The Endo train
Writing in The Endocrinologist (Issue 93, Autumn 2009), Stafford Lightman, Professor of Medicine at the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, summarised the wide range of work that goes on at the University of Bristol under the heading of ‘endocrinology’ - or the study of hormones.
Bristol was always one of the great port cities of the UK - and the second greatest trading city after London in the 18th century. It was ideally located to develop trading links with Europe, Africa and the American ‘Colonies’, and became rich from activities related to the slave trade, wine, spirits and tobacco. Not, perhaps, an auspicious ethical starting point for 21st century biological science, but important history that must not be forgotten.
But Bristol’s place in history is also reflected by Isambard Kingdom Brunel’s legacy - the SS Great Britain, the Clifton Suspension Bridge, and one of the world’s first railway stations. We have the replica of John Cabot’s ship, The Matthew, to remind us of his voyage to North America from Bristol in the 15th century. And then there are Concorde, the BBC Natural History Unit, Bristol International Balloon Fiesta, Wallace and Gromit, and Banksy, a local street artist whose activities are renowned worldwide.
Endocrinology - and in particular neuroendocrinology - also has a long history in Bristol. Hans Heller was appointed lecturer in charge of the newly created Department of Pharmacology in 1942, became Professor of Pharmacology in 1949 and developed an internationally renowned centre for research on the regulation of the neurohypophysis. His symposia on ‘The neurohypophysis’ in 1956, ‘Neurosection’ in 1961 and ‘Subcellular organisation and function in endocrine tissues’ in 1970 attracted endocrinologists from all over the world. Barry Cross, a protégé of Geoffrey Harris, was Professor of Anatomy from 1967 to 1974, and developed the technique of electrophysiology in the hypothalamus. He trained, amongst others, Richard Dyball, John Morris, Dennis Lincoln and Richard Dyer. Meanwhile, Brian Pickering’s MRC unit moved to the Department of Anatomy following Hans Heller’s retirement and continued the excellent work on understanding the regulation of neurohypophyseal secretion.
The opportunity for me, as a neuroendocrinologist, to come to such an excellent University with such a marvellous history in endocrinology was one I could not resist. I came from Charing Cross and Westminster Medical School with my clinical scientist colleague, Andrew Levy, who was soon joined by David Wynick and Colin Dayan, as well as our basic scientific colleagues Chas Chowdrey, Michael Harbuz and David Jessop. We moved to an area of refurbished laboratories in what had been dermatology wards around the back of the Bristol Royal Infirmary (BRI). These were exciting times and we were soon joined by superb basic scientists including David Murphy, Craig McArdle, James Uney, Nola Shanks, Christopher Lowry, Stephen Lolait, Anne-Marie O’Carroll, Hans Reul, Astrid Linthorst and Kei Cho.
After moving around the bowels of the BRI several times, we obtained a Wellcome Trust SRIF Award, which, with a grant from HEFCE and support from the University, allowed us to build the Dorothy Hodgkin Building, which now houses the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology. This has transformed our ability to perform integrative research from the most basic cell biology through to physiological studies and clinical translation.
Clinical endocrinology has expanded over the whole of the Bristol campus. In the BRI, my own research group works on the HPA axis, especially its regulation in health and disease. We have been particularly interested in the regulation of the ultradian pattern of cortisol secretion and how this regulates gene transcription. These in vivo and in vitro studies are now being applied to translational work in man, with potentially very important implications for steroid therapeutics, including a new understanding of the inadequacy of current steroid replacement regimens.
Andrew Levy is an internationally renowned authority on the pituitary gland and the aetiology of the development and maintenance of pituitary tumours. He has shifted the previously held paradigms on their causes and his concept of ‘exuberant normality’ remains the best conceptual understanding of cell activity in these fascinating tumours.
David Wynick has focused on the role of the neuropeptide galanin in neuropathic pain and neuronal protection. He is translating his work into preclinical drug development funded by a Wellcome Trust Seeding Drug Discovery Award, and most recently has started a research out-patient clinic in Bristol, focused on improving the management of diabetic neuropathic pain.
Colin Dayan’s interests cover both the thyroid axis and the immunotherapy of type 1 diabetes. He runs the joint thyroid eye clinic at Bristol Eye Hospital and is the principal investigator in the multicentre combined immunosuppression and radiotherapy in thyroid eye disease study, in close collaboration with Moorfield’s Eye Hospital and four other centres in London. His unit has also conducted the largest trial of combined T4/T3 therapy in the world, and has made fascinating progress in identifying common genetic variations that effect thyroid hormone action. Together with Susan Wong and Mark Peakman (King’s College London), he has collected 650 adult cases with newly diagnosed type 1 diabetes for immunological studies and has conducted the first phase 1 trial of peptide immunotherapy. Also, with Rob Andrews, he has established the early ACTID randomised controlled trial of intensive diet or intensive diet and exercise versus usual care in newly diagnosed type 2 diabetes. He runs our insulin pump clinic and, with Richard Smith, the regional pancreas transplant programme.
Susan Wong joined us from Yale University and has a major research focus on the immunopathogenesis of type 1 diabetes. She is interested in the role of CD8 T-cells, B-cells and innate/adaptive immune interface in the pathogenesis of type 1 diabetes. Her work in animal models is carried out in parallel with translational development of immunotherapy for type 1 in collaboration with Colin Dayan.
Rob Andrews, a senior lecturer in our department, has developed one of the country’s largest medical obesity clinics at Musgrove Park Hospital in Taunton. Last year saw over 1400 referrals and more than 400 surgical procedures. They have now been made lead centre in the south-west as an international centre of excellence for bariatric surgery. This programme importantly has a large research portfolio looking at the effect of weight loss and surgery on gut hormones and insulin secretion, signalling and sensitivity.
We have been fortunate in the appointment of Karin Bradley as full-time NHS consultant endocrinologist. With a DPhil in molecular endocrinology from the University of Oxford and extensive clinical experience, she has helped to optimise care for patients with multiple endocrine neoplasia and other rare genetic endocrine syndromes. She has developed a regular monthly neuroendocrine tumour multidisciplinary team at the BRI, which attracts referrals from across the south-west of England. Karin is also the endocrinology representative on the steering group investigating service delivery for ‘late effects’ patients living in the Peninsula region, and is helping to establish a co-ordinated local clinical service for these survivors of childhood cancer. Her interests and roles include endocrinology in a critical care setting and endocrine disorders during pregnancy, as well as diabetes care and general medicine. She has recently been joined by a second NHS colleague, Bushra Ahmad.
The University Hospitals Bristol NHS Foundation Trust (UHBT) also has an extremely active paediatric endocrine programme. It has one of the UK’s largest obesity services, run by Julian Hamilton-Shield, and one of the UK’s largest paediatric diabetes services, with an emphasis on research into rare forms of diabetes, neonatal diabetes, Down’s syndrome and autoimmunity. Julian in particular has been the driving force behind the discovery of 6q imprinting anomalies in neonatal diabetes, KCNJ11 mutations causing neonatal diabetes and the discovery of genes involved in neonatal glucose metabolism, PTFA1, ABCC8, HNF4 alpha and GLUD1 mutations and the cause of neonatal hyperinsulinaemia. Collaborative studies with Jeff Holly have focused on insulin resistance in obesity, including studies on adipocytes with respect to adipogenesis and insulin resistance.
Liz Crowne is Chair of the British Society for Paediatric Endocrinology and Diabetes, and her research has concentrated on the late effects of cancer treatment on endocrine systems. Reproductive endocrinology is led by David Cahill and Andrés López Bernal. David’s focus is on the endocrine status of serum and follicular fluid and its relationship with successful in vitro fertilisation. His data suggest differential regulation in patients with minor degrees of endometriosis. Andrés concentrates on CRH and oxytocin signalling in the normal and pregnant myometrium and the abnormalities that occur in premature labour. In north Bristol, Edwin Gale and Polly Bingley lead a major diabetes research centre. They have developed the current model for predicting future onset of diabetes in close relatives of an affected child. This led on to ENDIT (1994-2003), a multinational intervention trial.
Their interest in the epidemiology of type 1 diabetes has led to a close collaboration with Kathleen Gillespie, studying the role of NK cells in autoimmune diabetes and immunogenetic characterisation of diabetes in Down’s syndrome. Edwin played a prominent role in the early stages of the EURODIAB ACE network which has greatly clarified trends in the epidemiology of childhood-onset diabetes in Europe. He is Editor of Diabetologia.
Jon Tobias works on metabolic bone disease, with a particular interest in the pathogenesis and management of osteoporosis. Through the unique ‘Children of the nineties’ birth cohort, we are gaining important insights into the factors which affect skeletal development in childhood, such as maternal vitamin D exposure, fat mass, and a variety of genetic influences. Jon helps lead a nationwide study characterising the phenotype and genotype of individuals with extremely high bone mass, which has provided further evidence of an important link between obesity and bone metabolism. Through the COSHIBA study, he is examining whether a new clinical tool can identify patients with undiagnosed vertebral fractures. He has a strong local interest in steroid-induced osteoporosis, exemplified by randomised controlled trials examining the role of bisphosphonates in preventing bone changes following steroid therapy for inflammatory bowel disease and multiple sclerosis.
Jeff Holly was one of the first scientists to realise the importance of IGFs and he has been an active leader in the International Society for IGF Research. He played a major role in working out the inter-relationship of GH, IGF-1 and their metabolic effects, and now works closely with epidemiologists at the Department of Social Medicine in Bristol, studying a variety of large population cohorts to examine how metabolic and hormonal status relate to the development and progression of chronic diseases, particularly the hormone-dependent cancers.
Overall, there is a wealth of clinical and basic scientific expertise and activity in Bristol. With the proposed merger of the UBHT and the North Bristol NHS Trust, we expect even greater integration of research activities. We anticipate considerable development of the translational studies in the neuroendocrine and metabolic areas, and the synergies of the numerous research groups and our colleagues in Cardiff and the Peninsula will ensure Bristol remains a major hub of novel research and endocrine clinical development.
Please visit our websites (www.bristol.ac.uk/clinicalsciencesouth/hwline, www.bris.ac.uk/clinicalsciencesouth, www.bris.ac.uk/clinicalsciencenorth, www.uhbristol.nhs.uk, www.nbt.nhs.uk), and if anyone is interested in discussing research activities with us, then you are of course very welcome.
Source: University of Bristol
