Most diseases are diagnosed and classified on the basis of symptoms and a series of standardised tests that reflect structural changes in the diseased organ (e.g. x-rays, magnetic resonance imaging), the pathological process (e.g. histological analysis of tissue biopsies, cytological analysis) and function (e.g. blood tests, spirometric testing of lung function, stress testing of coronary flow and heart function). For some diseases, genetics is used both to diagnose the disease and estimate the risk of developing the disease. Infectious diseases rely on the identification of microbes and laboratory tests that help select the most appropriate anti-microbial agent (e.g. antibiotic). Such tests have enabled clinical, pathological and pathophysiological stratification of disease, resulting in clinical diagnoses of such common diseases as diabetes, coronary heart disease, various cancers, asthma, emphysema, Alzheimer’s disease and rheumatoid arthritis.
It is now widely recognised that this approach does not have sufficient resolution that would enable clinicians accurately to predict the course of the illness (i.e. prognosis) or respfonse to therapy. It is recognised that most diseases are not single clinical entities but are syndromes, i.e. clusters of pathological processes that have some similafrity but also significant heterogeneity.
Stratified medicine is a major focus of activity within Medicine at Southampton, engaging wet lab and in-silico lab expertise, the Institute for Life Sciences (IfLS) , Southampton Electronic and Computing Science and Mathematics , with world-class proteomics and lipidomics laboratories, including the facilities based in the Southampton Biomedical Research Units facilities which are applying the latest technologies to identify disease biomarkers.
Stratifying asthma for better diagnosis and drug discovery
(
Ratko Djukanovic
,
Peter Howarth
,
Anthony Postle
, Paul Skipp, David O’Connor,
Graham Roberts
)
Together with the University of Amsterdam and Imperial College, Southampton is leading an EU wide consortium called UBIOPRED (
Unbiased Biomarkers for the
Prediction of Respiratory Disease Outcomes
), a €22 million research programme applying an innovative systems biology approach to integrate high dimensional data obtained by different ‘omics’ technologies from bronchoscopic airway, sputum and blood samples, and non-invasive sampling, together with physiological measurements and patient reported outcomes. High-dimensional biology techniques, such as genomics, transcriptomics, andproteomics, hold out promise to identify new pathogenetic processes through measurement of thousands of different genes, proteins and metabolites in complex biological systems.
(
Stuart Clarke
, Saul Faust, Jeremy Webb, Paul Stoodley, Luanne Hall-Stoodley,
Rami Salib
,
Tom Wilkinson
,
Simon Bourne
, Mary Carroll,
Peter Howarth
,
Jane Lucas
)
The respiratory tract is a complex multi-strain, multi-species host-pathogen ecosystem. Strain mutation is generally considered to be responsible for the spread, persistence and pathogenicity of most infectious diseases. In the respiratory tract, this is compounded by the interactions between bacterial and viral species. Vaccines are the single most effective intervention against infectious diseases; it is for this reason that it is essential to understand better the carriage of microbes in the general population so that we can improve clinical care by informing vaccine and antibiotic development and policy. Vaccines are available against some respiratory pathogens and those of the conjugate type have been particularly successful in reducing vaccine-type disease (e.g. Hib and MenC vaccines). However, these vaccines are limited in their strain coverage. Southampton researchers have shown that the epidemiology of carried pneumococci (a common cause of pneumonia) has shifted dramatically after the introduction of pneumococcal conjugate vaccines in 2006. Research funded by the Bupa Foundation is now investigating the epidemiology of carried bacteria in the upper respiratory tract of large numbers of participants. This study will provide a basis for detecting a link between the changing epidemiology of microbial carriage and the burden of infection with different bacterial strains or species, and thereby inform vaccine and antibiotic policy. Further research funded by the pharmaceutical industry is looking at the changing epidemiology of pneumococcal carriage after the implementation of pneumococcal conjugate vaccines in young children, and the epidemiology of the microbiota in COPD patients in chronic disease and during exacerbations. The aim of these studies is to provide data that will support the development of novel vaccines and other therapies.
(
Christian Ottensmeier
,
Freda Stevenson
,
Graham Packham
,
Peter Johnson
)
Chronic lymphocytic leukaemia (CLL) is the most common Western adult leukaemia. Previously, it was considered as a single disease of variable clinical course. In Southampton, we have described a new prognostic factor, the immunoglobulin V-region gene (Ig V genes). Our findings have revealed that in cases derived from less mature B cells without somatic mutations in the Ig V genes, the prognosis is much worse (mean survival 99 months) than in cases derived from a later cell with mutations (mean survival 293 months). This widely confirmed correlation has had a dramatic effect on our understanding of pathogenesis, on clinical management and on patients’ perception. Our original paper (Hamblin et al, Blood 1999) has been cited >1500 times.
On-going research is targeted at understanding signalling via the B-cell receptor and the microenvironment in CLL. In vitro analysis of signalling has demonstrated that individual CLL samples differ in their ability to transmit signals via the cell surface B-cell receptor. Retained signalling is associated with the presence of poor prognostic markers (unmutated Ig V genes) and a poor clinical outcome. Thus, antigen signalling via the B-cell receptor, in the context of specific tissue microenvironments, is considered to play a key role in driving cell proliferation and survival, leading to disease progression.