Dr Tom Bird - Liver Disease and Regeneration

Honorary Consultant Hepatologist, University of Edinburgh and Royal Infirmary of Edinburgh

Wellcome Trust Intermediate Research Fellow

Introduction

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Hepatocytes are the key target for regenerative therapy for patients with liver disease. These cells show immense regenerative capacity but despite our current understanding of the mechanisms that control liver regeneration, no therapeutic breakthroughs have been achieved to date. Regeneration in other organs (e.g. gut) is now highly characterised, aided specifically by an understanding of the structural hierarchy of regenerating cells and their relationship to the tissue architecture. In hepatology, significant debate still exists regarding which cells regenerate, where they reside and how they are controlled. Specific regions of the liver regenerate in response to specific forms of injury. Our central hypothesis is that liver regeneration is orchestrated by a hierarchy within the hepatocyte population in both health and disease. This hierarchy is imposed by the local niche and bestows the ability to regenerate to some hepatocytes whilst preventing regeneration by others.

Our data indeed identifies that repeated hepatocyte division occurs principally in specific zones. We will dissect the role of the zonal niche in specifying hepatocellular regeneration in both health and injury, and its interaction with local inflammation. Wnt and TWEAK are two tractable candidate pathways involved in specifying and controlling hepatocellular regeneration. We are interrogating the role of these pathways in zonal hepatocellular regeneration with the aim of both improving our understanding of regeneration and to develop regenerative therapies for patients.


Exposing liver cancer

Read about Tom's collaboration with the University of Edinburgh's Centre for Statistics to improve early detection of liver cancer here.


 Other funding:
 
                              Wellcome Trust logo

 

 

 

 

Lab Report

icon Bird Lab Report

Key Publications

Bird TG, Muller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu WY, Jamieson T, Govaere O, Campbell AD, Ferreira-Gonzalez S, Cole AM, Hay T, Simpson KJ, Clark W, et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med 2018; 10: eaan1230 F1000

Bird TG, Dimitropoulou P, Turner RM, Jenks SJ, Cusack P, Hey S, Blunsum A, Kelly S, Sturgeon C, Hayes PC, Bird SM. Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection. PLoS One 2016; 11: e0156801.

Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, Guest RV, Wojtacha D, Man TY, Mackinnon A, Ridgway RA, Kendall T, Williams MJ, Jamieson T, Raven A, Hay DC, Iredale JP, Clarke AR, Sansom OJ, Forbes SJ. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17: 971-83.

Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, Taube J, Thomas JA, Wojtacha D, Gambardella A, Sansom OJ, Iredale JP, Forbes SJ. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. PNAS 2013; 110: 6542-7.

Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Medicine 2012; 18: 572-9.

Hsieh WC, Mackinnon AC, Lu WY, Jung J, Boulter L, Henderson NC, Simpson KJ, Schotanus B, Wojtacha D, Bird TG, Hay D, Medine C, Sethi T, Iredale JP, Forbes SJ. Galectin-3 regulates hepatic progenitor cell expansion during liver injury. Gut 2015; 64: 312-21.

Lorenzini S*, Bird TG*, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M, Alison MR, Iredale JP, Forbes SJ. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010; 59: 645-54.  *Joint first authorship

Biography

Education and qualifications

2015: Certificate of completion of training: Gastroenterology and Hepatology
2012: Specialty Certificate, Gastroenterology, Royal College of Physicians
2011: PhD, Liver Regeneration by Hepatic Progenitor Cells, University of Edinburgh
2005: MRCP, Medicine, Royal College of Physicians
2003: MA, Physiological Sciences, Oxford University
2002: BM BCh, Medicine, Oxford University
1999: BA (1st Class), Physiological Sciences, Oxford University

Appointments

2015: Honorary Consultant Hepatologist, Royal Infirmary of Edinburgh and Scottish Liver Transplant Unit
2013-2014: Hepatology Subspecialty Year, Royal Infirmary of Edinburgh
2011-2015: Clinical Lecturer in Hepatology, University of Edinburgh/Royal Infirmary of Edinburgh
2010-2011: ST Gastroenterology, Royal Infirmary of Edinburgh
2007-2010: Clinical Training Fellow, University of Edinburgh
2006-2007: Clinical Fellow, Royal Infirmary of Edinburgh
2005-2006: ST3 Renal and Liver Transplantation, Royal Infirmary of Edinburgh
2003-2005: Medical Senior House Officer, Western General Hospital, Edinburgh
2003: Surgical Pre-Registration House Officer, Royal United Hospital, Bath
2002-2003: Medical Pre-Registration House Officer, John Radcliffe Hospital, Oxford

Honours and awards

Andy Burroughs Young Investigator Award, 2015
British Society of Gastroenterology: Young Gastroenterologist of the Year - Clinical & Translational Science, 2015
Wellcome Trust Intermediate Clinical Fellowship, 2015
Wilfred Card Lectureship, 2014
Academy of Medical Sciences Start Grant for Clinical Lecturers, 2012
Sheila Sherlock Prize, 2011
ESOT Prize for scientific presentation, 2011
Anne Ferguson Prize, 2009
EASL travel bursary, 2009
Miss Urquart Charitable Trust Award, 2007
Wellcome Clinical Research Training Fellowship, 2007
BSG Travelling Fellowship, 2006
Griffith's Memorial Travelling Scholarship, 2001
Representative for the Queen's Award for Higher Education and Training, 2001
Martin Lawrence Memorial Scholarship, 2001
Paul Hayes Memorial Scholarship, 2000
Hobson Mann Oxford University Clinical Medical School Scholarship, 2000
Wronker dissertation prize, 1999

Recent Publications

2020

Müller M, Bird TG, Nault J-C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020; 72: 990-1002

Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, Perez-Garcia A, Kiourtis C, Dasgupta N, Lei X, Kruger PJ, Nixon C, Clark W, Jurk D, Bird TG, Passos JF, Berger SL, Dou Z, Adams PD. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes & development. 2020; 34: 428-445 

2019

Amoros R, King R, Toyoda H, Kumada T, Johnson PJ, Bird TG. A continuous-time hidden Markov model for cancer surveillance using serum biomarkers with application to hepatocellular carcinoma. Metron. 2019;77:67-86.

Drake TM, Bird TG. Editorial: simplifying screening for primary liver cancer - do the LCR1 and LCR2 tests hold the key? Alimentary pharmacology & therapeutics. 2019;49:612-613.

Gay DM, Ridgway RA, Mueller M, Hodder MC, Hedley A, Clark W, Leach JD, Jackstadt R, Nixon C, Huels DJ, Campbell AD, Bird TG, Sansom OJ. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nature communications 2019; 10: 723.

Liko D, Mitchell L, Campbell KJ, Ridgway RA, Jones C, Dudek K, King A, Bryson S, Stevenson D, Blyth K, Strathdee D, Morton JP, Bird TG, Knight JRP, Willis AE, Sansom OJ. Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas. Cell Death Differ. 2019; 26: 2535–2550

Muller M, Forbes SJ, Bird TG. Beneficial Noncancerous Mutations in Liver Disease. Trends in genetics. 2019; 35: 475-477

Teo YV, Rattanavirotkul N, Olova N, Salzano A, Quintanilla A, Tarrats N, Kiourtis C, Muller M, Green AR, Adams PD, Acosta JC, Bird TG, Kirschner K, Neretti N, Chandra T. Notch Signaling Mediates Secondary Senescence. Cell Rep 2019; 27: 997-1007

2018

Bird TG, Muller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu WY, Jamieson T, Govaere O, Campbell AD, Ferreira-Gonzalez S, Cole AM, Hay T, Simpson KJ, Clark W, et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med 2018; 10: eaan1230 F1000

Ferreira-Gonzalez S, Lu WY, Raven A, Dwyer B, Man TY, O'Duibhir E, Lewis PJS, Campana L, Kendall TJ, Bird TG, Tarrats N, Acosta JC, Boulter L, Forbes SJ. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat Commun 2018; 9: 1020

2017

Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM, Grellscheid SN, Hoeijmakers JHJ, Barnhoorn S, Mann DA, Bird TG, Vermeij WP, Kirkland JL, Passos JF, von Zglinicki T, Jurk D. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 2017; 8: 15691

Kelly S, Bird TG. The Evolution of the Use of Serum Alpha-fetoprotein in Clinical Liver Cancer Surveillance. J Immunobiol 2017; 1. pii: 1000116

2016

Bird TG, Dimitropoulou P, Turner RM, Jenks SJ, Cusack P, Hey S, Blunsum A, Kelly S, Sturgeon C, Hayes PC, Bird SM. Alpha-Fetoprotein Detection of Hepatocellular Carcinoma Leads to a Standardized Analysis of Dynamic AFP to Improve Screening Based Detection. PLoS One. 2016; 11: e0156801

Vidal V, Sacco S, Rocha AS, da Silva F, Panzolini C, Dumontet T, Thi Mai Phuong Doan, Shan J, Rak-Raszewska A, Bird T, Vainio S, Martinez A, Schedl A. The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3. Genes Dev 2016; 30: 1389-94

Lab Members

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Postdoctoral Scientists

Stephanie May
Miryam Mueller (Wellcome Trust)

Clinical Research Fellow

Tom Drake

PhD Students

Anastasia Georgakopoulou
Christos Kiourtis

Research

At the bench 3 160

Read more about the Research Groups working at the Beatson Institute.

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Seminars

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Find out more about our seminars including our Distinguished Seminar Programme.

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