Institute of Cellular Medicine

Staff Profile

Professor John Simpson

Dean of Translational Research & Professor of Respiratory Medicine, Newcastle University

Background

I am a member of the Respiratory Medicine Research Group

My research group is principally interested in understanding innate immune dysfunction in the setting of critical illness, with a view to developing biomarkers and novel treatments. Further details are found in the adjacent RESEARCH section. Selected publications are shown in the adjacent PUBLICATIONS section.

My clinical interests are in nosocomial infection (particularly pneumonia), pulmonary embolism and interstitial lung disease. I moved to Newcastle in 2010, having previously worked in the University of Edinburgh / MRC Centre for Inflammation Research, and in the Royal Infirmary of Edinburgh.

Current roles and responsibilities

Dean of Translational Research, Newcastle University

Clinical lead for academic respiratory medicine, Newcastle University

Director of the NIHR Diagnostic Evidence Cooperatives (DEC), Newcastle. DECs were established in order to improve methodological evaluation, and implementation into practice, of in vitro diagnostics (IVDs). The Newcastle DEC welcomes and encourages contact from IVD companies and from academics with an interest in developing IVDs.

I was previously Clinical Director of R&D in Newcastle upon Tyne Hospitals NHS Foundation Trust, 2013-February 2016.


Research

Our group’s work spans basic science, experimental medicine and randomised controlled trials (RCTs). The work focuses principally on innate immunity (with particular reference to neutrophil and monocyte function), and how this is impaired in critical illness.

We have identified biomarkers that effectively exclude ventilator-associated pneumonia in critically ill patients, and we are currently undertaking a multi-centre, randomised controlled trial (VAPRapid) to establish if these biomarkers can usefully influence antibiotic stewardship.

We have identified mechanisms by which neutrophils acquire a defect in phagocytic capacity during critical illness, and we have shown that this defect is independently associated with significantly increased risk of developing nosocomial infection in the intensive care unit (ICU). We have also described novel means by which to restore phagocytosis to normal (for example using GM-CSF), and we recently carried out an RCT (GRiP) of GM-CSF versus placebo in critically ill patients with evidence of impaired neutrophil phagocytosis.

Other related projects in the group include: studies of mitochondrial function during sepsis; regulation of neutrophil degranulation; biological effects of lipopolysaccharide (LPS) “mimics”; innate immune effects of inhaled LPS in human volunteers; and innate immune effects of surgical trauma.Newcastle upon Tyne Hospitals NHS Charities have recently funded a project expanding our LPS work to study endotoxaemia in healthy volunteers.

We also contribute to clinical research projects related to idiopathic pulmonary fibrosis and pulmonary embolism.

Collaborators

The VAPRapid project involves collaboration with investigators from multiple UK sites (Newcastle, Belfast, Birmingham, Chester, Coventry, Edinburgh, London (Chelsea & Westminster), Manchester, Newcastle, North Tyneside, Preston, Sunderland, Liverpool)

Our group is part of the MRC-funded SHIELD consortium, led by Prof David Dockrell in Edinburgh, which seeks to establish mechanisms of bacterial clearance by innate immune cells, and to establish ways of reducing antimicrobial resistance. The consortium brings together groups in Sheffield, Newcastle, Edinburgh and Birmingham

The GRiP project involved collaborations with ICUs in Gateshead, Newcastle and Sunderland

Other key collaborators include:

Professor Danny McAuley, Dr Cecilia O’Kane, Dr Ronan McMullan (Queen’s University Belfast)

Professor David Dockrell, Professor Steve Renshaw (Sheffield University)

Professor Adriano Rossi, Dr Donald Davidson, Dr Nik Hirani (Edinburgh University)

Dr Alistair Roy (Integrated Critical Care Unit, Sunderland)

Professor Paul Corris, Dr Tony De Soyza, Dr Ian Forrest, Dr Sophie West, Dr Stephen Bourke, Dr Patrick Kesteven, Professor Matt Collin, Professor John Dark, Dr Simon Baudouin, Dr Stephen Wright, Professor Muzz Haniffa (Newcastle University)


Grants as Lead Applicant (current and selected previous)

Current

Wellcome Trust/Department of Health Health Innovation Challenge Fund (HICF): Rapid detection and treatment of ventilator-associated pneumonia – towards improved antibiotic stewardship

NIHR Diagnostic Evidence Co-operative Award

Selected Previous

Sir Jules Thorn Charitable Trust Award for Biomedical Sciences 2003
Acute infective lung injury: towards cell therapy with antiprotease-infected monocytes.

Sir Jules Thorn Charitable Trust
A randomised controlled trial of monocyte depletion in acute neutrophil-mediated lung injury.

MRC Developmental Clinical Studies (DCS): Does GM-CSF restore effective neutrophil function in critically ill patients?


Abstracts for selected current work

Intravenous endotoxin challenge in healthy human volunteers

Sepsis is a life-threatening condition that arises when the body's response to infection injures its own tissues and organs. Every year the NHS deals with 150,000 cases of severe sepsis, and this results in a staggering 44,000 deaths. Human survival from infection requires an appropriate inflammatory response: an unbalanced, hyperinflammatory response predisposes patients to overwhelming inflammation and death in the early phase of sepsis, while protracted under-activity of the immune system is associated with organ dysfunction and heightened risk of infections and death in the late phase of sepsis.

Individuals can be divided simply into characteristic genetic categories (or haplogroups) based on the genes contained in their mitochondria (mitochondria are energy-producing components of cells, and interestingly they have a unique genetic code that is different from the "standard" genetic code found in nucleus of the cell). Each mitochondrial haplogroup is assigned and identified by a letter of the alphabet. An observational study performed in Newcastle suggested that patients with haplogroup H had a survival advantage in sepsis, and higher fevers, when compared with non-H haplogroups. Recent data from our laboratory suggest that mitochondrial genes regulate the expression of cell surface receptors on human white blood cells (monocytes), which in turn have a key influence on the early inflammatory response to LPS.

Previous research on sepsis has focused on the role of isolated molecules, often based on findings from animal models. This approach is becoming outdated, as it is clear that many cell types and molecules coordinate the response to sepsis, making it unlikely that "targeting" one will lead to useful new treatments. Furthermore, a growing body of research has recently questioned the validity of using mouse models (because the immune response differs fundamentally from the response in humans). Indeed, the human IV LPS model to be used here shows much greater correlation with genetic changes due to inflammatory stresses seen in human disease.

Injection of LPS, a non-infectious bacterial cell-wall product, is a well-recognised, safe, investigational technique that has been used experimentally for over 50 years. The dose used is adjusted to body weight to ensure a standardised reaction in all participants. While we recognise that administration of low dose endotoxin is not a clinical model of sepsis, it does represent a significant improvement in experimental modeling over animal studies. Human endotoxaemia reproduces the earliest features of the pathogenesis of sepsis (which are almost impossible to study in the clinical setting), paving the way to define mechanisms of pathogenesis, and potentially “drugable” targets.

Teaching

In 2009 I received an Edinburgh University Students' Association Teaching Award.

I regularly teach undergraduate medical students at Newcastle University

Current PhD/MD students 

I am lead supervisor for

Dr Tom Hellyer

Dr Jim Macfarlane

Dr John Widdrington

Dr Emma Browne

Dr Sarah Wiscombe

Dr Prosenjit Dutta

Dr Wendy Funston

Dr Kate Musgrave

Dr Jason Powell

I assist in the supervision of Dr Ben Prudon, Dr Carlos Echevarria, Dr Laura Jardine






Publications