Robert Semple (PhD FRCP(Ed) FRCP(Lon) FRSE)

Chair of Translational Molecular Medicine

Biography

Background

Robert Semple is Professor of Translational Molecular Medicine at the University of Edinburgh, where he is also the current Dean of Postgraduate Research for the College of Medicine and Veterinary Medicine. Since 2022 he has been vice chair of the MRC Population and Systems Medicine Board, with primary responsibility for its respond mode funding activity. He trained in Biochemistry and then Medicine at the University of Cambridge, with clinical postgraduate training in London and Cambridge, including a PhD in the laboratory of Prof. Sir Stephen O’Rahilly. He is clinically active in both diabetes and endocrinology, as well as leading a translational research programme.

Qualifications

2005:                    PhD: “Nuclear Hormone Receptors and their Accessory Molecules in the Control of Metabolism” (Supervisor Prof. Sir Stephen O’Rahilly), University of Cambridge

1997:                    MB BChir (with distinction in all subjects), University of Cambridge

1993:                    B.A. (Biochemistry; 1st class honours), University of Cambridge

Responsibilities & affiliations

2017-present        Professor of Translational Metabolic Medicine, University of Edinburgh

2012–present:      Wellcome Trust Senior Research Fellow in Clinical Science

2017-present:       Honorary Consultant Endocrinologist, NHS Lothian

2022-present:       Vice chair, MRC Population and Systems Medicine Board

2019-present:       Dean of Postgraduate Research, College of Medicine and Veterinary Medicine

2021-present:       DRWF Research Advisory Board member

2021-present:       Programme Secretary and Trustee, Society for Endocrinology

2019-present:       Deputy Chief Editor, European Journal of Endocrinology

Postgraduate teaching

Prof Semple is the current Dean of Postgraduate Research for the University of Edinburgh College of Medicine and Veterinary Medicine

Open to PhD supervision enquiries?

Yes

Current PhD students supervised

Sheldon D’Silva (Edinburgh-Copenhagen PhD programme)

Past PhD students supervised

University of Edinburgh

Eleanor McKay (BHF PhD programme)

 

University of Cambridge

David Bulger (NIH OxCam PhD programme)

Ralitsa Madsen (Wellcome Trust PhD Programme)

David Church (Diabetes & Wellness Foundation Sutherland-Earl Fellowship)

Patsy Tomlinson (Wellcome Trust PhD Programme)

Kimjee Goh (A*Star Programme, PhD)

Sarah Leiter (Cambridge MB PhD Programme)

Victoria Parker (Wellcome Trust Clinical Research Training Fellow)

Marina Minic (Gates Foundation, PhD)

Laura Schmidt (self funded, MPhil)

Matthijs Groeneveld (MRC PhD studentship)

Alexandra Gast (MPhil; Clare College Harrison Watson Studentship)

Eleanor Raffan (Wellcome Trust Clinical Research Training Fellow)

Isabel Huang-Doran (Cambridge MB PhD Programme)

Joshua Cook (MPhil; Gates Foundation)

Research summary

Reduced ability of insulin to lower blood glucose is known as insulin resistance. This is common, is closely associated with obesity, and is believed to drive numerous major diseases. We aim to understand how it occurs and how it is linked to diabetes, fatty liver, high blood fat levels, reduced fertility and cancer. To do this we focus on rare and severe disorders caused by changes in individual genes, including severe insulin resistance, low blood glucose, abnormal adipose tissue function and/or excess tissue growth. We study people with known genetic changes, looking for new causal genetic changes, investigating the changes we find in mice and cells, and undertaking experimental medicine studies and clinical trials in patients.. More recently such forward genetic approaches to severe phenotypes have been complemented by reverse genetic approaches, interrogating genes of interest in the rich and growing population-wide genetic datasets available nationally and internationally. 

