Principal Research Fellows
Principal Research Fellowships are the most senior of the Wellcome Trust's personal awards and provide long term funding for researchers of international standing.
Fellows' names are listed alphabetically by surname.
Professor Robin Allshire, University of Edinburgh
How centromeres are specified: the interplay between heterochromatin, CENP-A chromatin and kinetochore assembly
The central theme of Robin’s research is to understand mechanisms of epigenetic regulation: how specialised chromatin states are established and maintained through cell divisions. Robin’s current focus is on heterochromatin and CENP-A chromatin at regional centromeres, primarily using fission yeast as a model system. One aim of his research is to determine how centromeric heterochromatin, driven by methylation of histone H3 on lysine 9, is maintained and how it influences CENP-A chromatin assembly on adjacent sequences. Another aim is to uncover the cues in centromeric DNA that influence the assembly and retention of CENP-A chromatin at particular chromosomal locations.
Professor Dorothy Bishop, University of Oxford
Genetic, neurological and cognitive determinants of success and failure in learning a first language
Professor Neil Brockdorff, University of Oxford
Molecular mechanisms governing X chromosome inactivation: a model for understanding epigenetic regulation of the genome in differentiation and development
Professor Neil Burgess, University College London
Neural mechanisms of spatial memory
Neil investigates the neural mechanisms of memory using a combination of methods, including computational modelling, human neuropsychology, and functional neuroimaging and single-unit recordings in freely moving rodents. His main goal is to understand how the actions of networks of neurons in our brains allow us to remember events and the spatial locations where they occurred. This basic mechanistic understanding at the neural level can hopefully serve as a starting point for interpreting a variety of data, from psychology, psychiatry and neuropsychology, concerning how memory works and how it can go wrong.
Professor Doreen Cantrell, University of Dundee
Serine kinase pathways that determine T-lymphocyte activation and cell fate choices
Doreen is an immunologist based at the College of Life Sciences, University of Dundee. Her research explores how antigen receptors and cytokines control the development and immune activation of cytotoxic T lymphocytes, key cells in the adaptive immune system. A current focus is how T lymphocytes use networks of serine/threonine kinases to interpret information from antigens and cytokines to make appropriate responses that control peripheral T-cell function. The laboratory has identified essential regulators of T-cell metabolism, cytotoxic T-cell effector function and CD8 T-cell migration/trafficking.
Professor Michael Dustin, University of Oxford
Translation of the immunological synapse
Michael studies immunological mechanisms that lead to autoimmune diseases like rheumatoid arthritis. His focus is on the immunological synapse - the major conduit of information transfer between T lymphocytes and their partners. Correct function of the immunological synapse protects us from infection and many cancers, but dysfunction of the immunological synapse results in pathogen escape at one extreme and autoimmunity at the other. T lymphocytes from patients with autoimmune disease have defective immunological synapses, so the objective of Michael’s PRF is to build a platform for high-throughput analysis of immunological synapses to discover better treatments.
Professor William Earnshaw, University of Edinburgh
The role of non-histone proteins in chromosome structure and function during mitosis
William began his PRF in Edinburgh in 1996. His studies focus on the packaging and segregation of chromosomes during cell division. Achievements during his PRF include identification of the chromosomal passenger complex, construction of the first human synthetic artificial chromosome and its use to study the epigenetic regulation of kinetochore assembly, proteomics/systems analysis of the mitotic chromosome proteome, and advances in understanding the role of non-histone proteins in mitotic chromosome structure and function.
Professor Anke Ehlers, University of Oxford
Cognitive therapy and processes in posttraumatic stress disorder and social anxiety disorder
Professor Christopher Fairburn, University of Oxford
The global dissemination of psychological treatments
While effective psychological treatments have been developed for a range of mental health problems, there is good evidence that few people receive them. The overarching aim of Christopher's research is to develop and evaluate new methods for improving global access to evidence-based psychological interventions. The work includes creating scalable ways of delivering psychological interventions direct to users through the internet and, for those who require face-to-face treatment, novel ways of training large numbers of therapists simultaneously (web-centred training).
