Translational and Clinical

Professor Derrick Crook from our Experimental Medicine division tells us about his research on tracking infections Professor Derrick Crook's research consortium focusses on translating new molecular technologies and advances in informatics into the investigation of microbial transmission, diagnosis of infectious disease and identifying outbreaks of communicable disease. This research aims to translate deep sequencing of pathogens on an epidemiological scale for tracking infections, and is focussed on four different major pathogens: Staphylococcus aureus (including MRSA), Clostridium difficile, Norovirus and Mycobacterium tuberculosis. Understanding how an infection spreads is vitally important for prevention. Whole genome sequencing of microorganisms allows us to construct family trees of infections, from donnor to recipients, and understand how microbes behave in general. Through its genetic code, we can also predict whether a germ is susceptible or resistant to a specific antibiotic, and give patients a more stratified and personalised treatment.

Housed within the Target Discovery Institute, the Alzheimer’s Research UK Oxford Drug Discovery Institute (ODDI) juxtaposes drug discovery expertise alongside scientific and academic understanding of patients, disease mechanisms and model systems. The burden caused by Alzheimer’s disease and other dementias represents one of the biggest problems for our healthcare systems. The last medicine was approved in 2002 and today we only have symptomatic treatments. ARUK-ODDI brings together chemists, biologist, psychiatrists and neuroscientists, many of them with pharmaceutical background, aiming to accelerate the discovery of novel and effective treatments.

Professor Frank von Delft works to ensure that X-ray structures can serve as a routine and predictive tool for generating novel chemistry for targeting proteins. In the process of drug discovery, X-ray crystallography is the most sensitive way to find out which compounds bind to a target protein. Recent advances in technology allow researchers to test many more compounds, much more rapidly. The ultimate aim is to bring much needed new treatments to patients.

Dr Brian Marsden aims to make structural and chemical biology data accessible to non-experts, by providing computational resources including data management, sample tracking, in silico modelling support plus provision of public access to SGC data. Protein structures are powerful tools in the development of medical drugs, but they are not very accessible to non-specialists. Research informatics presents these structures more simply and interactively, and helps scientists make decisions. This will hopefully accelerate the development of new medicines.

Dr Nicola Burgess-Brown heads the Biotechnology Group at the SGC, which generates proteins suitable for structural and functional studies. Recombinant protein expression in host cells such as bacterial or insect cells facilitates the production of large amounts of proteins, which can be used for crystallisation to obtain the protein structure, or in cellular assays to look at their function. Collaborations with partners such as academics, industry and patient groups aim to find compounds that can be developed into potential drugs.

The development of new medicines is dependent on the identification of novel drug targets. CHEMICAL BIOLOGY In the search for new medicines for cancer or inflammatory disorders, small molecules are invaluable tools for testing the activity of possible target proteins. Those small chemical compounds can also affect the morphology and phenotype of cell samples collected from patients, opening the possibility to develop new therapeutics.

Growth hormones and cytokines regulate the key physiological processes of growth and differentiation as well as responses to injury and infection. FIBRODYSPLASIA OSSIFICANS PROGRESSIVA Growth factors and signals are fundamental to many diseases. A single point mutation in the DNA coding for a bone morphogenetic protein is responsible for the development of FOP, a very debilitating disease where muscles are progressively turned into bones. Understanding these mechanisms allowed the selection of a drug, currently used to treat cancer, that may possibly be repurposed to treat FOP.

The main aim of Dr Xue's research is to understand the molecular and cellular mechanisms mediating inflammatory diseases, and to translate their findings into therapeutic concepts to treat these diseases. Drugs and treatments for inflammatory diseases are scarce and often induce major side effects. A better understanding of the molecular mechanisms governing inflammatory diseases would allow us to develop new drug and treatments, at great benefit for both patients and the NHS.

Asthma and COPD (chronic obstructive pulmonary disease) are common conditions that affect the lives of many people. Dr Mona Bafadhel studies the pathophysiology of COPD (chronic obstructive pulmonary disease). There are broadly two inflammatory phenotypes of COPD that are clinically indistinguishable but have different treatment responses. Dr Bafadhel is working on the development of novel therapeutic strategies for COPD, particularly to treat the regular periods of worsened symptoms that patients experience.

Alteration of gene expression is fundamental to many diseases. A better understanding of how epigenetic proteins affect diseases provides a starting point for therapy development and the discovery of new drug. Professor Paul Brennan research focusses on epigenetics: the mechanisms that control gene expression. He studies how chemical probes interfere with epigenetic enyzmes that can be targeted to treat various diseases. Epigenetics combined with disease biology will ultimately accelerate drug discovery.

A missing step in a metabolic pathway leads to the build-up of toxic compounds, and the lack of materials essential for normal function. Professor Wyatt Yue explores how genetic defects lead to disease at the molecular level, by determining 3D structures and biochemical properties of enzymes and protein complexes linked to congenital genetic errors. Professor Yue works closely with clinicians and paediatricians to decipher the underlying genetic, biochemical and cellular mechanisms of these diseases. His long-term aim is to help design novel therapeutic approaches for metabolic diseases.

Video microscopy aims to improve target discovery and drug development and to do so generates large volumes of data. Professor Jens Rittscher has a joint appointment between the Ludwig Institute for Cancer Research, the Target Discovery Institute and the Department of Engineering Science. His research aims to enhance our understanding of complex biological processes through the analysis of image data acquired at the microscopic scale.

Dr Sebastian Nijman develops new approaches to study signalling networks in cancer cells and uncover specific weaknesses, particularly in breast and lung cancer. This can be used to develop more effective drugs and to better guide treatment decisions. In the context of cancer, genetic diversity means that we respond differently to various treatments. Pharmacogenomics sits at the intersection between genetics and drugs. Better understanding of the genetic landscape of cancer and the recent increase of targeted drugs allow us to better match patients with the best treatments, improving care.

Lowering cholesterol in chronic kidney disease The Study of Heart and Renal Protection (SHARP) concluded that around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of ezetimibe and simvastatin to lower blood cholesterol levels. The SHARP study involved almost 9,500 volunteers aged 40 or over with chronic kidney disease recruited from 380 hospitals in 18 countries. Volunteers were randomly allocated to take either cholesterol-lowering therapy with a tablet containing ezetimibe 10mg daily and simvastatin 20mg daily, or matching dummy "placebo" tablets for an average of 5 years.

Wider Statin Use Saves Lives The largest and most reliable study ever to examine the effect of statins has found them to reduce the risk of heart attacks, strokes and premature deaths among a wide range of apparently healthy people. The benefits greatly exceed any known risks associated with taking these drugs.

Airway inflammation Ian Pavord is Professor of Respiratory Medicine and has been joint Chief Medical Advisor to Asthma UK since May 2008. He has developed new techniques to get a better idea about airway inflammation and uses this information to investigate the best treatments to prevent asthma attacks.

Dr Trudie Lang tells us how the Global Health Network facilitates collaboration and resource sharing. Clinical trials establish the evidence base for prevention and treatment of disease and are critically important in the field of Global Health. Dr Trudie Lang leads the Global Health Clinical Trials group, which aims to promote and improve the conduct of non-commercial clinical research across all diseases in resource-poor settings.

Dr Najib Rahman talks about his research on respiratory medicine. The Pleura are thin membranes that cover the surface of the lungs. Dr Najib Rahman specialises in areas of respiratory medicine including pleural disease and the conduct and analysis of respiratory trials. Dr Rahman is currently conducting clinical studies in malignant and infectious pleural disease, and is Clinical Director of the Oxford Respiratory Trials Unit.

Professor Stefan Knapp tells us how the development of chemical probes helps us to find new drugs. The role of proteins in cellular signalling and disease is best studied through the development of highly specific chemical inhibitors, which can serve as a tool molecule for functional studies. Professor Stefan Knapp works to determine the structure of protein molecules to understand their regulation and to aid the design of selective inhibitors that can be developed further into efficient drugs

Dr Liz Carpenter talks about her research on membrane proteins and drug development. Membrane proteins are the gateways to our cells - with nutrients, waste products, and even DNA and proteins entering and leaving cells via these tightly controlled proteins. Drugs often target membrane proteins; therefore, understanding their molecular structure helps us design better drugs. Dr Liz Carpenter uses X-ray crystallography to solve membrane protein structures. This information is then used to improve treatments for heart disease and neurological diseases.

Dr Simon Travis tells us how clinical trials bring tomorrow's treatments to patients today. Before translating basic research into the clinic it is important to first undergo clinical trials in order to identify safe treatments and therapies for disease. Led by Dr Simon Travis, the Gastroenterology Clinical Trials Facility at Oxford University works to translate basic research into clinical trials of novel therapies for gastrointestinal and liver disease.

Dr Benedikt Kessler tells us how proteomics helps find biomarkers. Biomarkers are molecular features that give us clues about underlying biological processes. They are typically used to monitoring a disease or predicting the outcome of a treatment. Modern analytical equipment allows us to measure thousands of molecules at the same time. Dr Benedikt Kessler studies the role of deubiquitylating enzymes, involved in the elimination of proteins marked by the ubiquitin-proteasome system. Alterations in this process are responsible for many human diseases. Dr Kessler works to improve medical diagnosis and treatment through the use of biomarkers.

Professor Chas Bountra explains how new drugs can offer novel treatments for neurodegenerative and gastrointestinal diseases, as well as pain disorders. Professor Chas Bountra is interested in identifying and validating target proteins for drug discovery. Various technologies and strategies have allowed him to progress promising clinical candidates into Phase I, II, III studies, and to market. Drug candidates are first selected by screening compounds capable of binding to a target protein. Those compounds are then tested in various assay systems, healthy volunteers and finally in patients. Academic research excels at defining good target proteins. Pharmaceutical companies then facilitate the transition from basic research to clinical trials, producing new therapies for patients.