Collaborative Awards in Science: projects we've funded

This list includes current and past grantholders.

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2017

Understanding mammalian interphase genome structure in mouse embryonic stem cells

The nucleosome remodeling and deacetylation (NuRD) protein complex is thought to play a key role in controlling the way our genomes are packaged inside the cell, and whether particular genes are expressed. The NuRD complex controls gene expression as embryonic stem (ES) cells first start to differentiate into the different types of cells in the body.

We will conduct an inter-disciplinary research programme to study the structures of intact genomes in single cells, how genome structure is controlled by the NuRD complex, and how this changes during the early stages of differentiation. We will also attempt to develop small molecule inhibitors of NuRD complexes to control chromatin structure.

Our long-term goal is to use our findings to control the differentiation of stem cells. This could be applied to either ES cells, or adult cells that have been induced to become stem cells – induced pluripotent stem cells (iPS). It has enormous potential for providing a source of human tissue to study disease progression or to develop drugs for personalised molecular therapies. Our research may help our ability to directly influence gene expression profiles, stem cell differentiation and disease.

Putting genomic surveillance at the heart of viral epidemic response

In recent outbreaks of viral disease such as Ebola and Middle East respiratory syndrome coronavirus (MERS-CoV), molecular sequencing of the viral pathogen has revealed critical insights into the evolution and transmission of the disease. This suggests into the potential value of this approach when attempting to control viral outbreaks. However, the scale and impact of new DNA technologies has largely been stunted, in part due to the complexities and logistics of shipping samples for sequencing and resulting delays in the production of the sequence data meaning that the inferences have limited usefulness for the response efforts.

We aim to produce a cheap, mobile, virus sequencing system, supported by statistically rigorous analysis frameworks along with information sharing platforms to prepare for the next outbreak and ensure that viral genome sequencing can have a greater impact on the public health response.

Stronger-SAFE: understanding transmission and optimising interventions for an enhanced SAFE strategy for trachoma elimination

Trachoma is the commonest infectious cause of blindness and it particularly affects poor rural communities. It is caused by repeated infection with the bacterium Chlamydia trachomatis (Ct). The WHO-endorsed SAFE-Strategy aims to control infection through annual, single-dose, azithromycin antibiotic treatments given alongside water, sanitation, hygiene (WASH), and fly-control measures to suppress transmission of Ct. These interventions also help to improve general health and well-being. However, in areas with a very high starting prevalence of trachoma, the current antibiotic treatment schedule is not having the anticipated effect on incidence. As we do not understand how the Ct infection is passed from one person to another, it is difficult to know how to stop the infection spreading.

In this study we will try to determine the main roots of transmission. This will allow us to develop practical, targeted interventions to limit the spread from person to person. We will then investigate whether using a double dose of the azithromycin given two weeks apart, combined with the new measures to limit transmission can better control the infection.

South-east Asian Research Collaboration in Hepatitis (SEARCH)

Viral hepatitis can lead to liver cancer and liver scarring (cirrhosis). It is the seventh leading cause of death globally and hepatitis C (HCV) has been responsible for an increase in mortality rates over the past 20 years. HCV is curable and this substantially reduces the risk of complications. Until recently, treatment relied on long courses of medication with high rates of toxicity. Several new treatments that work directly against the virus are now available but access to them is limited. Vietnam has the strains of HCV seen throughout the world, but also one seen less commonly elsewhere (genotype 6) about which there has been little research. About one million people in Vietnam are infected with hepatitis C and as a lower middle income country, it is able to access cheaper, generic treatment for hepatitis C.

Our objectives are to establish a multidisciplinary collaborative study of HCV treatment in Vietnam and deliver a novel trial to evaluate different treatment strategies with two new therapies. We will then provide evidence to allow the treatment to be scaled up and made accessible to all.

The interplay between the oxygen sensors prolyl hydroxylase enzymes and the cell cycle

Oxygen is essential for life in multicellular organisms. Animals have evolved mechanisms to cope with decreased oxygen concentration (hypoxia), which can occur both in physiological and pathological situations. In humans, sensing and responding to changes in oxygen involves a class of proteins – prolyl-4 hydroxylase domain (PHDs) – that use oxygen to modify a specific protein, called hypoxia inducible factor (HIF), which is a master regulator of genes that helps cells handle low oxygen levels. We recently discovered that these oxygen-sensing PHD proteins also target proteins required for the key process of cell division. This unexpected finding suggests that sensing oxygen is crucial for regulating cell division, which we propose may be particularly important in tissues, where oxygen concentration can vary.

This collaborative project will build on our discovery by studying in detail the molecular mechanisms that connect oxygen-sensing enzymes and their targets to regulate cell cycle progression. We will test the hypothesis that the sensing of oxygen levels regulates cell division in human tissues and investigate how dysregulation of these mechanisms may contribute to human disease, with a major focus on diseases of the kidney, where PHD enzymes are known to have important roles.

