriate amyloid formation, and by using a multidisciplinary structural biology approach, Professor Matthews aims to unravel this extraordinary ability.

Professor James Naismith

University of St Andrews

Transport and polymerisation of bacterial polysaccharides: from cytoplasm to the outside world

Professor Naismith wishes to understand the transport and polymerisation of bacterial polysaccharides, the process by which sugar molecules synthesised within the cell cytoplasm are transported across the cytoplasmic membrane, polymerised and attached to the protein substrates. The first step of the process is coupling of sugar to a lipid carrier by two broad classes of integral membrane proteins that carry out this process. Professor Naismith’s group plans a study of the structures and mechanisms of action of these classes. The next step is flipping across the cytoplasm, carried out by the flippase protein, after which the units are polymerised into a defined length by a polymerase. While the polymer can be attached to a protein or exported or transferred to another receptor, the group will focus research on the attachment of the polymer to protein substrates. Extracellular polysaccharides play a variety of roles in bacteria, especially their role in bacterial pathogenesis. The sugar polymers can help evade the immune system, protect against the immune response or even modulate the immune system.

Professor David Price

Cardiff University

The immunopathogenesis of Epstein-Barr virus-associated malignancies

Professor Nazneen Rahman

Institute of Cancer Research

Genetic and epigenetic investigations of childhood cancer and overgrowth syndromes

The study of childhood cancer and associated syndromes, such as those that result in global or regional overgrowth, has resulted in important insights into basic biological processes and substantial clinical benefits. Professor Rahman’s research has already identified common and rare genetic and epigenetic susceptibility factors for these conditions. However, these only account for a minority of children. Professor Rahman will extend her research to employ genome-wide exomic, genomic and methylation analyses to discover new predisposition factors, together with targeted replication to define prevalence, penetrance, the spectrum of pathogenic mutations and genotype-phenotype associations. The data generated will be integrated to help define the clinically relevant information required for clinical translation of new genes/epigenetic defects, and to produce diagnostic, management and testing protocols for use in clinical practice.

Professor William Richardson

University College London

Transcriptional control of CNS myelination in development and maturity

Professor Richardson studies oligodendrocytes – cells in the CNS that form the insulating myelin sheaths that are necessary for rapid communication between neurons and their targets. Most oligodendrocytes develop early in life but they continue to be produced from their glial precursor cells well into adulthood. There is growing evidence from human brain imaging, as well as from animal models, that adult-born oligodendrocytes and myelin are involved in some forms of learning and memory (eg motor skills learning). In addition, new oligodendrocytes are required for repairing areas of acute myelin damage such as occur in the demyelinating disease multiple sclerosis. Professor Richardson will use his Investigator Award to study the molecular control of myelin development, with the long-term aim of learning how to stimulate normal learning processes or to repair myelin damage. He will focus on transcriptional control, because this is the convergence point of many signalling pathways that together orchestrate the myelination programme.

Professor Polly Roy

London School of Hygiene and Tropical Medicine

Understanding the infection processes of bluetongue virus as a model of complex, non-enveloped orbiviruses: viruses with segmented double-stranded RNA genomes and multilayered capsids

Professor Roy's main aim is to understand how complex, non-enveloped orbiviruses (family Reoviridae) successfully invade host cells, replicate and cause disease, and hence to understand how to better control virus outbreaks. The studies address the most challenging key stages of the orbivirus life cycle: how it breaches the plasma membrane of the host cell to deliver a large capsid into the cytoplasm, how it regulates the release of newly synthesised transcripts from the capsid into the cytoplasm, and how transcription complexes become precisely located at the capsid vertices and, lastly, how newly assembled subviral particles exit from their assembly site to leave the host cell. Together with a reverse genetics system that allows targeted mutations in the viral genome to dissect replication events of these complex capsid viruses, and the latest imaging technologies, Professor Roy will use advanced techniques pioneered in her laboratory: an in vitro cell-free infectious particle assembly system, for a complex dsRNA virus. The use of these hybrid approaches is allowing new findings in the biology of viruses and cells that would not have been possible even a few years ago.

Professor Pauline Schaap

University of Dundee

Molecular mechanisms of encystation and sporulation

Professor Schaap studies the genetically tractable Dictyostelid social amoebas. These have a sporulation phase in their life-cycle which is evolutionarily derived from encystation – a mechanism employed by pathogenic protozoa and which can cause problems, as cysts are resistant to immune clearance, antibiotics and biocides. Professor Schaap will use a Dictyostelid model to investigate the signalling pathways of encystation and explore whether crucial regulatory proteins in these pathways might be suitable targets for the design of drugs to inhibit encystation.

Professor John Schwabe

University of Leicester

The molecular functioning of HDAC:co-repressor complexes

Histone deacetylases (HDACs) are essential enzymes required for human development and homeostasis and they are increasingly recognised as important targets for the treatment of cancer and other diseases, including Alzheimer's. HDACs 1-3 serve as catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes remove acetyl groups from histones, resulting in the condensation of chromatin, which causes gene silencing. Professor Schwabe plans to determine the structures of the four HDAC1 and HDAC3 holo-complexes, in order to define the specificity of their assembly and their role in determining target gene and substrate specificity. He will also be researching the biological role of inositol tetraphosphate in regulating HDAC complexes and the potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides.

Professor Andrew Sewell

Cardiff University

Reducing transplant rejection by mapping the alloreactivity footprints of abundant virus-specific T-cell populations


Professor Martin Allday

Imperial College London

Epigenetic reprogramming of B cells in viral persistence, disease pathogenesis and tumour immunosurveillance

Professor Allday aims to understand how latent infection with Epstein-Barr virus (EBV) epigenetically reprograms mature human B cells and their progeny. This involves viral proteins manipulating host polycomb-group proteins to repress the transcription of specific host genes – including at least two tumour suppressors. The goal is to not only determine the role of these processes in EBV biology and EBV-associated cancers but also provide unique insights into the molecular mechanisms underpinning polycomb-group-mediated gene repression and how they can be manipulated by viruses and perhaps other microorganisms.

