Translational Medicine

Dr Janjira Thaipadungpanit from our MORU unit in Bangkok, Thailand, tells us about her research on molecular diagnosis and bacterial genotyping A molecular microbiologist, Dr Janjira's research focusses on using bacterial typing based on genome to confirm which disease is present in a patient. She aims to develop a single whole genome sequence type test using mutliple-PCR assays that can determine from a single sample of blood what bacteria or viruses are present in a patient's blood – thereby speeding up diagnosis and potentially saving lives in resource-limited settings. Head of Molecular Microbiology at MORU, Dr Janjira Thaipadungpanit's research interests include the molecular epidemiology of leptospirosis and melioidosis using multilocus sequence typing or genome data and molecular diagnosis to identify the causes of acute febrile illness and sepsis in patients.

Dr Markus Winterbert from our MORU unit in Bangkok, Thailand, tells us about his research on biomarkers for tropical diseases Having a background in malaria physiology and biochemistry, Markus Winterberg's research focus is on the interaction between host, pathogen and drug, the metabolism of antimalarial drugs and discovering biomarkers for tropical diseases. Markus aims to use these biomarkers to develop non-invasive, field-based rapid diagnostic tests for tropical diseases that quickly identify pathogens, thereby improving diagnostics and the treatment of patients. Dr Markus Winterberg is Head of Laboratory and a Principal Investigator in MORU's Department of Clinical Pharmacology. The key aspect of his research is ‘trop-med-omics', the application of mass spectrometry-based bioanalysis in tropical medicine, particularly using proteomics and metabolomics to identify a disease in a patient.

Premjit Amornchai from our MORU unit in Bangkok, Thailand, tells us about her work as biosafety level 3 lab manager and microbioogy safety officer To prevent relapse or reinfection, melioidosis requires a specific and prolonged treatment. Melioidosis is endemic at least 45 countries, but greatly under-reported, with a microbiological culture required to confirm diagnosis. This can take 2-7 days. In Thailand, up to 40 percent of hospital admitted melioidosis patients die. Premjit works with MORU researchers who have produced a rapid diagnostic test that aims to improve both diagnosis and public awareness of melioidosis. Microbiologist Premjit Amornchai heads MORU's Bio-Safety Level (BSL) 3 Laboratory in Bangkok, Thailand. Safety is very important for Premjit. The BSL3 Lab handles several dangerous materials, most notably, Burkholderia pseudomallei, a highly pathogenic bacterium commonly found in soil and water in Southeast Asia and northern Australia. The pathogen causes the difficult to diagnose, deadly bacterial infection melioidosis.

Professor Bob Snow from our KEMRI-Wellcome programme in Nairobi, Kenya, tells us how his research brings together epidemiological profiles and government policies to maximise malaria control programmes in Africa Quality data is vital to design better malaria control programmes. This project helps various African countries gather epidemiological evidence to better control malaria. Professor Bob Snow showed how sub-regional, evidence-based platforms can effectively change malaria treatment policies. Professor Bob Snow has developed a large programme of work on the phenotype of malaria disease, its relationship to parasite exposure and its wider public health burden. Technical advisor to the Kenyan Government (and member of a number of international malaria advisory panels), Professor Snow provides the bridge between basic malaria epidemiology and malaria control policy in the region. Malaria control in Africa.

Dr Lorenz von Seidlein from our MORU unit in Bangkok, Thailand, tells us about his research on malaria elimination in the Greater Mekong sub-region Multidrug resistant P. falciparum malaria is now established in parts of Thailand, Laos and Cambodia, causing high treatment failure rates for artemisinin combination therapies, the main falciparum malaria medicines. A further spread from Myanmar to India then sub-Saharan Africa would be a global public health disaster. TME seeks the best ways to eliminate drug-resistant malaria, using both technical solutions and novel ways that engage entire communities. Dr Lorenz von Seidlein coordinates MORU's Targeted Malaria Elimination (TME) study, which seeks to eliminate artemisinin resistant falciparum malaria by treating entire communities that have significant levels of subclinical malaria parasite infections and transmission with the antimalarial Dihydroartemisinin-piperaquine (DHA-PIP).

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.