Integrative transport phenomena in chemokine gradient establishment

White blood cells protect us from infection, but also contribute to the development of many diseases, such as asthma, arthritis, heart disease and cancer. To do this they move from the blood into our organs. This cell movement is guided by chemokines. These are attractant molecules that are released by cells and form ‘chemokine concentration gradients’ inside the tissues of our organs, with the highest concentration near the cell releasing the chemokine. White blood cells sense these gradients and move towards the source of the chemokine. If the gradients are not set up correctly, then white blood cells have trouble finding their way. This can have profound consequences in health and disease. It is important that we understand the complexities of how chemokine concentration gradients are set up, maintained and controlled, and develop a better appreciation of how they make white blood cells migrate.

The combined expertise of our multidisciplinary team of biologists, engineers and mathematicians will provide unique insights into these processes.

Our findings could ultimately benefit many areas of medicine.

Mechanics and execution of homologous recombination – biophysics to the organism

DNA, the molecule that encodes our genetic information, is under constant attack from both external and internal factors, such as UV light from the sun and by-products of cellular metabolism. These factors damage DNA and it must be repaired correctly to prevent mutations and more complex chromosome alterations, which drive ageing, cancer and other diseases. Arguably the most severe form of DNA damage is the double strand break (DSB), in which both strands of the DNA duplex are severed. Fortunately, cells possess several DNA repair mechanisms that can rejoin or replace the genetic information at a DSB, including non-homologous end joining and homologous recombination (HR).

We will investigate the mechanics of the HR process in unprecedented detail. Much of our collaborative work will focus on the regulation of a key HR protein Rad51, which has the remarkable ability to catalyse invasion of a broken DNA molecule into an intact template DNA duplex.

Many mutations we will study are found in breast and ovarian cancers and our work will lead to an improved understanding of these diseases.

Challenging trypanosome antigenic variation paradigms using natural systems

Several pathogens avoid host immunity by periodically changing the proteins they express on their surface – a phenomenon called antigenic variation (AV). An extreme form of AV is exhibited by African trypanosomes, which cause human disease, although their greatest impact is through causing disease in livestock which significantly limits economic prosperity in sub-Saharan Africa. The molecular mechanisms of antigen switching in trypanosomes have been extensively studied over the past three decades providing a classic model for AV. However, several key components of this model have been challenged through recent discoveries. This includes a new appreciation of the importance of gene mosaics in generating new variants, as well as the contributions of parasite development and body compartmentation to the infection dynamic. It has become clear that the existing infection model – Trypanosoma brucei in mice – poorly reflects the dominant infections found in livestock – T. congolense and T. vivax.

We will systemically compare the contributors to AV in different trypanosome species and hosts and analyse the effects of perturbing key molecular regulators. The outputs will be integrated into a mathematical framework to highlight important parameters in the infection dynamic.

Our research findings could be used to help combat the parasite.


Behaviour change by design: generating and implementing evidence to improve health for all  

If people ate less, drank less alcohol and didn’t smoke, diseases such as diabetes and many cancers would be far less common. These unhealthy behaviours are more common among poorer people and they contribute to the gaps in health and life expectancy between the richest and poorest people. Progress in changing these behaviours is slow. Traditional approaches to behaviour change are based on information giving. They are generally ineffective, particularly among the poorest. Approaches that nudge changes are potentially more effective and equitable, and can involve redesigning environments, for example reducing plate size to reduce how much people eat. However, evidence is lacking on how effective such interventions are in real-world settings.

We propose a novel collaboration between behavioural and cognitive sciences to address this knowledge gap. In a series of studies we will evaluate the most promising interventions to reduce consumption of food, alcohol and tobacco, conducted in supermarkets, bars and cafeterias and using laboratory studies to understand and optimise interventions.

We will help implement the evidence generated through various activities overseen by an implementation advisory panel, to help accelerating progress in changing behaviour by redesigning environments to improve health for all.

Microneedles: bypassing the gastrointestinal microbiota to circumvent antibiotic resistance    

Antibiotic resistance represents the biggest threat to health today. Oral administration of antibiotics contributes significantly to the development of antibiotic resistance, due to interaction of antibiotics with bacteria inhabiting the human gut. Injection of antibiotics significantly reduces development of resistance in gut bacteria compared with oral administration, especially if the antibiotic is predominantly excreted through the kidneys. Accordingly, avoiding antibiotic exposure of the gut bacteria may considerably extend the useful lifespan of existing antibiotics, providing vital time for development of new antibiotics. It is clearly impractical to expect patients to inject themselves at home, especially considering that more than 20 per cent of people have needle phobias, but admitting patients to hospital every time they need an antibiotic prove costly.

We will develop and evaluate an antibiotic patch that will bypass the gut bacteria and extend the useful lifespan of available antibiotics. On its surface will be tiny needles that painlessly pierce the skin, turning into a jelly-like material that keeps the holes open and allows delivery of antibiotics for absorption into the bloodstream, bypassing the gut bacteria. We will show that this prevents the development of antibiotic resistance.

This approach will significantly extend the lifespan of existing antibiotics, saving countless lives.

2016

Neurodevelopmental disorders: what happens when children grow up and why?

Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) affect at least 1 in 10 children. The disorders begin in early life and until recently most children were thought to grow out of their problems. However, we now know that the problems are not confined to childhood, although not much is known about how these problems present in adults.