Current research interests

The lab's work can be grouped by theme. The first is Insulin signalling: Insulin resistance (IR) due to insulin receptor or phosphoinositide 3-kinase (PI3K) mutations is used to test causal links among features of the metabolic syndrome. This has shown that primary IR lacks fatty liver, dyslipidaemia, and other hallmarks of the “common” IR, implying that some IR-related pathology is driven by increased insulin action. The lab also identified the first mutations activating intracellular insulin signalling to cause severe hypoglycaemia, establishing a new disease, guiding rational treatment, and providing a rare gain-of-function “experiment of nature” reciprocal to IR. The second theme is Adipose health: Adipose tissue buffers nutritional fluctuations to maintain metabolic health. The Semple lab investigates determinants of adipose resilience and ageing, stimulated by novel lipodystrophy/IR syndromes they have discovered or co-discovered. One such disorder of current interest is a mitochondrial cytopathy caused by MFN2 mutations that cause IR mediated by extreme adipose remodelling. Further interest is in IR/lipodystrophy caused by defects in DNA damage repair and/or centrosomal function. Collaborative studies identified that mutations in DNA polymerase delta cause a syndrome including severe IR and loss of muscle, bone and adipose tissue. The lab also showed that loss of NSMCE2, a SUMO ligase in the enigmatic SMC5/6 complex, of the pericentrosomal protein pericentrin, or of the centriolar protein POC1A, all cause dwarfism with extreme IR and lipodystrophic features. In aggregate with studies of the ciliopathy Alström syndrome these findings have consolidated evidence for a role of centrosomes in maintaining adipose health. The final theme is Mosaic overgrowth: The lab used exome sequencing opportunistically in collaboration with Prof Ines Barroso to identify mosaic PIK3CA mutations activating PI3K in devastating asymmetric overgrowth. It went on to assess the natural history of this family of disorders collaboratively, suggesting a disease classification, proposing consensus standards of care, and building a large patient cohort. In this cohort further novel mosaic genetic drivers of vascular overgrowth mediated by PI3K or RAS/MAPK pathway activation have been found. The group led an international repurposing study with colleagues in Dijon and at the NIH of sirolimus in PIK3CA-driven overgrowth, and instigated a pilot trial of another of PI3K inhibitor. A related drug was recently licensed in the USA. Given the complexity of modelling mosaic disease in vivo, the lab has more recently developed iPSC models which yielded fundamental insights into PI3K and stemness, and the importance of mutation dosage in modelling PI3K activation in cancer.

Past research interests

Hypogonadotrophic hypogonadism and regulation of puberty: After finding Kisspeptin receptor mutations causing pubertal failure opportunistically during my doctoral studies, my lab later collaborated with Prof Frank Reimann in characterisation of mutations in neurokinin B and its receptor identified by Prof Kemal Toplaglu in Adana Turkey. This gave critical insight into the poorly understood human GnRH pulse generator and pubertal initiation, and has motivated translational programmes developing small molecule neurokinin ligands for a variety of clinical indications.

Project activity

Massively Parallel Assays of Variant Effect (MAVEs) applied to insulin signalling genes (collaboration with Prof Greg Kudla)

The glut of genetic data emerging from exome and genome sequencing in diagnostic and population settings has greatly exacerbated the problem of “variants of unknown significance” (VUS). These are coding sequence variants whose effects, if any, on encoded protein function are unclear. VUS create a substantial signal-to-noise problem in rare disease genetic diagnosis. In collaboration with Prof Greg Kudla’s lab (MRC Human Genetics Unit) we have applied the approach of saturation mutagenesis to the insulin receptor gene, and have used massively parallel assays of variant effect (MAVEs) to assay the expression and signalling function of many thousands of the possible mutations simultaneously. We are currently addressing the potential of this approach to enhance diagnostic workflows, to inform structure function relationships, and to guide novel translational strategies to activate expressed but hypofunctional receptors.

 

Novel Approaches to Treatment of Insulin Receptoropathy (collaboration with Dr Gemma Brierley)

In people with biallelic loss-of-function mutations in the INSR gene often have extreme, life-limiting insulin resistance. In collaboration with Dr Gemma Brierley (Anglia Ruskin University, Cambridge) we are attempting to optimise monoclonal anti-receptor antibodies as candidate orphan therapies for such severe recessive receptoropathy, using studies in both cells and animals.

 

Mitochondrial Dysfunction and Lipodystrophy (collaboration with Prof David Savage)

Working with Prof David Savage’s lab (MRC Metabolic Diseases Unit, University of Cambridge) we were among the first groups to report a highly unusual form of insulin resistance and lipodystrophy caused by a specific mutation – R707W – in the MFN2 gene, encoding mitofusin 2. This lipodystrophy features loss of lower body fat and sometimes catastrophic hyperplasia of upper body fat, with paradoxically suppressed serum leptin concentrations despite overall increases in body fat. We believe that studying this condition will be informative about novel aspects of adipose tissue functional heterogeneity, and regulation of adipokine expression, as well as addressing major unmet clinical needs for affected patients. We are studying the condition at present in a novel animal model that we recently described with the Savage lab.

 

Mechanisms of Adipose Ageing

Metabolic health in the face of modern lifestyle requires healthy, dynamic adipose tissue. Ageing and loss of resilience of adipose tissue is believed to be one of the major determinants of insulin resistance and its sequelae, but mechanisms underlying this are unclear. We are addressing this issue by focusing on rare, informative monogenic disorders that feature premature adipose tissue loss due to defects in DNA replication and repair. Our main interest is in a rare form of lipodystrophy, combined with loss of lean mass, caused by heterozygous loss of function mutations in POLD1, encoding DNA polymerase delta. Our current mechanistic studies are based on cellular models including induced pluripotent stem cells.

 

Novel Forms of Severe Insulin Resistance

The lab continues to be interested in discovery and characterisation of novel forms of lipodystrophy and severe insulin resistance. Several such disorders, some identified in only one individual to date, are currently being addressed.

 

Alström Syndrome

Alström Syndrome is a complex, ultra rare recessive disease caused by loss of expression of the ALMS1 protein, a large protein which forms part of the structure of the basal body of primary cilia. We are specifically interested in disentangling the reasons for the early onset insulin resistance, adipose dysfunction and diabetes which are important elements of the syndrome, and understanding the relationship of these to severe, early fatty liver and heart failure. This work is currently being conducted in animal models in close collaboration with the NHS National Alström Syndrome clinical service in Birmingham.

 

Mechanisms of PIK3CA-driven mosaic overgrowth

The lab has spent 10 years helping to delineate the genotypic and phenotypic spectrum of asymmetric overgrowth disorders due to mosaic activating mutations in the PIK3CA gene. This group of disorders remains an area of active interest, with current effort focused on interrogating disease mechanism in induced pluripotent stem cell-based disease models (collaboration with Dr Ralitsa Madsen, MRC Protein Phosphorylation Unit, University of Dundee)

 

 

 

Current project grants

Research Grants
2022-23 LifeArc; Edinburgh Rare Disease Translational Research Pathfinder £500K (Co-Applicant)
2023-28 Diabetes UK Project Grant: Rational optimisation of agonistic INSR antibodies for the treatment of severe insulin resistance; £435K (Co-Investigator)
2019-24 British Heart Foundation (BHF) project grant: ABCC1-mediated corticosterone export protects from glucocorticoid-induced cardiometabolic toxicity;
£240K (Co-Investigator)
2022-25 CLOVES syndrome Community project grant: Zebrafish as a new tool to model CLOVES syndrome; £100K (Co-Investigator)
2021-22 CLOVES Syndrome Community project grant: “Human Pluripotent Stem Cells as a Model to Interrogate Pathogenesis and Developmental Origins of
CLOVES”; Amount of award $25K (P.I.)
2021-26 Wellcome Trust Multi-user Equipment Grant: “A facility for high resolution synchronised quantification of in vivo metabolism and behaviour”; Amount of
award £400K (P.I.)
2019-24 British Heart Foundation Edinburgh Centre of Research Excellence. Amount of Award: £3M (Co-I.)
2018-23 Wellcome Trust Senior Clinical Fellowship: “Causes and Consequences of Pathological Adipose Remodelling” Amount of Award: £1.9M (P.I.)