Dr Olga Tosas-Auguet from our unit in Kenya tells us about her research on mapping bacterial antibiotic resistance Dr Olga Tosas-Auguet aims to develop ad evaluate a new approach to large scale surveillance of bacterial antibiotic resistance in low income settings. This approach can then be taken forward to a testing stage, initially in partnership with an emerging network of policy makers and healthcare practitioners in Africa. Resistance to antibiotics is a growing issue worldwide. Mapping where the resistance is as well as its distribution and diversity is hampered by the lack of laboratory facilities in many parts of the world. New technologies allow the characterisation of whole pathogen communities, giving us clues where multi-drug resistant organisms come from. This can help set up a better public health perspective surveillance.

David Dance from our LOMWRU unit in Laos tells us about his research on bacterial infections in Laos, particularly melioidosis David Dance is a Clinical Microbiologist supporting the work of LOMWRU (Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit) on bacterial infections of importance to public health in Laos. He is particularly interested in all aspects of melioidosis (Burkholderia pseudomallei) infection, especially gaining a greater understanding of the global distribution of the disease and the environmental factors that underpin its distribution. Laos is seing a growing number of melioidosis, a bacterial infection caused by a bacterium that lived in the environment. Meliolidosis is a disease greatly under-recognised and treatment is specific, making it a major threat to farmers in developing countries. A better understanding of the prevalence of this infection and how it spreads allows us to better target prevention and treatment.

Dr Georgina Humphreys coordinates the WorldWide Antimalarial Resistance Network (WWARN) study groups by encouraging partner engagement and managing the data curation and development of publications. WWARN is a network of research that analyses pooled data of numerous clinical trials. The sheer size of those data sets allows study groups to answer questions that couldn't be asked of a normal size clinical trial, such as the efficacy of an anti-malarial drug on malnourished or severely anaemic children. This research helps design policies to maintain the efficacy of current anti-malaria drugs, currently threatened by growing resistance.

Dr Gail Carson is Head of ISARIC Coordinating Centre (International Severe Acute Respiratory and Emerging Infection Consortium), a network of networks established in 2011 to ensure a rapid research response to outbreaks of pandemic potential. A quick and efficient response to an outbreak requires strong central communication and coordination. Information needs to be shared quickly and then fed into patient care and policy. A wider approach, cutting across disciplines and specialities, helps limit the number of infected people and the impact on the economy.

Professor Skirmantas Kriaucionis aims to to elucidate the molecular function of DNA modifications in normal cells and cancer. Although all cells in our body have the same genome, they look different and perform different functions. Epigenetic modifications such as methylations ensure which sets of genes are expressed in specific cells and how this specificity is inherited. Cancer cells show particular epigenetic abnormalities which can be targeted for cancer therapies.

Professor Frank Smithuis is the director of MOCRU, Myanmar Oxford Clinical Research Unit. MOCRU involves a network of 6 clinics and 650 community health workers in remote areas. Up until now, Myanmar has spent little on heathcare and receive little assistance from rich countries. Prevention is difficult, which leaves diagnosis and treatment. MOCRU has set up a network of community health workers, trained and supplied with diagnostics and treatments, to help improve access to healthcare for remote communities.

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.

Dr Claire Palles studies whole genome sequencing data and targeted analyses with the aim of discovering genetic variants that affect susceptibility to colorectal cancer and Barrett's oesophagus. The gastrointestinal track is responsible for more cancers than any other system. A condition called Barrett's oesophagus, characterised by a change in the cells lining the oesophagus, can lead to oesophageal adenocarcinoma. Only few people with Barrett's oesophagus will go on to develop cancer, and genome sequencing studies aim to identify genetic risk factors and therefore better target high-risk patients.

LOMWRU researchers conduct clinical research to help improve global, regional and Lao public health. They focus on infectious diseases, and also investigate diseases of nutrition and poverty. Poor quality medicines are a serious threat to our health. Falsified medicines and substandards medicines are a problem for all countries, but particularly for low and middle income countries where we see, for example, a large epidemic of fake anti-malarial drugs. Globally, better medicine regulatory authorities will help improve the quality of our medicines.

Director of OUCRU-Nepal, Dr Buddha Basnyat studies high altitude illness as well as undifferentiated febrile illness in the tropics, both common but neglected problems in Nepal. High altitude illness can be prevented by a simple rule: don't go too high, too fast. Drugs can also be used, and Dr Basnyat showed that a much lower dose of Diamox, a commonly used drug, is as effective. His research also focusses on the effect of high altitude on pilgrims, an older, poorer and more vulnerable population.

Professor Kevin Baird leads our Eijkman-Oxford Clinical Research Unit (EOCRU) in Jakarta, Indonesia. Delivering health care in Indonesia is a challenge, made more difficult by the geography and distances. Our EOCRU unit specialises in clinical trials on tropical infections, particularly Plasmodium vivax malaria. Current treatments with primaquine are effective but very toxic for patients with G6PD deficiency. Better point of care diagnostics can help us treat all patients safely.

Dr Mehul Dhorda heads the Asia Regional Centre of the WorldWide Antimalarial Resistance Network (WWARN). Artemisinin resistance is firmly established in many parts of Southeast Asia and threatens the lives of millions of people. To improve regional intelligence and aid containment efforts, Dr Dhorda promotes the collection of high quality data on malaria drug resistance. His research aims to simplify and harmonise data, securely store results and analyse comparative or collective pooled analyses.

Professor Peter Simmonds studies the epidemiology, evolution and emergence of a wide range of human pathogenic viruses. RNA viruses are major pathogens that represent the majority of new viruses emerging over time. They are particularly good at evading the host's response to infection. A better understanding of the interaction between virus and host can lead to a better control of viral infections. Recent discoveries on viral genome composition and structure might allow us to manipulate this interaction and generate new, safer vaccines.

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.

Professor Ben Cooper from MORU in Thailand uses mathematical modelling and statistical techniques to help understand the dynamics of infectious disease and evaluate potential control measures. Antibiotic resistance is one of today's major global health problems. Mathematical models help us answer what if questions and evaluate the impact of specific interventions such as hands hygiene on the spread of bacterial drug resistance. Effective solutions are then translated into policy changes or changes in practice at national or international level.

Dr Richard Maude's work combines clinical studies, descriptive epidemiology and mathematical modelling of malaria in South and Southeast Asia. Malaria epidemiology focuses on two main challenges to malaria elimination: antimalarial drug resistance and the movement of people that are spreading the malaria parasite. Travel surveys and cellphone records, combined with population parasite genetics help predict the spread of malaria and of drug resistance. Close coordination with all groups and agencies involved is crucial to malaria surveillance and elimination strategies.

Naomi's work focuses on supporting researchers to collect, clean and store research data. PRESERVING EVIDENCE FOR THE FUTURE Research is only as good as the evidence it generates, and data management is a critical part of this process since it supports findings. High quality data must be preserved for long term use and available to the research community. Ultimately, data is not about numbers, but about people's lives and health.

Dr Kesinee Chotivanich's laboratory provides facilities and resources to researchers, students, and collaborators who are interested in tropical diseases, with the aim to improve patients' care. More effective diagnosis and treatments are needed to reduce the morbidity and mortality affecting malaria patients. Researchers at the Malaria Laboratory at MORU study the pathophysiology of the disease, and test new compound drugs for anti-malarial activity. In the context of growing artemisinin resistance, this research will have a global impact.

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 Ross Chapman studies the molecular events triggered by DNA damage detection, and why defects in these events lead to immune deficiency and cancer in humans. GENOME INTEGRITY Whilst controlled DNA breaks allow for our vast repertoire of antibodies, DNA damage happening out of context can lead to cancer or predisposition to cancer. Recent developments in personalised medicine exploit the DNA repair weaknesses of cancer cells to selectively kill them. A better understanding of the underlying mechanisms can help develop innovative and targeted therapies.

There is a great need for better treatments for malaria and for a preventative malaria vaccine. SPACIAL EPIDEMIOLOGY & VACCINES Understanding the variation of malaria risk between houses, villages or region, and how malaria is transmitted in and around that variability helps develop better malaria control programmes and use their resources more wisely. Since malaria control tools are becoming less effective with time, progress in vaccine design is essential.

The Cambodia Oxford Medical Research Unit (COMRU) is based in Siem Reap, northern Cambodia, which remains one of the poorest countries in South East Asia with extremely limited health services. PNEUMONIA IN CAMBODIA Infectious diseases are prevalent in Cambodia, a country that is struggling with poor infrastructure. Streptococcus pneumoniae causes the most severe form of pneumonia and is now targeted by the pneumococcal conjugate vaccine. Dr Paul Turner is studying the effect of this vaccine in field conditions in SE Asia, as well as other direct applications such as the evaluation of a new diagnostic test for Typhoid and interventions to reduce the burden of infections acquired within hospitals.

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.

Dr Direk Limmathurotsakul's research focuses on the epidemiology of melioidosis, a bacterial infection caused by Burkholderia pseudomallei. Melioidosis is endemic in at least 45 countries, but greatly under-reported. Up to 50% of cases seen in hospital die. Our researchers at MORU have produced a rapid diagnostic test that aims to improve both diagnosis and public awareness. Better coordination between researchers and policy makers is needed to face upcoming emerging infectious diseases.

Dr Claudia Turner heads the clinical research program at the Cambodia Oxford Medical Research Unit (COMRU), in collaboration with the Angkor Hospital for Children. Whereas children mortality has dramatically decreased over the past 15 years, almost half the remaining mortality still occurs during the first 4 weeks of age. Neonatology, or care of newborns, doesn't need to be difficult or expensive. Low cost intervertions involving communities, such as keeping babies warm, save lives.

Dr Chris Paton studies the use of open-source Electronic Health Records (EHR) software, online learning and mobile technology to improve healthcare delivery in low-resource settings. LEARNING HEALTH SYSTEM In a learning health system, health care providers use electronic health records to identify problems, implement local solutions and check if the solutions are effective. Health informatics, or the use of IT in healthcare, needs to find innovative solutions for low income settings, such as the use of open-source softwares and mobile technology. This approach has been used to deliver training to rural healthcare workers in Kenya.

With 390 million infections occuring each year, dengue is the most important mosquito-borne viral infection, and no vaccine is currently available. DENGUE The majority of people infected with the dengue virus experience a flu-like febrile illness, but in a small proportion of patients, particularly children, the virus causes the blood vessels to become leaky which can induce shock and lead to death. Improved diagnosis and understanding of the disease process enable better outcomes for patients with severe dengue.

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.

In pregnant women, severe malaria is responsible for high maternal mortality, and uncomplicated malaria results in in high morbidity. Professor Rose McGready works on the treatment and epidemiology of uncomplicated malaria in pregnancy. Pregnant women are particularly vulnerable as pregnancy reduces the immunity to malaria, increasing the susceptibility to malaria infection and the risk of illness, severe anaemia and death. For the unborn child, maternal malaria increases the risk of spontaneous abortion, stillbirth, premature delivery and low birth weight - a leading cause of child mortality.

Men who have sex with men (MSM) are a stigmatised group in Africa, but a predominant actor in the transmission of HIV. Professor Eduard Sanders is interested in putting together public health interventions to reduce HIV transmission in vulnerable populations, facilitating the early diagnosis of acute HIV infections and preventing its further spread. He also researches bacterial sexually transmitted infections in high risk populations, and HIV-1 early treatment trials.

Misfolded proteins can either create the loss of a cellular function, or escape degradation, causing aggregation diseases. Dr John Christianson's research focusses on ER-associated degradation, which is responsible for clearing non-functional and orphan translation products. These processes play a central role in inherited diseases such a cystic fibrosis and various forms of cancer. Dr Christianson's long term goal is to identify novel points of interventions for cancer therapies.

Chorea-Acanthocytosis: ChAc is a rare progressive neurological disorder caused by mutations in a very complex gene. Dr Antonio Velayos-Baeza is interested in two main projects: Chorea-acanthocytosis (ChAc), a rare autosomal-recessive disorder that is characterised by progressive neurodegeneration and red cell acanthocytosis (spiky red blood cells), and Developmental dyslexia, the most common of the childhood learning disorders.

Professor Robert Gilbert's research focuses on the molecular mechanisms underlying membrane pore formation and cell adhesion. Switching mechanisms within our cells are in part responsible for their development. MicroRNAs control a whole set of proteins associated with stem cell biology, particularly cancer stem cells. Targeting these components raises the potential for new anti-cancer therapeutics, which work by switching off protein production rather than inhibiting them later.

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.

Resistance to drugs in bacteria can be aquired by swapping genes between individual bacteria. Computer programs developed by Dr Iqbal enable doctors to predict which antibiotics will be met with drug resistance, enabling the selection of the right drug. BIOINFORMATICS & PATHOGEN GENOMICS Dr Zamin Iqbal studies the DNA of bacteria and parasites, and compares the genomes of individual pathogens to track the spread of antibiotic resistance. Pathogens accumulate small genetic changes over time, and by tracking these changes, it is possible to map the spread of an infection. This enables better surveillance of pathogen evolution, within a host, within a hospital and across the world.

Computational and stastistical methods help us understand evolution as well as genetic disease. Professor Gerton Lunter is interested in investigating the processes of evolution and biology using computational methods. His focus is on sequencing data; Professor Lunter develops methods to investigate evolutionary questions in population genetics.

Melioidosis is a neglected tropical disease, and a major infectious killer in South East Asia. Melioidosis particularly affects people with diabetes. Dr Susanna Dunachie works on tropical diseases such as melioidosis, scrub typhus and vivax malaria. Melioidosis is a bacterial disease that results in pneumonia, liver and splenic abscesses and septic shock. The disease can reactivate after a latent period and is inherently resistant to many standard antibiotics. People continue to die around the world from this infection for which there is no vaccine. Understanding the disease is therefore crucial.

Over 250 Institutions participate in the effort of sharing data on the efficacy of antimalarial drugs, which involves standardising and re-analysing data. Professor Philippe Guérin is Director of the WorldWide Antimalarial Resistance Network (WWARN). The best lines of defence against malaria are avoidance of mosquito bites and effective drug therapy. WWARN tracks the emergence of antimalarial drug resistance to ensure that anyone affected by malaria receives effective and safe drug treatment.

Artemisinins are very poweful tools in the treatment of malaria, and the emerging loss of their activity has the potential to create a major public health problem. MALARIA TREATMENT Dr Charlie Woodrow is based at MORU in Bangkok, Thailand, where he coordinates clinical and laboratory studies on resistance to artemisinins. Bringing together diverse datasets of clinical, in vitro and molecular data has helped better understand the emerging resistance, particularly in Myanmar.

Identifying and addressing ethical issues are key to the success of any clinical trials, particularly when working with vulnerable populations. Dr Phaik Yeong Cheah leads the Department of Bioethics & Engagement at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Thailand. She is particularly interested in ethical issues in community engagement, data sharing, consent and assent in paediatric research.

In settings with high level of poverty and over-stretched health services, researchers have even greater responsibilities to the communities and study participants. SOCIAL AND BEHAVIOURAL RESEARCH A social scientist and public health researcher based in Kenya, Professor Vicki Marsh aims to understand and strenghten policies based on social and ethical aspects of international collaborations. Improving communications between researchers and the patients and local communities is not only ethically important; it can also lead to better research.

Melanoma or skin cancer is one of the fastest rising cancer types. When identified early, melanoma is relatively easy to cure, but once it starts to metastasise, it becomes very difficult to treat. DEREGULATION OF TRANSCRIPTION The interface between signal transduction and transcription regulation coordinates gene expression. Deregulation of transcription is a key factor in cancer. Professor Colin Goding studies how a precise programme of transcription regulation is achieved, particularly in the transition between normal and cancer stem cells, and the parallels with normal stem cell populations.

Transcription is a tightly regulated process, where chemical modifications initiate the duplication of genetic material. This epigenetic process is often dysregulated in cancer, but it can be targeted with small molecule inhibitors. EPIGENETIC SIGNALLING Professor Panagis Filippakopoulos is interested in the molecular mechanisms of transcription, where the formation of non-covalent protein complexes is mediated by post-translational modifications. Dysfunction in this epigenetic signalling process is linked to disease, particularly cancer.

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.