Our study aims to find out what is ‘normal’ or typical. For the first time a large population of about 8,000 people, who have been studied from the time they were in the womb, will be assessed on neurodevelopmental measures in adult life at age 26 years. We will describe the neurodevelopmental problems at this age, find out how they are linked to profiles from childhood and adolescence and work with populations in other countries to ensure our findings are robust. We will also test the extent to which early life experiences (in the womb and the early years) make a difference to  neurodevelopmental health up until early adulthood. We will also include the contribution of genes.

The research covers international populations, which will strengthen the findings.

Using parasite population genomics to improve understanding of malaria epidemiology

Two major challenges to controlling malaria are finding where best to focus limited resources for maximum effect and how to combat the spread of drug resistance. There is a pressing need for better information about the parasite population, such as how it evolves from year to year and the routes by which drug resistance is likely to spread.

This project is a collaboration between laboratory and computational scientists who are developing genomic technologies and statistical methodologies, and clinicians, epidemiologists and public health agencies who are working to control malaria in the field. Our goal is to develop simple and inexpensive ways for local health workers to monitor the parasite population by collecting samples from patients with malaria. We will then analyse thousands of these samples by parasite genome sequencing and use this large amount of data to gain a detailed understanding of how the parasite population is moving, changing and evolving over time and space. We will translate this scientific understanding into actionable knowledge for malaria control programmes.  

We will use this approach to investigate local patterns of malaria transmission in Africa and the spread of antimalarial drug resistance in South-east Asia.

Transforming brain recordings with next generation probes

To understand how the brain works, we need to measure the electrical activity of the large teams of neurons that form the substrate of cognition. Existing technology to make such recordings is extremely limited, allowing recording of fewer than 100 neurons.

We have developed a neural probe technology that records  more than 500 neurons at the same time. We now want to deliver this technology to the community of neuroscientists, to extend this technology so that it becomes even more powerful and to integrate it with other recent techniques that are being developed to image neurons and identify brain regions. To do this, we have assembled a collaboration of laboratory teams with diverse sets of skills, in close interaction with a unique nanoelectronics research partner who will make the probes.

The results of this project promise to transform the field of neuroscience and enable a new understanding of brain function.

The Clostridium difficile S-layer in infection and transmission

One of the most common infections in hospitals today is caused by Clostridium difficile, a bacterium that is notoriously difficult to kill. Apart from its resistance to most antibiotics, C. diff, as it is commonly known, has two other features that are essential for infection: a protective shell made of protein that covers the cell, known as the S-layer, and the ability to produce dormant forms, known as spores. While the S-layer provides defensive armour that protects the bacteria from the hostile environment in the gut, spores that contaminate the environment are resistant to most cleaning strategies and are responsible for transmission of the infection. Recently, we have shown that C.diff that do not have an S-layer are unable to cause disease and are inefficient at making spores.

We will combine our joint expertise to study how the S-layer is organised and the precise role it plays in infection and transmission.

As the S-layer has been recently shown to be a valid drug target, these studies will also reveal potential new targets for future treatment development. Our work will provide an understanding of how C. diff causes disease and how key processes might be disrupted.

Moving functional brain imaging into the real world: a wearable, cryogen-free, magnetoencephalography (MEG) system

To understand how the brain works, researchers ask subjects who are lying inside brain scanners, to perform a task. By looking for changes in images acquired during the task, it is possible to see which parts of the brain are engaged. Magnetoencephalography (MEG) images the changes in electrical brain activity millisecond by millisecond. Unfortunately, MEG has major limitations: it is a one-size-fits-all scanner which means poor sensitivity in some people and the scanner environment is unnatural and claustrophobic and subjects must remain still. Consequently there are many things we cannot study using MEG, such as how people move or interact with one another, and there are some people who cannot be scanned, such as children or patients with movement disorders.

We will develop a new type of scanner that eliminates these problems. Our scanner will be worn like a helmet, meaning anyone can be scanned while moving freely. Because our scanner will be built using a new sensor type, it will be 5-10 times more sensitive than current machines.

This instrument will transform the scientific and clinical questions that can be addressed with human brain imaging.

Liquid droplets and hydrogels: protein phase transition in health and disease

Pathological accumulations of the RNA-binding protein FUS are observed in the nerve cells of some patients dying of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In a recent series of ground-breaking discoveries, we have shown that FUS transiently assembles into liquid protein droplets and small jelly-like granules (ribonucleoprotein granules) inside cells. This property, which is driven by a disordered low complexity domain of FUS, allows FUS to transport, store and process RNA and protein molecules that are critical for synaptic connections between neurons. Disease-causing mutations convert this reversible process into an irreversible process. 

We wish to understand normal assembly of the liquid protein droplets and how this goes wrong in disease. To accomplish this, we will apply a series of innovative tools, together with the expertise of the applicants in neurobiology, protein folding, RNA biology and biophysics.

Many other human proteins have similar LC domains and some cause disease. FUS itself is involved both in neurodegenerative disease and in cancer. Knowledge arising from this project will therefore inform a new area of biology and will provide previously unimagined clues to new ways to diagnose and treat patients with diseases caused by FUS and similar proteins.