Professor Jonathan Flint, University of Oxford
Genetic analysis of major depression
Professor Karl Friston, University College London
Functional architectures in the brain
Professor Gillian Griffiths, University of Cambridge
Molecular mechanisms controlling polarised secretion at the immunological synapse
Gillian has pioneered the use of cytotoxic T lymphocytes from patients with genetic disorders to study cell biology in a specialised cell type. Through an integrated approach combining genetic, biochemical and imaging approaches, her lab has shown that immune cells use lysosomes as secretory organelles, that the centrosome has a unique role in driving formation of the immune synapse, and that Hedgehog signalling is important for this. Her long-term vision is to understand the molecular mechanisms that control polarised secretion from cytotoxic T lymphocytes, and how these fit together to ensure accurate delivery to the immunological synapse.
Professor Michael Häusser, University College London
The elements of cerebellar computation
Michael’s work aims to identify the fundamental units of computation in a well-organised neural circuit in the mammalian brain, the cerebellar cortex. This requires identifying motifs of connectivity within the neural circuit that define their functional properties and provide computational building blocks that are engaged during sensation and generation of movement. To address these challenges, Michael’s lab is using in vivo and in vitro electrophysiological, imaging and anatomical techniques in combination with behavioural approaches. The findings provide crucial constraints for constructing models of cerebellar cortex and targets for manipulation that have potential translational relevance for the many movement disorders that have a cerebellar origin.
Professor Masud Husain, University of Oxford
Understanding the inattentive and impulsive brain
Masud is a neurologist and cognitive neuroscientist. He leads a programme of research on inattention, impulsivity and apathy in healthy people and patients with brain disorders. His group works on improving our understanding of brain mechanisms underlying short-term memory and motivation. They use behavioural and imaging techniques to investigate the contribution of brain regions to these processes in healthy individuals. They are also involved in developing treatments for inattention, memory loss and apathy in Parkinson’s disease, stroke and Alzheimer’s disease.
Professor Randall Johnson, University of Cambridge
The physiology of hypoxic response
Randall’s research for the PRF is focused on the relationship between fluctuations in oxygenation in tissues and cells, and the behaviours that result. Hypoxia, or low levels of physiologic oxygenation, drives changes in cell and tissue metabolism and survival, and can change the very structure of the tissues that experience it. Hypoxia occurs in cancer and in a wide range of tissue damage and disease, and influences both progression and prognosis. Randall’s PRF is allowing him to determine how the response to hypoxia influences tissue damage and how to manipulate this response to alter disease progression, and ultimately make better therapeutic choices in hypoxia-induced injury.
Professor Andrew King, University of Oxford
Adaptive coding and plasticity in the auditory system
Andrew is a neuroscientist who heads the Auditory Neuroscience Group in the Department of Physiology, Anatomy and Genetics at the University of Oxford. His research employs an interdisciplinary approach to investigate the neural basis of auditory perception and multisensory integration. He is particularly interested in the adaptive processes that take place in the brain to allow accurate hearing to be maintained in different acoustical conditions. This involves studying both short-term changes that help to compensate for the presence of background sounds and the longer-term plasticity induced at higher levels of the auditory system as a result of learning or by hearing loss.
Professor Paul Lehner, University of Cambridge
Viral and endogenous regulation of cellular immunoreceptors
Paul uses novel functional genetic and proteomic technologies to study how viruses evade the immune system. His aims are to identify cellular receptors manipulated by viruses and understand how and why these receptors are targeted. His group developed unbiased functional SILAC/TMT-based proteomic approaches, called plasma membrane profiling, to identify novel cell surface receptors manipulated by viruses. Complementary to this approach is the use of fluorescent-based genetic selection screens in haploid human cells to map genetic pathways which control receptor expression. Together these technologies provide a protein and gene discovery platform to identify novel genes and pathways required for viral and endogenous receptor regulation.