Professor David Attwell

University College London

The development, plasticity and pathology of myelinated CNS axons

Professor Attwell's lab is interested in the interaction between neurons and glial cells. With this award Professor Attwell will investigate the development, plasticity and pathology of myelinated CNS axons. Myelinated axons form the white matter of the brain and spinal cord. They are generated by a subtype of glia called oligodendrocytes that wrap myelin around axons, which speeds action potential propagation along the axons. However, myelinated axons are poorly understood, and Professor Attwell will address the following questions: (1) How is oligodendrocyte development regulated to set axonal conduction speed? (2) What are the mechanisms of white matter plasticity that may contribute to learning? (3) How is the oligodendrocyte-axonal unit disrupted in pathology? As well as increasing our understanding of myelinated axons, this research will also give insight into potential therapeutic approaches for protecting myelin and promoting myelination in de-/dysmyelinating disorders, such as multiple sclerosis.

Professor Shankar Balasubramanian

University of Cambridge

The chemical biology of the genome and epigenome

Professor Balasubramanian's research exploits chemical approaches to understand the structure, chemistry and function of DNA. His broad goals are to understand the importance of chemical modification of DNA bases, such as 5-methylcytosine and 5-hydroxymethylcytosine, in normal biology and disease states. He will exploit and develop new chemical and analytical approaches for exploring alternative bases in the genome, to include the recent inventions of quantitative sequencing of 5-hydroxymethylcytosine at a single-base resolution and the genome-wide chemical mapping of 5-formylcytosine from his laboratory.

Professor Richard Elliott

University of St Andrews

Molecular analyses of arbovirus-host interactions


Professor Gerard Graham

University of Glasgow

Dissecting the chemokine basis for the orchestration of the in vivo inflammatory response

Professor Graham's research intends to improve our understanding of how an inflammatory chemokine response is coordinated and regulated. Using cutting-edge genome engineering, his lab will generate mice with silenced inflammatory chemokine receptors. This silencing is reversible to allow the receptors to be selectively switched on in turn, as well as in select combinations, illuminating the role of each receptor in the orchestration of the chemokine-dependent inflammatory response. He also aims to determine the dynamics of receptor expression in the orchestration of tissue-specific in vivo inflammatory responses.

Professor Matthias Merkenschlager

Imperial College London

Genetic approaches to dissect the role of cohesion in gene regulation

Cohesin is a protein complex best known for its role in chromosome biology, but recent work suggests additional functions in gene expression, development and cancer. Research in Professor Merkenschlager's lab demonstrated that cohesin regulates gene expression independently of its canonical functions in the cell cycle. This realisation opened a new perspective on gene regulation, in line with growing awareness of the importance of higher order genome organisation. The aim of his research is to uncover the mechanisms by which cohesin regulates gene expression and eventually suggest approaches to the management of clinical conditions where cohesin function is compromised.

Professor Terence Rabbitts

University of Oxford

Tracing cancer evolution using mouse models

Professor Rabbitts is a molecular biologist who will be using models of cancer progression to determine the changes associated with the development of cancer from initiation to overt cancer. Specifically, he will be comparing which genes are expressed and which proteins are produced as tumours evolve in these different cancer models. These studies will identify new markers for diagnosis and new targets for therapy.

Dr Bénédicte Sanson

University of Cambridge

In vivo mechanisms of collective cell movement and cell sorting

Dr Sanson studies morphogenesis in the Drosophila embryo and is interested in how the action of genes and mechanical forces work together to shape developing tissues. With this award, she will be concentrating her studies on a short window in early development when the embryo’s tissues undergo changes that are common to all bilateral organisms, including humans.

Professor David Sherratt

University of Oxford

Illuminating the in vivo molecular mechanism of bacterial chromosome replication and segregation

Chromosome replication and segregation are critical processes for life but little is known about when, where and how these occur at the single-molecule level. Professor Sherratt will use state-of-the-art live cell imaging, which enables visualisation at the individual protein level of the assembly and action of individual molecular machines that act in bacterial chromosome replication and segregation. He aims to track the progress of a single replication fork from initiation to termination, to visualise the recruitment of recombination-repair proteins to site-specific double-strand breaks and to dissect the molecular mechanism of chromosome segregation.

Dr Benjamin Willcox

University of Birmingham

The molecular basis of gamma delta T cell recognition in health and disease


Claudio Alonso

School of Life Sciences, University of Sussex

The molecular regulation of Hox genes during animal development

Dr Alonso is a molecular biologist interested in how the process of animal development is molecularly controlled. More specifically, he studies the regulation of the Hox genes, a family of genes required for the correct head-to-tail patterning of animal bodies. His recent work indicates that RNA regulatory processes are important for Hox expression and function during the formation of the central nervous system (CNS) in Drosophila. He will be pursuing studies to understand more about the molecular mechanisms of Hox RNA regulation and investigate how these might contribute to Hox gene function within the developing CNS.

Dr James Briscoe and Dr Karen Page

The Francis Crick Institute and Department of Mathematics, UCL

Regulatory dynamics of vertebrate neural tube development

This joint Investigator Award will draw on the complementary expertise of Dr Briscoe and Dr Page in the areas of developmental biology and mathematics, respectively. The overall goal of their work is to understand the mechanisms of pattern formation in developing tissues, using the vertebrate neural tube as a model. The researchers will build on their recent studies in the neural tube, which have shed light on how patterns of gene expression are formed in response to external cues, by attempting to reconstitute neural tube development in silico and in vitro.

Professor Raymond Dolan

Wellcome Trust Centre for Neuroimaging, UCL

The neurobiology of motivation in health and disease

Professor Dolan's goal is to understand motivation in terms of the computational processes being undertaken by neural circuits in the brain. He will study this by using behavioural and neuroimaging techniques, in combination with computational models. He aims to determine how motivation impacts on behaviour, addressing how such processes may be altered when the brain is in a psychiatric state (e.g. in clinical depression). Ultimately he hopes to use his findings to refine psychiatric disorder classifications, which will help provide more focused targets for future investigations and for potential treatment options.

Professor Annette Dolphin

Department of Neuroscience, Physiology and Pharmacology, UCL

Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins

Professor Dolphin's research focuses on neuronal voltage-dependent calcium channels, in particular the role of the accessory subunits β and α2δ. Understanding these channels and their accessory subunits is highly relevant to neuropathic pain as both CaV2.2 and α2δ-1 represent important therapeutic targets. In this award, Professor Dolphin will research the interaction of the α2δ subunits with other proteins. Work from her lab has shown that α2δ subunits interact with trafficking proteins. Professor Dolphin therefore aims to examine how this interaction influences the trafficking of α2δ subunits and their associated calcium channels, and whether gabapentinoid drugs can disrupt this interaction. A second aim of her research is to look more broadly at whether α2δ subunits influence other proteins, with a particular focus on other ion channels.

Professor Jeffrey Errington

Institute of Cell and Molecular Biosciences, University of Newcastle

Chromosome segregation and cytokinesis in bacteria: mechanisms and regulation

Professor Jeffrey Errington is investigating the cell cycle, a pivotal process in biology, of which mechanistic details underlying many of the key events are not well understood. The ability to regulate chromosome replication, segregation and cytokinesis is one of the most fundamental processes for organisms as it is crucial for survival, fitness, reproduction and evolutionary success. Professor Errington plans to resolve the molecular details underlying these key events in bacteria, which have the advantage of relatively simple cells and genes and are therefore tractable in experimentation. A better understanding of this fundamental process in bacteria might enable scientists to interfere with essential functions in pathogenic bacteria, which could in turn inform antibiotic design.

Professor Elizabeth Fisher and Dr Victor Tybulewicz

Department of Neurodegenerative Disease, UCL and The Francis Crick Institute

Understanding Down's syndrome phenotypes through innovative mouse genetics

Professor Fisher and Dr Tybulewicz are building on previous Trust funding to extend their successful collaboration with a Joint Investigator Award. They plan to investigate the mechanisms involved in the translation of human chromosome 21 genes into the Down's syndrome phenotype. Down's syndrome is the most common form of intellectual disability, but the phenotype is highly variable and little is known about the mechanisms that determine which features are expressed. Professor Fisher and Dr Tybulewicz will use their award to concentrate on the cellular and molecular mechanisms underlying the cardiac development, learning and memory, and locomotor function deficits associated with the disorder.

Professors Joachim Gross and Gregor Thut

Institute of Neuroscience and Psychology, University of Glasgow

Natural and modulated neural communication: State-dependent decoding and driving of human brain oscillations

Professors Gross and Thut will be working in partnership to understand aspects of rhythmic network activity in the human brain. As part of this research, they plan to develop and use methodologies to decode and change brain communication by means of MEG/EEG and non-invasive brain stimulation. They seek to understand how the oscillatory network activity gives rise to the complexity and efficiency of human behaviour and to explore to what extent this activity can be controlled by brain stimulation in the healthy and diseased brain.

Professors Andrew Hattersley and Sian Ellard

Peninsula Medical School, Universities of Exeter and Plymouth

New insights from neonatal diabetes

Professors Hattersley and Ellard are together investigating the function and development of the human pancreatic beta-cell through genetic, functional, physiological and clinical studies of patients with neonatal diabetes. Neonatal diabetes is a rare monogenic subtype of diabetes that is diagnosed before six months. Their previous work led to hundreds of patients stopping insulin and achieving better control of their diabetes with sulphonylurea tablets. A rapid, comprehensive and international genetic testing service will provide a platform for recruitment and benefit patients throughout the world. They will use new DNA sequencing technology to identify novel genes, then characterise the gene defects using functional and physiological studies in patients.

Professor Ronald Hay

College of Life Sciences, University of Dundee

Determining the role and mechanism of action of the SUMO targeted ubiquitin ligase RNF4 in maintaining genome integrity

RNF4 is a protein that is important for maintaining the stability of the genome in higher eukaryotic cells. Professor Hay is aiming to define the role of RNF4 in the cellular response to DNA damage and to establish the molecular mechanism that is employed by RNF4 to catalyse the transfer of ubiquitin to substrates. Specifically, he will use quantitative proteomics to identify proteins that are targeted by RNF4 in response to genotoxic stress and he will establish how the RNF4-dependent ubiquitination leads to a functional change in protein activity. The impact of DNA-damaging cancer therapies is attenuated by the DNA repair process, so a better understanding of the actions of RNF4 may help in the design of DNA repair inhibitors that could have an enhanced effectiveness against cancer cells.

Professor Mark McCarthy

The Oxford Centre for Diabetes, Endocrinology and Metabolism and the Wellcome Trust Centre for Human Genetics, University of Oxford

Characterising causal alleles for common disease

Professor McCarthy's research focuses on using large-scale genetic and genomic approaches to understand the genetic variants underlying predisposition to type 2 diabetes and those influencing related phenotypes including obesity and glycaemia. His research seeks also to translate gene identification into biological insights and clinical advances. He will aim to define the mechanisms responsible for the pathogenesis of type 2 diabetes by integrating data emerging from large genetic studies in man with emerging insights from the genomic biology of key tissues and physiological studies in man.