Understanding cellular organisation: from archaea to eukaryotes

The diversity of life we can see with the naked eye is breathtaking. Nevertheless, at the microscopic scale, remarkable similarities become apparent in the sub-cellular organisation of plants, animals and fungi, which reflects their common origin. All are eukaryotes and all possess a nucleus, a complex network of internal membranes and mitochondria. The establishment and maintenance of these membrane-bound compartments remains poorly understood, in part due to the lack of experimental models of intermediate complexity between eukaryotes and the small, structurally simpler non-eukaryotic cells that gave rise to them. Remarkably, however, relatives of molecular machines once thought to define eukaryotic cell organisation were recently identified in archaea. Thus archaea, which have long been neglected because some live in extreme environments and do not cause many diseases, likely hold important clues about our origins and provide us with stripped-down systems in which to better understand eukaryotic cell biology. 

By studying how the conserved archaeal molecular machines contributed to the transition between prokaryotic and eukaryotic cell organisation, we aim to gain new insights into the cell biology of eukaryotes: from malaria to cancer and stem cells. 

We expect our findings to have profound implications for human health and the treatment of disease.

Increasing the flavivirus envelope glycoprotein dimer stability to elicit potent and broadly neutralising antibody responses

Dengue is a mosquito-borne virus infection of the tropics and subtropics. About  400 million infections occur annually of which one quarter lead to overt illness. About 1-5% of infections are severe and can lead to the condition dengue haemorrhagic fever with dramatic fluid loss and bleeding which is life threatening. Dengue frequently occurs as an epidemic and puts huge pressures on the healthcare systems in affected countries. A recent large-scale trial of an anti-dengue vaccine gave some protection, but this was below that expected and although the vaccine has been licensed it cannot be used in children under the age of nine meaning that further development of dengue vaccines will be required. Through our work on dengue immune responses in infected people we have identified a key group of antibodies which can potently neutralise dengue infection. We have recently demonstrated that these same antibodies can also neutralise Zika virus.

Defining the site where these antibodies bind onto the dengue and Zika viruses will point the way to a novel dengue vaccine design. We have assembled a team of researchers to further the design and testing of this new dengue/Zika vaccine approach.

Determination of the prevalence breast cancer predisposition genes in South East Asian women and development of an Asian polygenic risk assessment tool

Although breast cancer incidence in Asians historically has been less than half of that in Europeans, it is rising by more than 3% per annum because of changing lifestyle such as decreased parity and breastfeeding, and increasing Westernisation and urbanisation. Today, more women die of breast cancer in Asia than in North America and Europe. In Malaysia, breast cancer is the most common cancer across all ethnicities, accounting for 31% of cancers in women, and it is the most common cause of cancer-related deaths. In part because of lack of funding in the national health services and lack of justification for population-based screening, only opportunistic screening is practiced, but this is suboptimal and inequitable. A viable alternative is to identify high-risk women who should be targeted for screening, particularly given the financial constraints that prohibit population-based screening.

We plan to bring technological advances in the understanding of breast cancer genes to develop tools to identify women at high-risk of breast cancer and to obtain individualised breast cancer risk estimates to enable shared decision-making between clinicians and patients.

This study will facilitate the wider use of clinical genetic testing and the development of informed risk-stratified approaches to screening.

The connectome of olfactory memory circuits in the adult fly

The brain is an interconnected network of specialised, electrically active cells called neurons. Storing and retrieving memories is vital to the brain’s control of behaviour and therefore the subject of intense study. Although the connections between neurons are known to be critical for brain function, the detailed set of connections required for memory storage and retrieval remain unknown. A new area of neuroscience, connectomics, aims to describe the complete set of connections in large brain areas. Neuronal connections are tiny and are measured in nanometres and can only be resolved using electron microscopy to reveal structures smaller than 1/10,000 of a hair’s width. Imaging a whole brain at this resolution is technically challenging, but this has now been done for the fruit fly, a key model for understanding mechanisms of learning and memory.

In this project, teams from Cambridge, Oxford and the US will: produce a freely available connection atlas (connectome) of a memory centre; develop the necessary computer technology and organisational strategies;and show that this connectome helps us better understand the brain.

Reconstructing a small vertebrate brain will be a huge undertaking, but future projects will build on the foundations laid here.

Why do Norovirus pandemics occur and how can we control them?

Norovirus is the commonest cause of vomiting and diarrhoea worldwide and the cause of more than 200,000 deaths every year affecting predominantly babies in developing countries. In the UK, norovirus outbreaks, particularly in winter months, are the most common reason for hospital ward closures, as well as affecting schools, care homes and even cruise ships. Although new vaccines are being developed, the worldwide spread every two to five years of a new ‘pandemic’ norovirus strain may reduce their effectiveness.

We propose to analyse noroviruses collected over the last 20 years to work out how many different strains a vaccine would need to protect against. Using information on where and when each norovirus was collected will help us understand the time and place of origin for each new pandemic strain. By measuring antibodies to norovirus in stored blood samples from the same time period, we will work out how quickly new norovirus pandemics spread and whether children are the first to be infected.

We will analyse all the data together to work out who should be vaccinated, how often and whether we can predict which strains are more likely to cause problems.

