Prof Tom Bird - Liver Cancer, Disease and Regeneration
Honorary Consultant Hepatologist, University of Edinburgh and Royal Infirmary of Edinburgh
Wellcome Trust Intermediate Research Fellow
Introduction
Liver cancer is the third most common cause of cancer-related death worldwide. It is becoming an increasing problem, particularly in the Western world, and its rates have trebled in Scotland in the last 20 years. Despite some improvements in outcomes for those patients in whom the disease is detected early, there remains a limited range of only minimally effective treatment options for the overwhelming majority of patients who have their disease detected at a later stage. Precision medicine offers the potential to target more effective therapies to individuals with different forms of this disease, across this highly heterogeneous cancer.
My group has been interested in studying the regenerative responses to injury and aberrant proliferative responses in cancer of hepatocytes, the principle functional cell of the liver. These cells show immense regenerative capacity but are also the source of the most common primary liver cancer, hepatocellular carcinoma (HCC).
We have described how these cells enter a state of shock, named senescence, in response to injury, and how preventing them from doing so can promote liver regeneration. We are also investigating how this same senescent state occurs during early cancer formation as an anti- cancer therapeutic target.
To further understand these processes, we have developed a state-of-the-art suite of genetically engineered models of HCC, which mimics key features of the human condition. This suite is based upon the range of genetic mutations which drive HCC across the spectrum of human disease. Cross comparing between the models and patients we are able to identify novel pathways for therapy and some drug combinations which are highly effective in our cancer models. Working with academic and industrial collaborators, we are using these avatar-like models to uncover and test novel therapies, which could be used to target precision medicine dependent on the underlying characteristics of tumours in different patients.
EmailExposing liver cancer
Read about Tom's collaboration with the University of Edinburgh's Centre for Statistics to improve early detection of liver cancer here.
Lab Report
Key Publications
Nehme J, Borghesan M, Mackedenski S, Bird TG, Demaria M. Cellular senescence as a potential mediator of COVID-19 severity in the elderly. Aging Cell. 2020:e13237.
Müller M, Bird TG, Nault J-C. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020; 72: 990-1002
Hughes DM, Berhane S, Degroot ECA, Toyoda H, Tada T, Kumada T, Satomura S, Nishida N, Kudo M, Kimura T, Osaki Y, Kolamunage-Dona R, Salvador RA, Bird TG, Fiñana MG, Johnson P. Serum Levels of Alpha Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2020;19:162-170
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
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.
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
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.
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 
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
2020: Reader, University of Edinburgh
2016: Senior Lecturer, University of Glasgow
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
UEG Rising Star award, 2019 – annual award by United European Gastroenterology
Francis Avery Jones Medal Winner, 2019 – annual award by the British Society of Gastroenterology
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
2023
Krishna A, Meynert A, Kelder M, Ewing A, Sheraz S, Ferrer-Vaquer A, Grimes G, Becher H, Silk R, Semple CA, Kendall T, Hadjantonakis A-K, Bird T, Marsh JA, Hohenstein P, Wood AJ, Ozdemir DD. Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signalling and clinical traits. bioRxiv. 2023:2023.2011.2009.566307.
May S, Müller M, Livingstone CR, Skalka GL, Walsh PJ, Nixon C, Hedley A, Shaw R, Clark W, Voorde JV, Officer-Jones L, Ballantyne F, Powley IR, Drake TM, Kiourtis C, Keith A, Rocha AS, Tardito S, Sumpton D, Le Quesne J, Bushell M, Sansom OJ, Bird TG. Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration. J Hepatol. 2023; 78: 1028-1036
Moore M, Pardo L, Mitchell L, Schmidt T, May S, Mueller M, Strathdee D, Bryson S, Hodge K, Lilla S, Zanivan S, Waldron J, McGarry L, Peter-Durairaj R, Kanellos G, Nixon C, Ballantyne F, LeQuesne J, Sansom OJ, Bird T, Bushell M, Norman JC. The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation. bioRxiv. 2023;Volume:2023.2008.2016.553544.