Dr Simon Myers

Department of Statistics, University of Oxford

Development of statistical and experimental approaches to understand the roles of recombination and migration in human biology and disease risk

Professor Sussan Nourshargh

William Harvey Research Institute, Queen Mary, University of London

Mode and dynamics of neutrophil transmigration in vivo: mechanisms and implications to pathological inflammation

Neutrophils are a major component of innate immunity and are indispensable for host defence against invading pathogens. As recent evidence indicates a broader role for these cells in inflammation and immunity than conventionally considered, there is a need for better understanding of the mode, mechanisms and implications of neutrophil trafficking in vivo. With this award Professor Nourshargh proposes to investigate how pathological inflammatory insults impact the dynamics of neutrophil-vessel wall interactions and the implications of disrupted modes of neutrophil transmigration on inflammatory disease development and dissemination. By using advanced 4D imaging platforms to analyse neutrophil transmigration, Professor Nourshargh's work aims to unravel previously unexplored cellular and molecular physiological concepts and identify disease-specific phenomena.

Professor Guy Rutter

Section of Cell Biology, Imperial College London

Understanding pancreatic beta cell dysfunction in diabetes

Professor Rutter will exploit findings from recent genome-wide association studies (GWAS) and a family of genes that are strongly and selectively inactivated in healthy beta cells but upregulated in these cells in diabetes. His approach will include combining bioinformatic, in vitro and in vivo analyses in model systems to assess the potential of novel GWAS genes as targets to improve insulin secretion in type 2 diabetes. He will also work towards early translation of his work, through high-throughput platforms to identify both endogenous and small molecule regulators of the best-defined GWAS genes.

Professor Benjamin Simons

Department of Physics, University of Cambridge

Lineage tracing as a strategy to resolve mechanisms of stem cell fate: from development and maintenance to disease and ageing

Professor Simons has a background in condensed matter physics but since 2005 has turned his expertise towards answering fundamental questions in stem cell biology. With this award, he will be using a combination of experimental and theoretical approaches to study how stem cells are regulated in tissue maintenance, development and disease. His work will focus on a wide range of biological systems, including the epidermis, neuroepithelia and gut.

Professor Molly Stevens

Department of Bioengineering and Materials, Imperial College London

Exploring and engineering the cell-material interface for regenerative medicine

Professor Stevens takes the approach of exploring the cell-material interface and then engineering it to deliver a new generation of cell instructive biomaterials. The overall goals of her work are to develop state of the art materials and characterisation approaches so that she can identify subtle phenotypic changes in cell differentiation or biological activity in response to engineered materials implanted in the body. Professor Stevens’ innovation of novel biomaterials that actively interact with the body will contribute to her ultimate aim of the regeneration of failing organs.

Professor Gabriel Waksman

Institute of Structural and Molecular Biology, Birkbeck College and UCL

An integrated study of a bacterial secretion nanomachine

Professor Miles Whittington

University of York

Learning and sleep: a network dynamic approach

Professor Whittington aims to explore the neural brain rhythms associated with sleep and how these may relate to both learning and memory, as well as the pathologies associated with neurological and psychiatric illness. A key question that Professor Whittington will address is how disrupted network dynamics during sleep contribute to learning disability. He will achieve this by combining a variety of techniques from the microscopic to the macroscopic level.

Professor Xiaodong Zhang

Division of Molecular Biosciences, Imperial College London

Structures and mechanisms of key components in the DNA damage response

The fidelity and stability of a cell's DNA are critical for the survival and proper functioning of an organism. There are tens of thousands of DNA damage events every day, and a double-strand break is one of the most severe types that can occur. Consequently, damaged DNA needs to be repaired rapidly as failure to do so can lead to cell death or the development of cancer. As a result, cells have evolved systems to sense, signal and repair this damage. The focus of Professor Zhang's Investigator Award will be using structural biology approaches to provide a mechanistic insight into key steps in the cell’s response to a double-strand break.


Professor Francis Barr

University of Oxford

Mechanism and structural analysis of Rab GTPase control systems in normal cells and human disease states

Professor Barr will be studying a family of proteins known as Rab GTPases that regulate many steps in membrane trafficking. Rab GTPases form part of an essential recognition system which gives unique identity to organelle and vesicle membrane surfaces, enabling vesicles to be specifically recognised during transport. Professor Barr will explore how Rab GTPases are involved in membrane trafficking pathways within human cells in both normal and disease states.

Dr John Christodoulou

University College London

Structural biology of protein folding on the ribosome

Dr Christodoulou studies the co-translational folding process, which transforms a nascent polypeptide chain into a fully folded and functional protein as the chain emerges from the ribosome (the protein synthesis machinery in cells). His research will look at the structure and dynamics of nascent proteins during their synthesis, how they interact with the ribosome and molecular chaperones (proteins that aid folding) and how the ribosomal machinery aids trafficking to the correct cellular compartment. This knowledge of how protein three-dimensional structures arise or misfold is important in a range of metabolic, oncological and neurodegenerative conditions.

Professor Harry Gilbert

University of Newcastle

Understanding the contribution of the human microbiota to human health

Professor Gilbert, a carbohydrate biochemist based at Newcastle University, aims to gain a better understanding of the role the human intestinal microbiota - the community of microorganisms resident in our gut – plays in health and disease. Specifically, he will investigate how the uptake and breakdown of dietary glycans – complex carbohydrates such as pectins and starch - contribute to the survival of dominant members of the microbiota in the human large bowel and their ability to modulate our metabolism and our immune system.