A cluster for the development of dynamic 3D nanoscopy

Microscopy has been an essential tool in advancing our understanding of biology for centuries. Observing the impact of diseases on the cellular level has led to better treatments and improves human health. The ultimate goal of a microscope is to watch our cells at work at the nanoscopic level of individual proteins, the key players in our cells. However, current technology does not allow this: we can either study them at high resolution in a static, fixed setting, or alive but at limited resolution and not for very long since we damage them in the imaging process.

Our team of physicists, engineers, computer scientists, chemists and cell biologists in Cambridge, Oxford and Yale will develop the necessary optical, labelling and data analysis technology to achieve live-cell optical nanoscopy that can image cells in 3D for hundreds of movie frames in living tissues. Our project builds on our consortium’s breakthroughs in live-cell and 3D nanoscopy.

The unprecedented imaging capabilities we aim for will open the door to major advances in physiology and medicine.

An integrated approach to the muscle Z-disk: from atomic structure to human disease

The action of normal heart and skeletal muscles relies on hundreds to thousands of repeating units called sarcomeres. The boundary between individual sarcomeres is called the Z-disks. The main function of these structures is to join adjacent sarcomeres and to transmit contractile force along the chain of sarcomeres, but they also sense, integrate and transmit signals that are important in controlling muscle growth and adaptation to physiological conditions. Z-disks are very hard to analyse as they contain very many components and are difficult to directly visualise even under powerful microscopes. However, improved understanding of Z-disk composition and its regulatory roles is increasingly important, not only for understanding its normal functions, but also because there is recognition that inherited heart muscle diseases can be caused by genetic defects in components of the Z-disk.

Our work unites experts in structural biology, cell biology and human genetics in a mission to determine how Z-disk mechanical, architectural and signalling functions operate from the atomic to the physiological level and how they are disrupted by genetic defects.

Our findings will enable greater understanding of disease-causing mutations, improve diagnostic accuracy and create the foundation for the development of new therapeutic approaches for these diseases.

Analysis of cytomegalovirus pathogenesis in a human challenge system  

Immunosuppressive drugs that prevent the rejection of transplanted organs also reduce immune responses that normally protect patients from virus infections. With previous Wellcome Trust support, we pioneered a way of detecting the most important virus, human cytomegalovirus (HCMV) in the blood to identify those at risk of disease. Based on our research, a pre-emptive therapy involving prompt administration of antiviral drugs at the first detection of HCMV was introduced into clinical practice and reduced the development of serious diseases caused by this virus. Among the patients that all received the same immunosuppressive drugs, only some have HCMV detectable in the blood, showing that they have poor immune control of HCMV. This phenotype could be explained if there were genetic differences in some strains of the virus.

We will exploit recent changes in contemporary medical practice that mean samples can now be obtained from donors. A multidisciplinary team will assess how HCMV evolves after transplant from one person to another and relate the results to measures of how active different components of the immune system are against HCMV. 

As with our earlier research, we expect the results will explain the phenotypes observed and find immediate practical applications in the management of patients.  

Multi-user ultra-high field clinical imaging research centre for London

Using magnetic resonance imaging and spectroscopy (MRI/S) to study patients can provide unparalleled anatomical, functional and biochemical information completely non-invasively without using ionising radiation. Most clinical and research scanners operate with 1.5T or 3T magnets. This proposal will fund an ultra-high-field MRI system with a stronger 7T magnet that produces larger MRI/S signals that can provide more information. The signal increases allow higher resolution imaging and the signal changes can allow detection of subtle disease properties. This offers enormous potential for research and clinical investigation, but is very demanding technically, so integrated teams of doctors, biologists, physicists, engineers and computer scientists are needed to make best progress.

We will create a collaborative MRI/S research facility to be located at St Thomas’ Hospital as a regional resource to be used by clinical researchers drawn from the major London universities (King’s, Imperial and University College), the Institute of Cancer Research and other leading institutions.

This will allow a world-leading multidisciplinary group to tackle major scientific questions and clinical challenges. This will substantially increase understanding of disease processes and ultimately enhance patient care.

2015

Improving the efficacy of malaria prevention in an insecticide-resistant Africa

Malaria is a parasitic disease transmitted by the bite of a mosquito. Deaths from malaria have halved over the past decade due to extensive financial investment in proven tools that can prevent transmission such as insecticide treated bednets. However, these gains are fragile. More than 600,000 people still die from malaria each year, the majority children in Africa. There are signs that the most effective malaria prevention tools are beginning to fail as mosquitoes develop resistance to the insecticides used on bednets or adapt their behaviour to feed at times when bednets are not in use. It is critical that we understand how these changes are affecting our ability to control malaria so that we can adapt control measures accordingly.

This project involves scientists with expertise in measuring and understanding mosquito and human behaviour, mathematicians who will quantify the impact of these traits on the predicted efficacy of different packages of interventions and economists who will consider the cost of these alternative approaches.

This holistic approach will enable us to propose a pragmatic, affordable solution to ensure that successes in reducing the devastating effects of malaria in Africa are sustained.

Building a platform for genetic inference from the Genomics England data

Genomics England is creating a lasting legacy for patients, the NHS and the UK economy by sequencing 100,000 genomes from about 70,000 people. This dataset will uncover genetic mutational difference between people and together these will constitute a resource of genetic variation that can be used by researchers working to uncover the genetic basis of complex and rare diseases.

The genome of any individual in this study is comprised of paternal and maternal genetic material. A key task for the data analysis is to separate the genome into these two constituent parts, called haplotypes. This is a substantial computational and statistical challenge that requires new methodological development. We will also work to provide a web-server interface that allows researchers to use these haplotypes to make predictions about which mutations are carried by the people they are studying. A major component of this research will investigate the fine-scale ancestry of the samples.

Understanding how genetic material has spread geographically via historical migrations is important when studying the spread of disease variants and uncovering the genetic history of the UK is of wide public interest.

The evolution of influenza virus: studies of within host and between host evolution to improve pandemic risk assessment and vaccine updates

Seasonal influenza epidemics and pandemics create substantial public health and economic burdens. These burdens are perpetuated by the continual evolution of influenza viruses to adapt to new hosts and to escape immunity generated by previous infections and vaccination. Understanding this evolution will make it more predictable and create opportunities to save lives. Influenza viruses continuously evolve and transmit efficiently from person-to-person.

How efficiently the viruses transmit is a critical determinant of how quickly an outbreak can spread and how many people are affected. We will study transmission using an animal model in which ferrets are infected deliberately with a known virus, with other animals then exposed to the virus. These techniques are widely used but most experiments use a very small number of animals and artificially severe infecting doses meaning that the results provide crude information. We will use improved experimental designs, mathematical models and genetic sequencing to simultaneously study virus evolution and transmissibility.

The information we gather will enhance pandemic preparedness by identifying which animal viruses are most likely to cause the next pandemic. This will help when choosing viruses that will be included in the annual update of seasonal flu vaccine.

A reappraisal of peripheral pain pathways

Pain is a poorly treated problem for one in five people. New drugs are needed but many drug trials for painkillers have failed even though the drugs work in rodents. We have learned a lot about pain from genetic studies that show some nerves in the skin and viscera are only involved in pain pathways. However, we do not know the relationship between human nerves and mouse nerves.

We will characterise the properties of individual nerve cells in macaques. We are unable to do this in humans because we need fresh nerves for the analysis. However, we can search for heritable pain genes in people who suffer ongoing pain as these may be useful drug targets. We plan to analyse the nerve types involved in different types of pain in mice, and catalogue the genes linked to specific pain conditions in animal models. By artificially stimulating or silencing sets of nerves in living mice we can find out more about the physiological processes that lead to pain – and find new ways to treat it.

Genetic and chemical validation of sugar nucleotide biosynthesis as a target against Candida albicans

Fungi are widespread bugs and most of us carry some of these organisms. Normally our immune system is able to suppress their growth. However, when the immune system is weakened, for instance during chemotherapy, organ transplants or HIV infection, these microbes are able to establish lethal infections that are not uniformly treatable with currently available drugs.

We aim to understand proteins that are important for building the cell wall of the fungal pathogen Candida albicans – a structure that protects this microbe from its environment.

This work will ultimately lead to the identification of opportunities for the discovery of novel anti-fungal drugs by the pharmaceutical industry.

What causes major depression?

The objective of this proposal is to discover what causes depression using genetic information. We emphasise that because of the intertwined nature of genetics and environment in the causation of depression, obtaining information about the genetic roots of the illness allows us to investigate its environmental aetiology. Success requires the collection of a suitably characterised large sample.

We will interrogate subjects about all known and putative risk factors. Our primary aim is to collect 24,000 cases of recurrent major depression and 24,000 screened controls using a collection strategy that maximises clinical severity and homogeneity. Together with our existing sample of 12,000, the total sample will be 60,000, which is sufficient to identify at least 30 genetic risk loci.

Our findings will transform our understanding of the origins and nature of major depression and provide a starting point for improvements in mental health care.

Comprehensive resistance prediction for tuberculosis: an international consortium (CRyPTIC)

In 2013, 9 million people developed tuberculosis (TB) and 1.5 million died from it. An estimated 480,000 new TB cases were resistant to the main antibiotics in 2013, known as multi-drug resistant TB (MDR-TB). But under half of drug-resistant cases were detected, reducing the chance of curing infections and complicating how we control the spread of disease. To address this problem, we need to be able to quickly test which antibiotics kill TB so that the best combination of drugs can be given. We currently rely on slow, cumbersome, labour-intensive and expensive techniques to do this.

This research will use whole-genome sequencing, a method of reading the more than 4 million letters of each TB germ’s genetic code. We will study more than 90,000 TB germs from around the world, many of which will be drug-resistant. We need to study such large numbers to find nearly all the changes in the genetic code that could cause drug-resistance, including very rare ones. We will develop new computer methods to analyse this large amount of genetic data to accurately predict drug-resistance in new TB germs.

Our findings will allow future TB cases to be treated with the best drugs more quickly, thus contributing to worldwide TB elimination.

Genetic approaches to reducing vector competence of Aedes aegypti for chikungunya virus

Dengue, chikunguya and other mosquito-borne viral diseases carry significant morbidity and mortality and there are few licensed drugs or vaccines available for these diseases. However, the dependence of these viruses on specific mosquito species, combined with recent advances in mosquito synthetic biology, has the potential to provide new approaches.

Aedes aegypti is a key mosquito species for the transmission of many viruses and we will engineer it by reducing its ability to transmit viruses. We will focus on the chikungunya virus, which is rapidly becoming a global threat, though successful development would be significant for a much wider range of viruses. We will pursue three approaches in parallel which will mitigate the risk that one of these approaches may not fully achieve its design goals. It will also provide multiple independent means to interfere with virus transmission, which in combination would greatly reduce the possibility of virus escape mutants. Two of these approaches aim to make mosquito cells more resistant to incoming viruses, the other aims to kill cells upon infection so that they are unable to support virus transmission. Each of these approaches is inspired by natural anti-virus defence mechanisms and they are based on our collective track record in molecular virology and mosquito synthetic biology.

Our findings will help develop new treatments and vaccines to help control the transmission of the chikungunya virus.

TREAT-HD: targeting neurodegeneration in Huntington's disease

Huntington’s disease (HD) is a devastating inherited neurodegenerative disease. A faulty gene causes the build-up of a toxic protein – mutant-huntingtin – which damages brain cells, leading to problems with movement, thinking and behaviour. Currently, no treatments slow down the underlying disease process.

We want to improve understanding of the disease process in HD and its response to treatment. We will study a cohort of young adults who carry the faulty gene decades before symptoms begin, to find the earliest changes in the brain or behaviour. We will also link with the first human trial of a drug which effectively ‘silences’ the gene-producing mutant huntingtin using short DNA strands, known as antisense oligonucleotides (ASOs). We want to develop a new generation of treatments based on this ASO approach which target a specific part of the mutant huntingtin that we know is harmful. We will also investigate how early therapies should be administered.

HD shares many similarities with other neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. Consequently this work may also accelerate the development of treatments not just for HD but also other more common diseases, thereby reducing the public health burden.

Understanding bacterial host adaptation to combat infectious disease

The increasing levels of antibiotic resistance are a global concern for both human and animal health and food security. Accordingly, alternatives to antibiotics are required for the control of human and livestock infections. Staphylococcus aureus is a major human pathogen responsible for hospital and community-associated infections of humans including skin and soft tissue infections, necrotising pneumonia and infective endocarditis. S. aureus is also an economically important pathogen among livestock, responsible for mastitis in dairy cows, sheep and goats, and joint infections causing lameness in poultry. In addition, farmed pigs are a reservoir for the emergence of antibiotic-resistant strains of S. aureus which has the capacity to transmit to humans.

Our previous work has identified that S. aureus has undergone numerous host-switching events during its evolutionary history and that successful host switches require bacterial adaptation to the new host. The project will involve a comprehensive examination of the genetic basis for host adaptation in S. aureus and the characterisation of the adaptive mechanisms required to evade the innate immune response of different host species.

Host/pathogen interactions that are identified to be important for host-specific pathogenesis will be explored for their potential as novel therapeutics for controlling infections in humans and livestock.

The Genome Campus Alliance

The Global Alliance for Genomics and Health (GA4GH) is an international consortium committed to ethically sharing DNA sequence and clinical data to address pressing research questions and to develop new clinical applications. Its major activity is to develop open technical and operational standards for these types of data. The added value of the GA4GH will be to connect all the existing genetic and medical records that are otherwise isolated from each other. However, translating these standards into concrete solutions requires implementation and testing of the proposed interfaces and practices.

The Genome Campus Alliance (GCA) is a collaboration between the European Bioinformatics Institute (EMBL-EBI), the Wellcome Trust Sanger Institute (WTSI) and ELIXIR to create, deploy and manage a full-scale implementation of the GA4GH standards and interfaces that are used by programmers to access data. Our open source tools will be designed to access existing databases at EMBL-EBI and WTSI using the GA4GH methods and standards.

We will identify additional shareable data through ELIXIR, coordinate the implementation of GA4GH standards across Europe and deliver training to maximise GCA’s impact.

An integrated approach to the muscle Z-disk: from atomic structure to human disease

Contraction of heart and skeletal muscles relies on the highly regular assembly of two main contractile protein filaments, actin and myosin, into sarcomeres. Actin and myosin are cross-linked in transverse planes in parallel arrays of interdigitating filaments, enabling their sliding motion to generate force. Anti-parallel actin filaments are cross-linked at the Z-disk, requiring the coordinated action of the cross-linker α-actinin and the sarcomeric blueprint titin. Z-disks are stable yet flexible tensegrity networks acting possibly not only as mechanical integrators, but also as mechanosignalling platforms via protein kinases, phosphatases and adaptor proteins, sensing and relaying information on biomechanical stress.

The Z-disk is extremely difficult to analyse by conventional top-down ultrastructural methods, so we will pursue a bottom-up molecular approach. Mutations in Z-disk protein genes and those controlling its turnover are emerging as major causes of dilated and hypertrophic cardiomyopathy (DCM, HCM), left-ventricular non-compaction (LVNC), myofibrillar myopathy (MFM) and others. Our work will unravel how Z-disk mechanical, architectural and signalling functions operate from the atomic to the cellular and physiological level and how it is disrupted by cardiomyopathy mutations.

Our findings will allow better understanding of novel disease-causing mutations in Z-disk genes and reiteratively drive the fidelity of variant interpretation.

Protein antibiotics: discovery, mode of action and development

We are rapidly approaching a crisis point in the treatment of bacterial infections, a consequence of the steep rise in antibiotic resistance and the lack of any new antibiotics in almost 30 years. The situation is acute for multidrug resistant Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae which cause life-threatening lung and blood infections in neonates and patients who are immunocompromised. Recent data from the World Health Organization indicate that more than 50% of P. aeruginosa isolates are resistant to most commonly used antibiotics and often resistant to last resort antibiotics such as the carbapenems.

Our objectives are to understand how protein toxins, known as bacteriocins, which are produced by bacteria to kill closely related kin, enter and kill target cells and to develop them into therapeutic protein antibiotics (PAs). Proteins have yet to be exploited as antibiotics even though they are increasingly being used to treat other human diseases such as cancer.

This five-year programme will uncover the basic mechanisms by which these potent antibiotics kill specific bacteria and test the PAs in animal models of bacterial disease. Our study will lay the foundations for a completely new form of antibiotic therapy that could eventually be deployed in humans.

Establishing a feeder EM facility for South Parks Road, Oxford

The cell is the fundamental unit of all life and our understanding of how it functions is about to be transformed. This will set the stage for a big change in medicine and biotechnology, as well as being likely to be the basis of whole new industries. It will be similar to the molecular biology revolution of the 20th century. These changes are being catalysed by many advances, but the most direct technological revolution has been in cryo-electron microscopy. In the last two years a convergence of a newly powerful electron microscopes, new direct electron detectors and new algorithms for image analysis have closed the longstanding ‘resolution gap’ between atomic structures and the limits of resolution available from light microscopy. It is now possible to look directly at molecules with an electron microscope and rapidly solve their atomic structure. Even more revolutionary, tomographic methods allow direct imaging of the internal machinery of cells at the level of single molecules.

This project will allow researchers to establish a microscopy facility where they can apply this new technique to research questions ranging from infection and immune responses to fundamental processes involved in cell division.

The Human Behaviour-Change Project: building the science of behaviour change for complex intervention development

Changing how we behave is central to addressing the economic, health, and environmental challenges we face, for example what we eat and how we recycle. Efforts by individuals, organisations and governments to change such behaviours have been only partially successful. Every day more than 2,000 scientific articles are published on how to change behaviour. However, the evidence is not presented in a uniform way so it is difficult to collate and use, often taking many months or years to integrate evidence about the techniques that can change behaviour.

Our project will revolutionise this situation by developing new ways to make sense of the enormous amounts of scientific evidence. It brings together human expertise in behaviour change with new computer power and machine learning methods to produce a framework for classifying relevant features of behaviour change interventions in a standardised way, combining them and retrieving answers to questions from researchers, practitioners and policy makers.

At the end of this project we will have a much better understanding of behaviour change as well as a searchable, up-to-date database of evidence that will allow people to design the best possible behavioural intervention for their circumstances.

Collaborative network to define the molecular determinants of G protein-coupled receptors' clinical efficacy

Many drugs, for example beta-blockers for the treatment of heart disease, act on a family of proteins in our body called G protein-coupled receptors (GPCRs). Despite some notable successes, most of the attempts to make drugs that act on GPCRs have failed. Since GPCRs are involved in many human diseases, the failure of the pharmaceutical industry to find ways to make drugs that work on GPCRs has been a serious barrier to the development of new medicines. If we could find ways to make drugs that act on GPCRs we could unlock the door to many new medicines. 

By drawing together leading scientists from around the world, we will ask what are the molecular features that make drugs able to act on GPCRs. We will focus on the muscarinic receptor family, a GPCR family involved in memory loss in Alzheimer’s disease and in schizophrenia.

We will reveal how to make drugs that act on GPCRs generally and also address how, by specifically targeting the muscarinic receptor family, we can make drugs that treat memory loss in Alzheimer’s disease and treat symptoms of schizophrenia.

Regulation of protein synthesis by elongation control in health and disease

Protein synthesis is the process by which DNA is converted, via an intermediary substrate called mRNA, into proteins. For proteins to be made, the mRNA must interact with a large complex called the ribosome which consists of RNAs and proteins.

Ribosomes can therefore be thought of as ‘molecular factories’ that make proteins. They do this by decoding the genetic information that is held in the mRNA and bringing all the building blocks together to synthesise proteins. The rate at which proteins are made is very highly regulated and cells respond to alterations in the external environment, including temperature change, exposure to toxic chemicals, viral infection and other diseases by modifying both the rate at which they make proteins and, importantly, the types of proteins that they make.

We aim to identify the mechanisms that allow the cells to produce selective protective proteins so that we can manipulate and mimic aspects of this process. In the longer-term, we will use this to provide novel ways in which to treat neurological disorders and cancers.

People we've funded

Many of our grantholders carry out research in Africa and Asia. See our directories: