Academic research community (GECIP)

When the human body senses germs, the immune system sends out a large army of forces to fight against infections. When these defences are weak, especially in the periods immediately after birth or in early childhood, babies and children are rendered helpless at the most critical time points in life. Severe and unusual infections, and other diseases in childhood can arise due to errors in the genetic blueprint. As a result, the development of major milestones like first steps, first words, or complex thoughts can be severely affected. In some cases, these genetic errors may even cause cancer or early ageing. The most crucial mechanisms in our body are found in replicating our genes ("genome stability") and recycling old material ("autophagy"). By analysing the genes in affected individuals and healthy family members, this project aims to uncover how the immune system protects the human brain. This will help both in genetic counselling and helping patients and families what to expect from their condition and how best to look after themselves.

We know that patients afflicted with Schizophrenia are also more likely to be hospitalized with severe infections or to be diagnosed with autoimmune diseases and allergies. The probability of being affected by diseases of the immune system is influenced by the HLA region in our DNA. This region is responsible for producing proteins which recognize molecules of foreign origin like viruses and bacteria. However, in autoimmune diseases (e.g allergies, Coeliac disease) those same proteins wrongly identify harmless molecules as infections. Understanding in how far the genetic makeup of the HLA region in Schizophrenia patients differs from neurotypical participants can give us a better understanding why Schizophrenia patients are more often found to be also affected by diseases of the immune system. Furthermore, we might be able to better identify Schizophrenia patients with higher risk of autoimmune diseases or severe infections based on their DNA sequence in the HLA region. We also hope to understand better which specific infections or autoimmune diseases are more common in Schizophrenia patients with different genetic variants in the HLA region by analysing their electronic health records.

This project aims to improve efficiency of early research and discovery, one of multiple steps in the complex chain of drug development, production and market launch. Deploying ways that bring more biological relevance process into R&D enables faster and more accurate target identification and drug discovery. Ultimately, this enables more therapies to be released to the market, and for these to be more effective to targeted indications. In this instance, rare, genetic syndromes can provide information on the effect of a gene and its role within a biological pathway. Understanding these mechanisms in normal and perturbed states is crucial for target identification and validation, leading to development of novel drug candidates. In this instance, we are interested in several variants altering the activity of key immune response genes (KIG). These have been previously associated with diseases such as Inflammatory Bowel Disease. However, their functional impact remains largely unknown. We aim to explore the impact of KIG loss and gain-of-function variants on the regulation of the immune system.

Biogen is exploring genes for the targeted treatment of a several severe rare diseases in neurology and immunotherapy for which there are no specific drugs. This project aims to use the Genomics England Rare Disease dataset to understand how the patterns of disease-associated genetic variants and clinical records relate to each other. Adding additional information on disease-associated genetic variants to Biogen’s compendia of knowledge on gene targets has the potential to significantly improve decision making during the research and development of new drugs such as: Which gene are priority targets for new drugs? How best to design and recruit for clinical trials?

Autoimmune diseases affect around 5-10% of the world’s population, and have a huge impact on patient morbidity and mortality, as well as on healthcare costs. The term autoimmunity covers a number of complex disorders that are often very different in both clinical presentation and cause, including systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. Although environment and hormonal factors can contribute to the development of autoimmunity, the strong heritability of autoimmune diseases cannot be ignored and is still not fully understood. By studying the genetic basis of autoimmune diseases, we will gain further insight into what causes the development of autoimmunity, ultimately allowing better design of targeted treatments for these diseases.

Despite significant advances in medical research we still do not fully understand the molecular basis of many human diseases, particularly those that are very variable, such as cancer, or those that are rare. Large scale genetic analyses of rare and complex diseases provides an opportunity for investigators to identify patients with genetic variants in specific genes or gene families. Our group is interested in a gene family that use oxygen to control molecular switches in critically important cellular processes that are deregulated in disease. Here we aim to identify patients with variants in these so called ‘oxygenases’. We aim to study and model these variants in our laboratory, in order to help understand the molecular basis of cancer and unexplained rare diseases.

UCB are developing medicines for patients whose needs are not currently met with existing therapies, with a focus on epilepsy and with disorders of the immune system. Many such patients are not adequately treated – current medicines do not work for them and so there is a need to develop new strategies for their treatment. Genetic studies of patients with rare and extreme diseases can provide very useful insights into the biology underlying these types of diseases, and we have already identified some novel genetic variants which we believe to be important drivers in some patients. To enhance our confidence in these findings, it is important to try to find other clinically similar patients and see if they also carry variants in these genes. In this respect we are employing several approaches, including using resources such as GeneMatcher and extended networks and we would like to determine if any Genomics England participants with similar disorders also carry these variants.