Villar VH, Allega MF, Deshmukh R, Ackermann T, Nakasone MA, Vande Voorde J, Drake TM, Oetjen J, Bloom A, Nixon C, Müller M, May S, Tan EH, Vereecke L, Jans M, Blancke G, Murphy DJ, Huang DT, Lewis DY, Bird TG, Sansom OJ, Blyth K, Sumpton D, Tardito S. Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer. Nature Chemical Biology. 2023;19:292-300.
May S, Bird TG. How the liver keeps itself in shape. Elife. 2023;12.
2022
Humpton TJ, Hall H, Kiourtis C, Nixon C, Clark W, Hedley A, Shaw R, Bird TG, Blyth K, Vousden KH. p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl(4). Cell Death Differ. 2022;29:514-526.
Humpton TJ, Hock AK, Kiourtis C, De Donatis M, Fercoq F, Nixon C, Bryson S, Strathdee D, Carlin LM, Bird TG, Blyth K, Vousden KH. A noninvasive iRFP713 p53 reporter reveals dynamic p53 activity in response to irradiation and liver regeneration in vivo. Sci Signal. 2022;15:eabd9099.
Leslie J, Mackey JBG, Jamieson T, Ramon-Gil E, Drake TM, Fercoq F, Clark W, Gilroy K, Hedley A, Nixon C, Luli S, Laszczewska M, Pinyol R, Esteban-Fabró R, Willoughby CE, Haber PK, Andreu-Oller C, Rahbari M, Fan C, Pfister D, Raman S, Wilson N, Müller M, Collins A, Geh D, Fuller A, McDonald D, Hulme G, Filby A, Cortes-Lavaud X, Mohamed N-E, Ford CA, Raffo Iraolagoitia XL, McFarlane AJ, McCain MV, Ridgway RA, Roberts EW, Barry ST, Graham GJ, Heikenwälder M, Reeves HL, Llovet JM, Carlin LM, Bird TG, Sansom OJ, Mann DA. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 2022;10.1136/gutjnl-2021-326259:gutjnl-2021-326259.
Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2022;19:257–273
2021
Barthet VJA, Brucoli M, Ladds M, Nössing C, Kiourtis C, Baudot AD, O'Prey J, Zunino B, Müller M, May S, Nixon C, Long JS, Bird TG, Ryan KM. Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver. Sci Adv. 2021;7: eabf9141
Burton A, Tataru D, Driver RJ, Bird TG, Huws D, Wallace D, Cross TJS, Rowe IA, Alexander G, Marshall A. Primary liver cancer in the UK: Incidence, incidence-based mortality, and survival by subtype, sex, and nation. JHEP Rep. 2021;3(2):100232.
Haq MI, Drake TM, Goh TL, Ahmed A, Forrest E, Barclay S, Gillespie R, Priest M, Evans J, Graham J, Ballantyne S, McMillan DC, Hayes PC, Bird TG, Stanley AJ. Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study. J Clin Med. 2021;10:2770
Kiourtis C, Wilczynska A, Nixon C, Clark W, May S, Bird TG. Specificity and off-target effects of AAV8-TBG viral vectors for the manipulation of hepatocellular gene expression in mice. Biol Open. 2021; 10: bio058678
Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021.
Müller M, May S, Bird TG. Ploidy dynamics increase the risk of liver cancer initiation. Nat Commun. 2021;12:1896.
2020
Hughes DM, Berhane S, Degroot ECA, Toyoda H, Tada T, Kumada T, Satomura S, Nishida N, Kudo M, Kimura T, Osaki Y, Kolamunage-Dona R, Salvador RA, Bird TG, Fiñana MG, Johnson P. Serum Levels of Alpha Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2020;19:162-170
Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen L-A, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nature Metabolism. 2020; 2:1350–1367
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
Nehme J, Borghesan M, Mackedenski S, Bird TG, Demaria M. Cellular senescence as a potential mediator of COVID-19 severity in the elderly. Aging Cell. 2020:e13237.
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
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