Professor Eleanor Maguire, University College London
Scenes, space and the neural basis of memory
Eleanor’s research has three main goals. The first is to provide a unified and mechanistic account of how the human hippocampus, deep in the brain’s temporal lobes, supports episodic memory, imagining the future and spatial navigation. Her second goal is to determine the exact timescale of hippocampal involvement in episodic memory. Her third goal is to establish what aspects of hippocampal processing are distinct from other brain areas, including parahippocampal, retrosplenial and ventromedial prefrontal cortices. Overall, she aims to provide a theoretically enriched understanding of hippocampal function in everyday cognition that in turn elucidates how its dysfunction leads to pathological states.
Professor Read Montague, University College London
Computational neuroscience of social behaviour and psychopathology
Read’s research seeks to uncover the computational and neural mechanisms underlying social cognition in humans and its derangement in response to disease and injury. Social exchange is a core capacity necessary for interacting with other humans, alone and in groups. Read’s research applies functional magnetic resonance imaging, computational modelling and real-time neurotransmitter recordings as associated experimental approaches to the neural underpinnings of social exchange in humans.
Professor David Owen, University of Cambridge
Structural cell biology of transport vesicle and organelle biogenesis
Professor Cathy Price, University College London
Predicting language outcome and recovery after stroke
Cathy’s goal is to generate a new neurological model of language that predicts language outcome and recovery after stroke. Her work uses: structural neuroimaging and behavioural assessments, to identify lesion and non-lesion factors that are most and least likely to cause long-term communication difficulties; functional neuroimaging and dynamic causal modelling, to provide a mechanistic understanding of the language pathways that support recovery after damage to the normal system; and machine learning algorithms, to generate the most accurate data-led predictions of language outcome and recovery without requiring a full understanding of the language model.
Professor Lalita Ramakrishnan, University of Cambridge
Fundamental and therapeutic insights into tuberculosis from the zebrafish and its application to humans
Lalita studies the pathogenesis of tuberculosis, primarily using the zebrafish model that she and her colleagues have developed. The zebrafish’s optical transparency and genetic tractability allow for the stepwise dissection of pathogenesis. Her research has revealed surprising new insights into pathogenesis that have potential therapeutic implications. She aims to continue to identify and characterise host determinants that alter the outcome of infection, using both forward and reverse genetic approaches. The goal of this work is to identify therapeutic targets for tuberculosis.
Professor Randy Read, University of Cambridge
Protein crystallography: development of new methods, and application to the study of pathogenesis
Randy is a structural biologist with a particular interest in the methods used to determine the 3D structures of biological macromolecules using X-ray crystallography. By developing new methods based on the statistical concept of likelihood, his group has helped to accelerate and optimise the process of structure determination, so that better structures can be determined more quickly. He has also applied crystallography to the study of a number of medically relevant systems, including bacterial toxins, proteins that carry hormones in the blood, and enzymes mutated in inherited metabolic diseases.
Professor Elizabeth Robertson, University of Oxford
Genetic control of cell fate decisions in the developing mouse embryo
Liz exploits mouse genetics to investigate the key signalling cues and transcriptional regulators governing mammalian development. She initially focused on Nodal/Smad activities responsible for establishment of the anterior-posterior or ‘head-tail’ axis and subsequently discovered BMP/Smad signals essential for germ cell specification. Current work aims to elucidate how downstream target gene expression is controlled in diverse tissue contexts. How does the transcription factor Eomes orchestrate cell fate decisions during gastrulation? How does the repressor Blimp-1/PRDM1 globally regulate cell-type-specific transcriptional programmes? She is also characterising the cis-acting regulatory elements that direct dynamic gene expression patterns in the early embryo.