Current Training Grants
2021-24 Edinburgh-Karolinska-Glasgow Precision Medicine Doctoral Training Programme. Amount of award £10M (Lead applicant)
2019-24 CRUK TRACC Clinical PhD Programme. Amount of award £6M (Co-I.)

Past project grants

2016-19 Diabetes UK Project Grant: “Investigation of anti-insulin receptor antibodies as a potential therapy for extreme insulin resistance due to insulin receptor
mutations” Amount of Award: £280K (P.I.)
2012-17 Wellcome Trust Senior Clinical Fellowship (098498/Z/12/Z): “Genetic Dissection of Mechanisms Linking Insulin Resistance to Major Human Disease”
Amount of Award: £1.6M (P.I.)
2015 Pfizer provision of sirolimus for pilot study in segmental overgrowth. Amount of Award: £47K (P.I.)
2015 Diabetes & Wellness Foundation Project Grant: “Investigation of anti-insulin receptor antibodies as a potential therapy for genetic insulin receptoropathy”
Amount of Award: £20K (P.I.)
2015 NIHR Biomedical Research Centre Sequencing Grant: “Genome Sequencing in Segmental Overgrowth Disorders” Amount of Award: £100K (P.I.)
2015-17 NIHR Rare Disease Translational Research Collaboration: “Segmental Overgrowth due to Mosaicism for Mutations Activating Phosphatidylinositol-
3-Kinase Signalling” Amount of Award: £200K (P.I.)
2013-15 NIHR Rare Disease Translational Research Collaboration: “Segmental Overgrowth due to Activating Mutations in PIK3CA” Amount of Award: £200K (P.I.)
2007-12 Wellcome Trust Intermediate Clinical Fellowship (080952/Z/06/Z): “Clinical, cellular and molecular characterisation of novel syndromes of growth and
Insulin action” Amount of Award: £674,660 (P.I.)
2002-05 Wellcome Trust Clinical Research Training Fellowship (066765/Z/01/Z): “PPARalpha in the control of glucose and lipid metabolism in human cells”
Amount of Award: £166,794 (P.I.)

View all 66 publications on Research Explorer

Dr Vahid Aslanzadeh (postdoctoral research associate)

Dr Ineke Luijten (postdoctoral research associate)

Dr Gokhan Akman (postdoctoral research associate)

Dr Xiong Weng (postdoctoral research associate)

Sheldon D'Silva (PhD student)

Ami Onishi (Animal technician)

University of Edinburgh

Dr Dominique McCormick (postdoctoral research associate)

Dr Ralitsa Madsen  (postdoctoral research associate)

Dr Eleanor McKay  (PhD student)

 

University of Cambridge

Jian-Hua Chen (postdoctoral research associate)

Nuno Rocha (postdoctoral research associate)

Gemma Brierley (postdoctoral research associate)

Albert Kwok (postdoctoral research associate)

Ben Challis (clinical lecturer)

David Church (Clinical Research Training Fellow)

Patsy Tomlinson (PhD student)

Ralitsa Madsen (PhD student)

Kimjee Goh (PhD student)

Sarah Leiter (MB PhD student)

Victoria Parker (Clinical Research Training Fellow)

Marina Minic (PhD student)

Matthijs Groeneveld (PhD student)

Eric Wang (PhD student)

David Bulger (MB PhD student)

Eleanor Raffan (Clinical Research Training Fellow)

Isabel Huang-Doran (MB PhD student)

Laura Schmidt (MPhil student)

Alexandra Gast (MPhil student)

Joshua Cook (MPhil student)

Julie Harris (research nurse)

Claire Adams (research nurse)

Jenny Wilson (research nurse)

Cornelia Gewert (lab manager)

Rachel Knox (research assistant)

Bernat Elvira Jimenez (research assistant)

Danielle Newby (research assistant)

Iona Isaac (research assistant)

Belinda Smillie (research assistant)

Kathryn Cantone (research assistant)

Caroline Hyden (research assistant)

Keith Porter (research assistant)

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