Professor Raymond Goldstein

University of Cambridge

Synchronization of cilia

Professor Goldstein's research focuses on cilia, conserved cellular appendages which play an important role in many aspects of life, from transport of fluid in the respiratory tract to signal transduction in the eyes. The coordinated beating of groups of motile cilia is often crucial to their function, and Professor Goldstein will use advanced microscopy, micromanipulation and theoretical modelling to address the mechanism underlying the synchronisation of cilia.

Professor D Grahame Hardie

University of Dundee

Non-canonical pathways for regulation of AMPK

The AMP-activated protein kinase (AMPK) has key roles in the regulation of eukaryotic cell function. Professor Hardie played a major role in uncovering the 'canonical' pathways by which AMPK is activated by energy stress and by calcium ions, but it now also appears to be regulated by other‘non-canonical’ pathways, and the focus of this Investigator Award will be to investigate these. He will study how the pathway is down-regulated in rapidly proliferating cells, how it can monitor cellular glycogen reserves, how it is involved in responses to the commonly used drug aspirin, and how it is activated by DNA-damaging agents. These studies should provide insights into, and may have applications in, both cancer and diabetes.

Professor Paul Martin

University of Bristol

Investigating the links between inflammation and fibrosis during tissue repair

Using a multi-model organism approach, Professor Martin is investigating the cell biology of each step of tissue damage-triggered inflammation: from inflammatory cell recruitment/activation, to the change in fibroblast deposition of collagen that leads to a scar. He will use this cell biology knowledge to identify further mechanistic links between inflammation and scarring, to inform potential therapeutic strategies for blocking fibrosis. A better understanding of the steps leading to the fibrotic process is clinically significant in contexts beyond scarring of skin wounds, as extensive tissue damage-triggered inflammation underlies many human pathologies, including rheumatoid arthritis and liver cirrhosis.

Professor Stephen McMahon

King's College London

Identifying novel pain mediators and mechanisms

Professor McMahon will be examining the sensory neurobiology of chemokines and testing the hypothesis that some of these may function as novel pain mediators. This is important because the identification of new mediators will drive drug development programmes focussing on the amelioration and alleviation of chronic pain.

Professor Daniel Wolpert

University of Cambridge

Computations in sensorimotor control

Professor Wolpert's research will focus on understanding how the brain controls the body for real-world tasks. He will use theoretical, computational and experimental studies to investigate three key components of sensorimotor control: decision making, learning mechanisms and internal representations. He will aim to integrate the models developed for each component into a unifying framework for sensorimotor control.



Professor Julian Blow

University of Dundee

Understanding the cellular response to replication inhibition 

Professor Blow will study how cells respond to the inhibition of DNA replication. His goal is to determine whether mutations in cancer cells can make them susceptible to chemotherapeutic drugs that target DNA replication.

Professors William Cookson and Miriam Moffatt

Imperial College London

Genetics and genomics and respiratory disease

Professors Cookson and Moffatt will be using the latest genetic and genomic tools to uncover the basic mechanisms that cause childhood asthma. Asthma is the most common chronic disease of childhood, but its causes remain unknown. Their aim is to translate this knowledge into new treatments for patients with the respiratory disease.

Professor Mark Harris

University of Leeds

Coordinated use of the hepatitis C virus genome during the virus lifecycle

Professor Harris seeks to achieve a comprehensive understanding of key events in the lifecycle of the hepatitis C virus, with the ultimate goal of developing new antivirals. The questions that underpin his vision involve defining in molecular detail the processes by which the virus genome is replicated and packaged into virus particles, and determining how these events are coordinated.

Professor Derek Jones

Cardiff University


Professor Jones will focus on the development and application of tractometry, a non-invasive MRI-based approach to obtaining detailed information about the microstructure of white matter, the connections that carry information between different regions of the brain. Professor Jones believes that this approach will become commonplace in all neuroimaging studies alongside functional imaging of grey matter, where the information is processed, and will be instrumental in advancing our understanding of the brain in health, development and disease.

Dr Steven Kennerley

University College London

Neuronal mechanisms underlying value-based decision-making and action selection

Dr Kennerley will use his award to investigate the neuronal mechanisms supporting optimal learning, decision-making and action selection. He uses sophisticated techniques to record the electrical activity of individual and populations of neurons in the frontal cortex and basal ganglia. His goal is to better understand how the brain evaluates the potential costs and benefits of a decision, and how dysfunction of this evaluative system might lead to neuropsychiatric diseases associated with impaired decision-making.

Dr Peter Lawrence

University of Cambridge

Planar cell polarity and morphogenesis

Cells in epithelial sheets are polarised in the plane of the sheet, as shown by the patterned orientation of mammalian hairs and insect bristles. This fundamental phenomenon, known as planar cell polarity (PCP), is seen across animal and plant development. Dr Lawrence studies PCP in the fruit fly Drosophila, the model system best suited to genetic and molecular analysis. He aims to understand the molecular mechanisms whereby cells read their orientation within an animal or organ and communicate that information to neighbouring cells. The mechanisms use intercellular molecular bridges.

Professor Troy Margrie

MRC National Institute for Medical Research

The function and connectivity of cortical cells and circuits

The wiring and function of cortical circuits underlies brain operation and thus our ability to think, feel and behave. To genuinely understand this process, a detailed knowledge of cell-to-cell connectivity and neuronal network function is required. Professor Margrie aims to generate the first detailed wiring diagram of sensory cortex by combining classic in vivo electrophysiological approaches with two-photon microscopy and rabies-virus-based neuronal tracing methods. By establishing the function of individual cells and identifying the local and long-range circuits in which they operate, he will generate three-dimensional connectivity maps and use them to quantify the function and structure of cortical circuits. This combinatorial approach will then be applied to investigate and quantify the wiring profiles of healthy and diseased brains.

Professor Patrick Maxwell

University College London

Oxygen sensing

A fundamental challenge for complex multicellular organisms such as humans is continuous distribution of sufficient oxygen to all cells throughout the body. As such, oxygen plays a central role in health and disease and changes in oxygenation are critically involved in many disease processes, including myocardial ischaemia, stroke and even cancer tumour behaviour. Professor Maxwell aims to establish how different cells and organisms adapt to changes in oxygenation and whether we can use knowledge of molecular oxygen-sensing pathways to understand and treat disease.

Dr Venki Ramakrishnan

MRC Laboratory of Molecular Biology, Cambridge

Structure and function of ribosomes

Ribosomes are complex structures within cells that use instructions in our genes to synthesise protein chains from individual amino acids, a process known as translation. Dr Ramakrishnan will continue his world-leading work to elucidate the structure and function of the ribosome, in particular studying the mechanism of translation and ribosomal stress response in bacteria, as well as the initiation and termination of translation in eukaryotes (higher organisms, including humans, whose cells contain a nucleus).

Professor Azim Surani

University of Cambridge

Principles and programming of the mammalian germ line

Primordial germ cells, which give rise to eggs and sperm, are the focus of Professor Surani's research. These cells generate totipotency, which allows transmission of genetic and epigenetic information to a new individual and subsequent generations. Professor Surani's studies on mammalian germ cells will aim to elucidate the molecular mechanisms of how germ cells are formed and how they acquire their unique properties, and to inform the application of this knowledge towards manipulation of normal and aberrant cell fates.

Professor Henning Walczak

Imperial College London

Studies of linear ubiquitin and different modes of cell death induction by TNF family members in aetiology and treatment of autoimmunity

Professor Walczak's work examines the modulation of cell death in the context of experimental and clinical autoimmunity. With this award he will investigate the control of different forms of cell death and the determinants of whether cell death leads to inflammation or autoimmunity, through an analysis of the different cell death modalities induced by members of the TNF cytokine family and the role linear ubiquitination plays in determining this.

Professor Fiona Watt

Centre for Stem Cells and Regenerative Medicine, King's College London

Reciprocal signalling between epidermal stem cells and their neighbours

Using mammalian skin as an experimental model, Professor Watt is identifying the intrinsic and extrinsic signals that regulate stem cell behaviour in adult tissues, and thereby uncovering strategies to treat disease. The focus of her award is reciprocal signalling between epidermal stem cells and cells in the underlying connective tissue, the dermis. Relationships between different dermal cell populations will be elucidated as well as how these cells communicate with epidermal stem cells.

Dr Finn Werner

University College London

An integrated study of RNA polymerase transcription

RNA polymerase (RNAP) facilitates important regulatory events in the cell through its pivotal role in transcription. Dr Werner aims to characterise RNAP and its interactions with partner molecules in a group of organisms called Archaea, which is emerging as a versatile model system owing to the stability of their proteins and simplicity of their genetics, genomes and regulatory networks. Investigating the molecular mechanisms of transcription is important because it expands our knowledge of fundamental processes that are essential to all life. Illuminating structure-function relationships of RNAPs is also needed to rationalise the mechanisms of drug action, and thus holds great promise for the development of novel improved drugs to combat agents of infectious diseases by interfering with transcription.

Professor Rose Zamoyska

University of Edinburgh

Mechanisms that regulate T cell responses and their failure in autoimmunity

Autoimmune diseases are those in which dysregulation of immunity leads to attack of body tissues. Professor Zamoyska will examine the cell-signalling events that underpin the regulation of autoimmune T cells, with particular focus on PTPN22, a gene that has been implicated in several human autoimmune diseases.


Professor Jürg Bähler

University College London

Non-coding RNA (ncRNA) function in genome regulation and cell maintenance

Genome sequences often contain large non-coding regions, also known as 'gene deserts', which produce ncRNAs. Genetic variations associated with complex disorders frequently map to these areas, raising important questions about how much genetic information is transacted by ncRNAs. Professor Bähler will investigate the role of such ncRNAs in cellular function and ageing, using fission yeast (Schizosaccharomyces pombe) as a model system. He aims to explore the ability of these ncRNAs to tune gene expression, mediate gene-environment interactions, and generate phenotypic variation and plasticity.

Professor Juan Burrone

King's College London

Homeostatic plasticity: from synapses to the axon initial segment

Our bodies tightly regulate many aspects of their inner physiology, such as temperature, blood pressure and glucose levels. This process, known as homeostasis, serves to keep certain key physiological events constant in the face of a continually changing environment. Neuronal homeostasis is known to play an important role in the stabilisation of brain function. However, little is known about the mechanisms that control it, the site in the neuron at which it takes place and even the levels of activity a neuron senses as abnormal. Professor Burrone aims to tackle these questions by using techniques that provide fine control of the electrical activity of neurons by means of light. This non-invasive approach will enable the study of neuronal homeostasis and could uncover potential new targets for epilepsy treatment.

Professor Javier Caceres

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh

RNA-binding proteins in health and disease

Professor Caceres will be studying the roles of RNA-binding proteins involved in gene expression, a process that leads to the production of proteins and small RNA products through transcription, RNA splicing and translation. As there is a wide variety of RNA-binding proteins, each with a unique binding activity to RNA, these proteins have a profound effect on gene expression networks in cells, making them highly significant to normal and disease-related biology. The work will contribute to a better understanding of the fundamental biological processes involved in gene expression.

Professor Matteo Carandini

University College London

Integration of internal and external signals in sensory cortex (joint award with Professor Harris)

Professor Carandini is interested in understanding how the brain processes visual information. To do this he records the brain activity of mice while they navigate a virtual environment, and looks at the activity of both single and multiple neurons in populations. During his award he will be seeking, alongside Professor Harris, to understand how the brain integrates signals from multiple sensory streams and both sensory and non-sensory modalities.

Professor V Krishna Chatterjee

University of Cambridge

Disorders of nuclear hormone synthesis and action: genetics and pathophysiology

Professor Chatterjee will explore the role in disease of nuclear hormone receptors, a class of proteins in cells that sense molecules including steroids and thyroid hormones. By studying the genetics of patients with conditions that affect the body’s hormone balance, Professor Chatterjee aims to find unknown causes of gene defects in three conditions: congenital hypothyroidism, resistance to thyroid hormone and peroxisome proliferator activated gamma (PPARγ)-mediated insulin resistance. Success in these studies would lead to better clinical diagnoses and potentially treatment for the disorders.

Professor Alister Craig

Liverpool School of Tropical Medicine

Cytoadherence-mediated pathology in cerebral malaria

Professor Craig will be examining how cytoadherence – the process whereby red blood cells infected with the malaria parasite adhere to the walls of blood vessels – leads to severe cases of malaria. Working with colleagues in Liverpool, Glasgow and at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Professor Craig hopes the knowledge gained will help in the design of new drug treatments for severe malaria, targeted at preventing or reversing the adhesion of the red blood cells to blood vessels in the brain. Around one million people die each year from severe malaria, mainly young children and pregnant women in low-income countries.

Professor Peter Donnelly

University of Oxford

Statistical methods development and analysis of genomic data in health and disease

The use of high-throughput sequencing technologies signals a new era in genetic research, but will present major challenges in data interpretation and analysis. To help harness the potential benefits of this new technology, Professor Donnelly aims to develop new statistical methods and bioinformatics tools to robustly extract information from the large datasets generated. These applications will focus on the genetic basis of human disease and on the transmission of bacterial pathogens and their evolution, naturally and under pressure from vaccines and antibiotics. He will also undertake a series of experimental studies to better understand the process of meiotic recombination in mammals.

Professor Anne Ferguson-Smith

University of Cambridge

Genomic imprinting and the epigenetic control of genome function

Regulation of gene expression is in part controlled by epigenetic modifications that place DNA in its functional chromosome context. Unlike the DNA sequence, these modifications can change in response to the normal environments that cells are exposed to and influence genome function. Professor Ferguson-Smith will apply knowledge of genomic imprinting (an epigenetic process causing genes to be expressed according to which parent they are inherited from) to study the relationship between the DNA and the epigenetic modifications that regulate it. Experiments will explore how the epigenetic code controls gene expression, how epigenetic states are maintained or change during development, and how a developing organism’s normal or abnormal environment affects gene expression, with implications for health and disease.

Dr Pedro Hallal

Federal University of Pelotas, Brazil

A life-course approach for understanding levels, trends, determinants and consequences of physical activity, and to inform interventions and policy for global action

Based in Brazil, Dr Hallal's research focuses on understanding how physical activity is affected by factors throughout the life course, beginning with maternal physical activity during the early phases of fetal development. Chiefly based on a longitudinal study design that follows 16,000 people in four cohorts, the research takes a multidisciplinary approach (based on epidemiology, social science and physiology) to understanding both the determinants of physical activity and its association with chronic disease. Dr Hallal’s strategy also involves coordinating both national and international health policy makers, to promote the uptake of research evidence in the design and evaluation of public health interventions aimed at promoting physical activity and health.

Professor Kenneth Harris

University College London

Integration of internal and external signals in sensory cortex (joint award with Professor Carandini)

Professor Harris's research focuses on the mechanisms by which populations of cells in the brain form information-processing assemblies. In conjunction with Professor Carandini, Professor Harris will employ his award to understand how the brain integrates multiple signals, applying a computational approach to model neuronal signal interactions in the cortex.

Professor David Holden

Imperial College London

Intracellular biology of salmonella and streptococcus

Professor Holden will investigate two important bacterial pathogens of humans: Salmonella and Streptococcus pyogenes. The award will focus on the deployment of novel approaches to dissect the molecular mechanisms that they use to survive and replicate inside host cells.

Professor Dimitri Kullmann

University College London

Synaptic neurology

Professor Kullmann's interests centre on the mechanisms that underlie normal and abnormal excitability of nerve and muscle. Much of his research addresses the basic properties of synapses in the central nervous system, synaptic plasticity, and the biophysical consequences of inherited mutations of ion channels implicated in neurological disease. Professor Kullmann is using his award to address a number of questions about how synapses work, their complement of ion channels, how dysfunction leads to diseases and what this may tell us about treatments, and how interneurons underpin information processing and memory storage.

Dr Mate Lengyel

University of Cambridge

Normative neurophysiology

Dr Lengyel aims to investigate the connections between the biophysical properties of neurons and cognition. He will identify conditions for the optimal operation of neural circuits, and investigate how their various biophysical properties contribute to such near-optimal functioning. These questions will be addressed using cutting-edge theoretical techniques from computational neuroscience, information theory, signal processing and machine learning.

Dr Jan Löwe

MRC-LMB, Cambridge

Molecular architecture of the bacterial actin cytoskeleton

Dr Löwe’s research will focus on understanding the molecular arrangement of filaments in the bacterial cytoskeleton and how these filaments maintain cell shape. To answer these fundamental questions about bacterial cytoskeletal architecture, he will use X-ray crystallography, electron cryomicroscopy, cellular tomography and biochemical techniques.

Professor Stephen O'Rahilly

University of Cambridge

Insulin resistance: lessons from extreme phenotypes

Professor O'Rahilly will use a unique resource established in Cambridge, the Severe Insulin Resistance Cohort, to further explore the genetic contribution in the development of severe insulin resistance. Using a candidate gene approach, along with exome sequencing and cellular investigations, applied to extreme and other phenotypes, the research aims to uncover unrecognised syndromes of insulin resistance and provide insight into mechanisms of disease that might be susceptible to specific therapeutic interventions.