The ability of cells to move and change their shape is critical to their function. In the developing brain, the neurons must change shape to grow and to transmit the nerve impulses along the length of the nerve cells, thereby contributing to the plasticity of the brain. Similarly, immune cells must be dynamic to respond to pathogens through a process known as phagocytosis thereby supporting the body’s first line of defense against bacteria and other foreign bodies. variants in genes contributing to the maintenance or dynamics of the cytoskeleton may therefore compromise these processes. We wish to investigate the role of these genes in neurological and immunological disorders through access to the 100,000 Genomes Project.

White cells help the body to fight against infections by travelling where pathogens are, recognising them and clearing them out. This ability is provided by the coordinated function of many genes in the white cells. variants affecting the function of some of these genes, such as two members of the DOCK gene family, are known to cause immune disease. Whole genome sequencing studies conducted in our laboratory suggest that variants in other DOCK-family members could lead to immune disease, either alone or in association with variants in other genes. In order to demonstrate this, we would like to investigate a larger number of patients (available in the GEL cohort) with variants in the DOCK gene family and the variants present in other genes.

Inflammatory bowel disease (IBD) is a life-long condition where the immune system attacks the gut. Many patients will require multiple surgeries and strong suppression of their immune system to tackle the associated pain and infection. Occasionally some patients have a single gene that is dysfunctional and this puts them at high risk of developing IBD. These patients often get IBD in childhood, the disease can be very severe and the normal treatments may not work. Where we understand the mechanism driving the disease in patients with a single gene problem, particular therapies can be used, which would not work for most patients. In this project we will try to identify which gene is causing the problem and if there is a pattern in their appointments, surgeries and hospital admissions that identifies these patients.

Chronic, recurrent and/or persistent viral infections are rare in the population but at the same time a common reason for presentation to immunology clinics. In our local clinic, we currently take care of approximately 40 individuals who suffer disproportionately but do not have a known diagnosis of immune disease.

The human immune system has evolved to protect us from a bewildering array of germs, a job it usually performs unnoticed. We can think of the immune system as a network of armed forces that cooperate to defend us. When one element of these defences is weakened, it can leave us critically exposed to certain threats. It stands to reason that the same weapons also pose a threat if mistakenly targetted to our own tissues, so the healthy immune system is actively held in check. Severe and unusual infections, and/or self-directed, autoimmune diseases, can reflect an underlying problem in the genetic blueprint for the immune system. By analysing the DNA of affected individuals, and comparing its sequence with that of healthy family members, the current research aims to uncover the genetic origins of immune disorders. This knowledge may assist doctors and patients/families in making clinical decisions, and will add to scientific understanding of the healthy immune system.

Worldwide, over a million people are diagnosed with colorectal cancer each year. Only clinical stage is used as a crude guide (or biomarker) to help determine how long a patient will survive and to help inform their treatment options. There is a clear need for more accurate measures of survival and toxicities to treatment. Our group is investigating whether a patient's genetic code in their blood and cancer can be used for such measures. We have already shown that genetic changes within the cancers themselves can have a major effect on survival. Furthermore, we have recently shown that a genetic change in a patient's blood DNA can also influence survival. We have now carried out a full screen of the entire genome and identified many further genetic biomarkers which we aim to confirm. Genetic biomarkers promise to inform patient survival and treatment options for improved quantity and quality of life. They may also inform the development of better therapies.

Mutations in genes produce non-functional genes that can lead to various diseases. There is however another mechanism that can cause disease even when the genes themselves are intact. This is because for normal development and health, it is crucially important when during development, and where in the human body, a gene is active. This is determined by so-called enhancers which act like molecular switches to turn genes on. When these enhancers are mutated (non-functional enhancers), genes are either not expressed, or they are expressed at the wrong time or in the wrong tissues, and this can lead directly to a range of diseases. The mechanisms that underpin these forms of disease predisposition and progression are much less well understood, compared to the disease-causing mutations in genes themselves. This is mainly because enhancers can be located far away from the genes they switch on; therefore, it is very challenging to identify which enhancer regulates which gene. We have developed a method that can link the enhancers with the genes they control in the entire human genome through our pioneering technology. This allows us to identify potential novel causal disease genes that cannot be identified using other approaches. Establishing these enhancer-gene links is therefore a crucial step to better understand diseases, and represents a highly promising avenue for the development of novel drugs to target causal disease genes, and for treatments to ameliorate diseases.