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.

Translational and Clinical

Tracking infections

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.

Why we work on Alzheimer’s disease

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.

X-rays for drug discovery

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.

From information to structure

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.

Unravelling proteins

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.

Targeting drug discovery

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.

Understanding growth signals

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.

Inflammation in disease

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.

A deep breath in

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.

Chemistry, epigenetics and drugs

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.

The genetics of 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.

Biological imaging

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.

Pharmacogenomics

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.

SHARP

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.

Wider Statin Use Saves Lives

Translational and Clinical Medicine is the ongoing effort to bring basic science from the bench to the patient, as well as to elucidate safety and effectiveness of the medicines on which we depend. The NDM podcasts on translational and clinical medicine detail our work in this wide-ranging field, from the identification and design of new medicines to clinical trials and trial design and regulation.

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Translational and Clinical

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