Dr Klaus Okkenhaug

The Babraham Institute, Cambridge

PI3K signalling in immunity and infection

Phosphoinositide 3-kinases (PI3Ks) are enzymes that become activated within cells of the immune system in response to pathogens. As part of this award, Dr Okkenhaug will investigate different forms of PI3K and their roles in immunity and infection.

Professor Laurence Pearl

University of Sussex

Mechanisms of client protein activation and regulation by the Hsp90 molecular chaperone system

Professor Pearl will study at a structural level the molecule Hsp90, believed to have a key role in cancer as well as in viral and parasitic infections. In particular, he will be examining whether the molecule is an appropriate drug target for a wide range of diseases.

Professor Fiona Powrie

University of Oxford

Immune pathways in the intestine in health and disease

Our intestines contain a huge number of microbes that play an important part in our health. In inflammatory bowel disease, the beneficial relationship we have with these bacteria breaks down, resulting in chronic and painful intestinal inflammation. Professor Powrie will be investigating how the 'dialogue' between the intestinal immune system and intestinal bacteria breaks down and why this leads to disease.

Professor Sara Rankin

Imperial College London

Pharmacological mobilisation of progenitor cells for tissue regeneration

Professor Rankin is building on previous funding from the Wellcome Trust with the aim of developing innovative ways to activate stem cells to stimulate the regeneration of tissues. In particular, she will investigate the factors that regulate the mobilisation of stem cells from bone marrow as well as characterising these mobilised stem cells. Her research will lead to major advances in our understanding of the biology of stem cells, including the role these cells play in disease pathogenesis, and it will hopefully also lay the foundations for the development of new regenerative medicines.

Professor Wolf Reik

The Babraham Institute, Cambridge

Epigenetic reprogramming in mammalian development

Reprogramming is the erasure and rewriting of epigenetic marks, such as the methylation of DNA and the modification of histones. This phenomenon naturally occurs in germ cells (sperm and eggs) and in the newly formed embryo after fertilisation and is crucial for the establishment of totipotency (the ability of a cell to divide to produce all of the differentiated cells necessary for an organism). Professor Reik will explore the mechanisms of DNA demethylation; the types of epigenetic information that are resistant to erasure, potentially leading to inheritance of epigenetic marks; and how insights from this work can improve approaches in stem cell science and regenerative medicine.

Professor Patrik Rorsman

University of Oxford

Metabolic and hormonal regulation of pancreatic hormone secretion

Professor Rorsman will investigate how islet cells in the human pancreas function in health and disease by understanding the mechanisms that control the secretion of hormones, particularly insulin. Specifically, he plans to show how islet cells respond to the availability of nutrients and examine the crosstalk between the islets and the rest of the body. Professor Rorsman hopes that the knowledge gained will aid in the design of new drug treatments for diabetes.

Professor Peter Rothwell

University of Oxford

Improving prevention of stroke by better understanding of existing risk factors and treatments

A physician and epidemiologist, Professor Rothwell will address the most important – but, he believes, tractable – issues in stroke prevention, including how best to diagnose and treat high blood pressure, how to further reduce the risk of recurrent stroke and how to identify patients at high risk of vascular dementia. He will study patients in two large longitudinal cohorts (Oxford Vascular Study and Oxford Vascular Cognitive Impairment Cohort), using state-of-the-art imaging, biomarker and genetic studies as well as standard clinical investigations to achieve better phenotyping of stroke and hence greater understanding of aetiology and prevention. He will also study how we can increase the benefit of existing treatments, including whether we should use aspirin to prevent cancer as well as heart attacks and strokes.

Professor Christiana Ruhrberg

University College London 

Defining signalling pathways that control neurovascular interactions in the brain and retina

The interaction between nerve cells and cells in our blood vessels controls the development of the brain and retina, regulates traffic across the blood-brain and blood-retina barriers, and promotes the formation of new nerve cells. Professor Ruhrberg will explore the mechanisms that regulate these interactions in normal development, with the aim of identifying therapeutic targets for diseases such as age-related macular degeneration or diabetic retinopathy, in which the nerve cells and blood vessels fail to communicate normally and blood vessels function poorly.

Professor Gavin Screaton

Imperial College London

Studies of immunopathogenesis in dengue virus infection

Professor Screaton will analyse several aspects of the immunology of dengue virus infection, a serious emerging tropical disease. Previous exposure to dengue virus can mean that an individual becomes more unwell when they encounter the virus on a second occasion. To allow better vaccine design and monitoring, there is a need for greater clarity about which components of the immune response are protective and which are damaging to the host.

Professor Christopher Thompson

University of Manchester

Generating order from chaos: understanding how heterogeneity, stochastic differentiation and cell sorting can result in robust developmental patterning

Professor Thompson will be studying a fundamental question in development: cell fate choice and pattern formation. As a model, he will use the social amoeba Dictyostelium. When starved, many thousands of individual amoebae aggregate to form patterned multicellular structures with a small number of different cell types. The patterning mechanism is evolutionarily conserved, but poorly understood as it is based on stochastic differentiation followed by sorting out. Using this model, he will identify and analyse genes that underlie this patterning process and the regulation of altruistic cell death.

Professor Dale Wigley

Imperial College London

Understanding the structure and mechanism of macromolecular machines that regulate chromatin dynamics

Eukaryotic genomes are packed into a highly ordered structure called chromatin, which provides organisation and stability to genetic material. Professor Wigley will study the structure and mechanism of several large protein complexes that interact with nucleosomes to regulate chromatin structure and dynamics in fundamental cellular processes such as transcription, replication and repair.

People we've funded

Many of our grantholders carry out research in Africa and Asia. See our directories: