Blizard Institute - Barts and The London

Professor Gareth Sanger, BSc (Newcastle), PhD, DSc (Manchester), FBPhS, FRSB

Gareth

Professor of Neuropharmacology

Centre: Centre for Neuroscience, Surgery and Trauma

Email: g.sanger@qmul.ac.uk
Telephone: +44 (0) 207 882 6027

Profile

Gareth Sanger obtained his BSc in Physiology at the University of Newcastle-upon-Tyne and his PhD in Physiology at the University of Manchester, followed by a fellowship at King’s College Hospital Medical School in London, training in pharmacology. He now uses pharmacology to solve physiological problems. Moving to the pharmaceutical industry (Beecham, SmithKline Beecham, GlaxoSmithKline) he isolated a novel 5-HT receptor function (later named 5-HT4) and identified the role of 5-HT3 receptors in emesis, leading to new anti-emetic drugs and a revolution in cancer care. For this, he received the Pharmaceutical Research & Manufacturers of America Discoverer's Award and the Sir James Black Award for Contributions to Drug Discovery. He has helped define many other drug targets (most recently the neuropharmacology of motilin and ghrelin), led numerous research and drug discovery teams and entered multiple NCEs into clinical development. Establishing an independent laboratory at Queen Mary University of London, he uses human gastrointestinal tissues to conduct functional, structural and molecular studies into the dysregulated movements of the stomach during nausea and the neurodegenerative changes during constipation of advanced age. The laboratory has been recognized by the NC3R and LUSH organizations for providing an alternative to animal use.  He was elected Fellow of the British Pharmacology Society and the Royal Society of Biology. He has twice served on the editorial board of the British Journal of Pharmacology.  He is a consultant and advisory board member for the pharmaceutical industry in gastrointestinal research. He teaches gastrointestinal biology, pharmacology and drug discovery processes.

Summary

BSc (University of Newcastle), PhD (University of Manchester), DSc (University of Manchester). Post-doctoral fellow with Professor Alan Bennett (Kings College Hospital Medical School). Fellow of the British Pharmacology Society. Drug Discovery and Gastrointestinal Research at GlaxoSmithKline. Experience in all phases of drug discovery, placing 7 novel compounds into development, including granisetron (now an anti-emetic drug).

Research achievements have include the proposal that a novel receptor mediated the ability of 5-HT to increase gastrointestinal motility, later named by others as the 5-HT4 receptor. Identification of the role of the 5-HT3 receptor in the mechanisms of emesis, which led to the development of new drugs and a major change in the treatment of cancer. Jointly awarded the 1998 Discoverer’s Award by the Pharmaceutical Research and Manufacturers of America (PhRMA). Exploration actions mediated by NK3, ghrelin and motilin receptors. Consultant on gastrointestinal drug discovery and development.

Research profile: functional human tissue assays

Using fresh, ethically-obtained human gastrointestinal tissues to predict activity in vivo. Functional human tissue assays include those which study neuromuscular pharmacology, human mucosal permeability and mucosal secretion and in the near future, human peristalsis. Assays are complimented by human gastrointestinal immunohistochemistry, to confirm the cell types of interest. In the functional human tissue assays, actions of novel substances are benchmarked against those of clinically-relevant drugs, enabling us to predict physiological, therapeutic and adverse effects of novel substances in the clinic, and the potency and doses of new drugs. Our focus on human tissue pharmacology means we are involved in basic research with immediate clinical relevance, as well as providing contract services to industry, playing a vital role in innovative drug discovery.

Teaching

BSc Bioscience Year 3: Module lead – Drug Discovery & Development

BSc Pharmacology & Therapeutics Year 3: Drug Discovery – Overview, Challenges, Screening Cascade Principles & Pharmacology

BSc Global Health Year 3: Principles of Drug Discovery and Challenges

MBBS Year 1 & 2:  Problem-Based Learning; Gastrointestinal Movements; Nausea & Vomiting; Fundamentals of Pharmacology; Drug Discovery

MSc Gastroenterology: Drug pharmacology, Gastrointestinal Movements, Nausea & Vomiting

PhD examiner

Research

Research Interests:

Different regions of mammalian stomach contract in a tonic or phasic manner, influenced by slow wave electrical activity of interstitial pacemaker cells. In human stomach these are poorly understood. During nausea, a human experience with uncertain existence in animals, gastric movements are disrupted, but it is unclear if this is cause or consequence of nausea so treatments are difficult to define.

  • Using human gastric distal fundus and proximal antrum, we are modelling muscle tension and phasic contractions, analyzing by comparing with amplitude, frequency and velocity of movements in vivo (collaboration with surgeons and bioengineers) and understanding how these might be modulated by agents which affect pacemaker cell functions (with industry).
  • In the different regions of the human stomach muscle movements can be disrupted with vasopressin and other nauseogenic stimuli released during nausea but with unclear actions.
  • As a potential model of nauseogenic activity, validation is being sought by comparing with the rat (unable to vomit) and by comparing the activity and effective concentrations of nauseogenic hormones alone and in combination, with their blood concentrations during nausea.
  • In the near future long-term models will be established, possibly by cell culture to investigate potential pathological mechanisms of relevance to disorders such as gastroparesis.

During advanced age (>65 years) we have shown that cholinergic function declines in the ascending but not descending human colon, while nitrergic and muscle functions remain unchanged and the total number and phenotype of myenteric neurons are not altered. An increase in choline acetyltransferase within cholinergic cell bodies was the basic for speculating that as in other age-related neurodegenerative disorders, cholinergic function is under stress in a region-dependent manner.

  • Preliminary evidence suggests that mRNA for the senescence gene p16 (not p21) and also for TNFalpha and other genes are preferentially unregulated during advanced age, also in the ascending colon. Experiments are ongoing to validate and extend by staining with a p16 antibody in a large cohort of patients of different ages. Preliminary data suggests preferential staining of myenteric neurons not glial cells.
  • Following digestion, primary cultures of human colon myenteric neurons and glial cells have been created for functional evaluation by electrophysiology and by application of NGF, prior to investigating the biological activity of biopsies prepared from the colon of patients with IBS and thought to be enriched with NGF (prepared by collaboration). One the model is established methods of provoking senescence will be explored.
  • Preliminary experiments, within a collaboration, suggest that following digestion, primary cultures of human glial cells can be used to establish neurogenesis; experiments await further validation. Once established the mechanisms and clinical use of neurogenesis will be explored.

Publications

Key Publications

Broad J, Kung VWS, Palmer A, Elahi S, Karami A, Darreh-Shori T, Ahmed S, Thaha M, Carrol R, Chin-Aleong J, Martin JE, Saffrey MJ, Knowles CH, Sanger GJ (2019). Changes in neuromuscular structure and functions of human colon during ageing are region-dependent. Gut 68:1210–1223

Broad J, Maurel D, Kung VWS, Hicks GA, Schemann M, Barnes MR, Kenakin TP, Granier S, Sanger GJ (2016). Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design. Sci Rep 6, 30797; doi: 10.1038/srep30797

Broad J, Mukherjee S, Samadi M, Martin JE, Dukes GE, Sanger GJ (2012). Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists. Br J Pharmacol, 167, 763-774

Dass NB, Monunyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, Morgan M, Sanger GJ (2003). Growth hormone secretagogue receptors in the rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience, 120, 443-453

Miner WD, Sanger GJ (1986). Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol, 88, 497-499

All Publications

Supervision

Marie-Ange Kouassi

Marilisa Straface