Professor Margaret (Scottie) Robinson, University of Cambridge
Coated vesicle adaptors
Scottie is a cell biologist who is interested in membrane traffic: how proteins find their way to the right part of the cell. Her lab works on adaptors, components of vesicle coats that determine which proteins are packaged as cargo in the vesicles, for transport to a different subcellular compartment, and which proteins remain behind. Adaptors are frequently hijacked by pathogens, and used either to invade the cell or to change the protein composition of the plasma membrane. There are also several examples of mutations in adaptors giving rise to genetic disorders.
Professor David Ron, University of Cambridge
The physiology and pathophysiology of unfolded protein responses
David is a physician-scientist based at the Cambridge Institute for Medical Research, University of Cambridge. His research seeks to understand how eukaryotic cells adapt to changing levels in the load of unfolded proteins that are presented to the folding machinery in the endoplasmic reticulum, the gateway to the secretory pathway. This problem extends from the molecular basis of the intracellular signal transduction pathways to the biological consequences of endoplasmic reticulum stress in whole organisms. The latter is relevant to our emerging understanding of the links between protein misfolding and diseases of ageing and the importance of protein-folding homeostasis to health.
Professor David Rubinsztein, University of Cambridge
Autophagy in health and disease
David’s laboratory is based at the Cambridge Institute for Medical Research, University of Cambridge. Their work is increasingly focused on studying autophagy and neurodegeneration after they discovered that this pathway could clear intracytoplasmic aggregate proteins causing conditions like Huntington’s disease, Parkinson’s disease and tauopathies. David’s research aims to understand the machinery and signalling pathways that regulate autophagy. Using cell biology and animal modelling, his laboratory is currently elucidating how autophagy perturbations may impact on the pathogenesis of various neurodegenerative diseases. His group also have a major interest in developing therapeutic approaches to such diseases by finding safe drugs that upregulate autophagy, an area that they have pioneered.
Professor Dmitri Rusakov, University College London
Neural coding with the tripartite synapse
Professor Wolfram Schultz, University of Cambridge
Neuronal reward mechanisms
Wolfram’s group is interested in relating the mechanics of brain activity to measurable behaviour. They combine behavioural, neurophysiological and neuroimaging (fMRI) methods to investigate the neural mechanisms of learning and economic decision making at the level of single neurons and individual brain structures. They use behavioural concepts from animal learning theory and economic decision theory to study neural reward signals in specific brain regions, including the dopamine system, striatum, orbitofrontal cortex and amygdala. Wolfram’s research currently investigates basic reward and risk decision variables, reward prediction errors, learning, irrational decisions, and social interactions.
Professor Angus Silver, University College London
Synaptic and neuronal determinants of network function: application of new optical and computational tools
Angus’s research focuses on information processing in the brain. He combines both experimental and theoretical approaches to study the mechanisms underlying synaptic transmission, neuronal integration and signal processing in cerebellar and neocortical networks. He also develops new optical and neuroinformatics tools for studying brain function. These include an acousto-optic lens microscope for high-speed two-photon imaging of neuronal signalling in 3D space and software tools for building and analysing biologically detailed models of neurons and networks. He leads the international team that develops NeuroML, a language for defining models in computational neuroscience, and the Open Source Brain initiative, a web-based repository of standardised models and a framework for collaborative modelling that is based on open source software development.
Professor Geoffrey Smith, University of Cambridge
Poxvirus immune evasion strategies
Geoffrey’s laboratory studies the mechanisms by which vaccinia virus (VACV), the live vaccine that was used to eradicate smallpox, inhibits innate immunity and thereby affects virus virulence and immunogenicity. VACV is a DNA virus that replicates in the cytoplasm and encodes scores of proteins to suppress innate immunity. The Wellcome Trust has supported this lab with a PRF for the last 14 years. Current work includes structural and functional studies of a family of small intracellular VACV proteins with structural similarity to Bcl-2 proteins and which inhibit activation of intracellular signalling pathways that lead to activation of pro-inflammatory transcription factors.
