Professor Gareth Sanger, BSc, PhD, DSc, FBPhS, FRSB

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 uses pharmacology to solve physiological problems. Working in 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. He received the Pharmaceutical Research & Manufacturers of America Discoverer's Award and the Sir James Black Award for Contributions to Drug Discovery. Within industry he defined many other drug targets (e.g. the neuropharmacology of motilin and ghrelin), led numerous research and drug discovery teams and entered multiple NCEs into clinical development. After then establishing an independent laboratory at Queen Mary University of London, he uses human gastrointestinal tissues to conduct functional, structural and molecular studies into dysregulated movements of the stomach during nausea and in neurodegenerative changes during constipation of advanced age. The laboratory was 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.

LinkedIn: /gareth-sanger-21a31810

Teaching

BSc Bioscience Year 3: Module lead, lecturer, tutor and examiner – Drug Discovery & Development

BSc Pharmacology & Therapeutics Year 3:  Module lead, lecturer, tutor and examiner – Drug Discovery & Development

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

External examiner (University of Cork)

Research

Research Interests:

Different regions of the 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, gastric movements are disrupted, but it is unclear if this is cause or consequence of nausea so treatments are difficult to define.

• Using human proximal (fundus/corpus) and distal (antrum) stomach, we model muscle tension and phasic contractions, analyzing the amplitude, frequency, rate and AUC of the region-dependent movements, before comparing with in vivo studies (collaboration with surgeons and bioengineers), determining how these are modulated by hormones and 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. Importantly these act in synergy and we hypothesize that this is necessary to provide sufficient interoception to ‘drive’ the sensation of nausea during gastrointestinal disease.
• As a potential model of nauseogenic activity, validation is being sought by comparing with the mouse (unable to vomit) and by comparing the activity and effective concentrations of nauseogenic hormones alone and in combination, with their blood concentrations during nausea.
• We are currently experimenting with different ways of establishing long-term models of gastric functions, so that we can investigate the effects of long-term expose to 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.

• We have evidence to suggest that the 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. This pattern of expression has been confirmed by staining with a p16 antibody in a large cohort of patients of different ages.  Preliminary data suggests preferential staining of myenteric neuron cytoplasm not glial cells.
• Following digestion, primary cultures of human colon myenteric neurons and glial cells have been created for functional evaluation by calcium imaging 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). Once 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.

McGuire C, Boundouki G, Hockley JR, Reed D, Cibert-Goton V, Peiris M, Kung V, Broad J, Aziz Q, Chan C, Ahmed S, Thaha MA, Sanger GJ, Blackshaw LA, Knowles CH, Bulmer DC (2018). Ex vivo study of human visceral nociceptors. Gut 67, 86-96.

Hellstrom PM, Tack J, Johnson LV, Hacquoil K, Barton ME, Richards DB, Alpers DH, Sanger GJ, Dukes GE (2016). The pharmacodynamics, safety and pharmacokinetics of single-doses of the motilin agonist camicinal, in type 1 diabetes mellitus and gastroparesis. Br J Pharmacol, 173, 1768–1777.

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.

Farmer AD, Ban VF, Coen SJ, Sanger GJ, Barker GJ, Gresty MA, Giampietro VP, Williams SC, Webb D-L, Hellström PM, Andrews PLR, Aziz Q (2015). Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans. J Physiol 593.5, 1183–1196.

All Publications

Supervision

Marie-Ange Kouassi

Marilisa Straface