Professor Robert Snow, University of Oxford
The malaria transition in East Africa
Africa has witnessed a malaria transition since 2000, in part as a result of unprecedented increases in overseas development assistance to fund the delivery of vector control and improved clinical management of the disease. In East Africa, there is evidence that the decline in malaria transmission and disease began before the scaled delivery of insecticide-treated nets, indoor residual house-spraying and changing drug policy; furthermore, the epidemiological transition has not been equivalent everywhere, with some areas remaining resistant to current control strategies. Robert’s PRF aims to unpack the complex dynamics underlying long- and short-term cycles of malaria transmission, while simultaneously working in close collaboration with governments in the sub-region to use evidence to design the future of control.
Professor Peter St George-Hyslop, University of Cambridge
Deciphering the fundamental roles of two proteins involved in neurodegenerative disease
Professor Tomoyuki Tanaka, University of Dundee
Molecular mechanisms regulating the kinetochore-microtubule interaction in mitosis
Tomo’s research goal is to understand how cells ensure proper chromosome segregation prior to cell division. Proper chromosome segregation is required for cells to maintain their genetic integrity. Failure in this process can lead to cell death or various human diseases, such as cancers and congenital disorders, which are characterised by chromosome instability and aneuploidy. Revealing the mechanisms for high-fidelity chromosome segregation should provide clues to understanding how various human diseases develop. Tomo’s group currently investigates how kinetochores initially interact with spindle microtubules, how this interaction develops, and how any error could be corrected to ensure proper chromosome segregation.
Professor Adrian Thrasher, University College London
Refinement of gene and cell therapies for inherited immunodeficiencies based on human interventions and developing technologies
Adrian is Professor of Paediatric Immunology at the Institute of Child Health, University College London, and Honorary Consultant Paediatric Immunologist at Great Ormond Street Hospital for Children NHS Foundation Trust. His current PRF programme is focused on the following themes: development of human stem cell (HSC) gene therapy for primary immunodeficiencies (PID) as a medical need; utilising PIDs as a paradigm for HSC gene therapy; identification of mechanisms leading to toxicities; redesign of and pre-clinical evaluation of transgene additive vectors; development of refined technologies to target genetic modifications; and evaluation of reduced-intensity conditioning strategies for engraftment of gene-corrected cells.
Professor David Tollervey, University of Edinburgh
Nuclear RNA processing and surveillance
The aim of David’s group is to understand the nuclear pathways that process newly transcribed RNAs and assemble the RNA-protein complexes. They are also interested in the mechanisms that regulate these pathways and the surveillance activities that monitor their fidelity. To allow mechanistic insights, the group has developed techniques for transcriptome-wide analyses of RNA-protein interactions (CRAC) and RNA-RNA interactions (CLASH). These techniques are currently being used to define the in vivo targets of nuclear surveillance systems, determine how the many non-protein-coding RNAs (ncRNAs) are distinguished from messenger RNAs (mRNAs) and identify direct mRNA targets for ncRNAs including microRNAs, long-ncRNAs and small nucleolar RNAs.
Professor Andrew Waters, University of Glasgow
Conditional translation repression: a core regulatory mechanism of gene expression during development of the malaria parasite – study and applications
Professor Nick White, University of Oxford
Improving the treatment of malaria
Nick’s PRF aims to improve the treatment of malaria and thereby contribute to malaria elimination. Building on extensive studies of antimalarial pharmacokinetics, pharmacokinetic-pharmacodynamic relationships will be characterised for efficacy and toxicity. This involves development of field-adapted assay methodologies, optimal design population pharmacokinetic studies, and clinical studies in severe and uncomplicated falciparum and vivax malaria. Dose modification in important sub-groups such as young children, pregnant women, and HIV and tuberculosis co-infected patients should improve therapeutic responses and reduce selective pressures to the emergence of resistance.