Overview

Pluripotent stem cell biology

Pluripotency is the capacity of single cells to generate all cell types of the animal. This cellular plasticity is the foundation of mammalian development. In the embryo pluripotency is short-lived, but in vitro pluripotent stem cells may be propagated without limit. Pluripotent stem cells may remain in a naive undifferentiated state while retaining the ability to differentiate into multiple cell lineages including the germline. Our aims are:

1. to understand the conditions required to capture pluripotency from the early embryo;
2. to define the regulatory network that confers broad developmental competence;
3. to elucidate and take control of the mechanisms that direct alternative cell fates.

Collaboration with bioengineers, biophysicists, bioinformaticians and computational modellers is embedded in our research.  Our main interest is fundamental understanding. In addition, however, we aim to provide robust pluripotent stem cell platforms for biomedical applications and bioindustry.

Research Team

Group members

• Francesca Carlisle, Experimental Officer
• Tao Huang, Research Associate
• Zhili Ren, Research Associate 
• Somayyeh Tahajjodi, Research Assistant
• Zhi (Klein) Zhang, PhD Student 
• Jing Yen Yong, PhD Student
• Ethan Sung, PhD Student

Enquiries are welcome from prospective PhD students and post-doctoral researchers, including compuational biologists, bioengineers and bioinformaticians. 

Principal Investigator Profile

Austin Smith studied Biochemistry at the University of Oxford where he became fascinated by pluripotency. He pursued this interest in PhD studies with Prof Martin Hooper at the University of Edinburgh and post-doctoral research in Oxford with Prof John Heath.  Austin then joined the Centre for Genome Research in Edinburgh as a Group Leader. In 1995 he became Director of Centre which he transformed into the Institute for Stem Cell Research. In 2006 Austin moved to the University of Cambridge and was founding Director of the Cambridge Stem Cell Institute until 2016. In 2019 he took up the post of Director of the Living Systems Institute at the University of Exeter.

Qualifications

Degrees

BA (Hons), Biochemistry, University of Oxford, 1982
PhD, Developmental Genetics, University of Edinburgh, 1986

Awards

• 2000    Pfizer Academic Award, 'For pioneering work in the field of stem cell science'
• 2002    Ellison-Cliffe Medal, Royal Society of Medicine
• 2003    Fellow of the Royal Society of Edinburgh
• 2003    Medical Research Council Professor
• 2004    Member of the European Molecular Biology Organisation
• 2006    Fellow of the Royal Society of London
• 2010    Prix Louis-Jeantet de médicine
• 2010    Member of Academia Europaea
• 2016    McEwen Award for Innovation, International Society for Stem Cell Research

Career

• Feb 1986-May 1986   Research Assistant, Dept. Zoology, University of Oxford
• Jun 1986-Dec 1986    Postdoctoral Research Assistant, Dept. Zoology, University of Oxford
• Jan 1987-May 1990    Postdoctoral Research Assistant, Dept. Biochemistry, Oxford
• Jun 1990-Dec 1994    Group Leader, Centre for Genome Research, University of Edinburgh
• Jan 1995-Dec 1995    Acting Director, Centre for Genome Research, University of Edinburgh
• Jan 1996-Jul  2006     Reader, from 2001 Professor, University of Edinburgh
  •    1996-2005     Director, Institute for Stem Cell Research (formerly Centre for Genome Research)
  •    2004-2005     Director, MRC Centre Development in Stem Cell Biology
• Aug 2005-Jul 2020     Professor, Department of Biochemistry & Cambridge Stem Cell Institute, University of Cambridge
• Jan 2007-Mar 2016    Director, Wellcome Trust Centre for Stem Cell Research, later Wellcome-MRC Cambridge Stem Cell Institute
• Nov 2019 - present     Director, Living Systems Institute, University of Exeter

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Research

Research interests

Pluripotent Stem Cell Biology
Our research focusses on understanding the developmental and molecular foundations of pluripotency in vivo and derivative pluripotent stem cell states in vitro. We seek to uncover the basic rules that govern pluripotent stem cell behaviour and apply this knowledge to control their generation, self-renewal and lineage commitment. To identify generic principles and expose species-specific adaptations we compare pluripotent cells from rodents, humans and other mammals. Our overarching goal is to recapitulate ex vivo the developmental trajectory from an emergent naïve population, through acquisition of multi-lineage competence, to lineage specification.

Research projects

Current research grants:

• Medical Research Council Programme Grant – Human pluripotency
• ERC Advanced Grant – Plasticity of the pluripotency network

Prospective PhD projects

• I will be happy to consider potential PhD candidates in the field of pluripotent stem cell biology and early human development.
• Wellcome GW4-CAT PhD Programme for Health Professionals -  I welcome expressions of interest; two clinical fellows and one MB PhD student have previously completed successful PhDs in my research group.

Publications

ORCID 0000-0002-3029-4682; 223 journal articles; H-index 103 (Scopus, Jun 2022)

Current Preprints

• Branching topology of the human embryo transcriptome revealed by entropy sort feature weighting            www.biorxiv.org/content/biorxiv/early/2023/10/23/2023.10.12.562031.full.pdf

• ERK signalling orchestrates metachronous transition from naïve to formative pluripotency  www.biorxiv.org/content/biorxiv/early/2023/07/20/2023.07.20.549835.full.pdf

• Embryonic stem cells commit to differentiation by symmetric divisions following a variable lag period. bioRxiv, 2020.2006.2017.157578. 

Selected Recent Papers

• Radley, A., Corujo-Simon, E., Nichols, J., Smith, A., and Dunn, S.-J. (2023). Entropy sorting of single-cell RNA sequencing data reveals the inner cell mass in the human pre-implantation embryo. Stem Cell Reports, doi: 10.1016/j.stemcr.2022.09.007
• Guo, G., Stirparo, G.G., Strawbridge, S., Spindlow, D., Yang, J., Clarke, J., Dattani, A., Yanagida, A., Li, M.A., Myers, S., Özel, B.N., Nichols, J. and Smith, A. (2021). Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential. Cell Stem Cell, doi: 10.1016/j.stem.2021.02.025
• Kinoshita, M., Barber, M., Mansfield, W., Cui, Y., Spindlow, D., Stirparo, G.G., Dietmann, S., Nichols, J., and Smith, A. (2021). Capture of mouse and human stem cells with features of formative pluripotency. Cell Stem Cell, doi: 10.1016/j.stem.2020.11.005 
• Stirparo, G.G., Smith, A., and Guo, G. (2021). Cancer-Related Mutations Are Not Enriched in Naive Human Pluripotent Stem Cells. Cell Stem Cell 28, 164-169 e162, doi: 10.1016/j.stem.2020.11.014
• Kalkan, T., Bornelöv, S., Mulas, C., Diamanti, E., Lohoff, T., Ralser, M., Middelkamp, S., Lombard, P., Nichols, J. and Smith, A. (2019). Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency. Cell Stem Cell, 24, 785-801.e7 doi: 10.1016/j.stem.2019.03.017
• Rostovskaya, M., Stirparo, G. G. and Smith, A. (2019). Capacitation of human naïve pluripotent stem cells for multi-lineage differentiation. Development 146, doi: 10.1242/dev.172916

Review

• Smith, A. (2017). Formative pluripotency: the executive phase in a developmental continuum. Development 144, 365-373. doi: 10.1242/dev.142679

Past Highlights

• Smith, A. G., Heath, J. K., Donaldson, D. D., Wong, G. G., Moreau, J., Stahl, M. & Rogers, D. (1988). Inhibition of Pluripotential Embryonic Stem Cell Differentiation by Purified Polypeptides. Nature, 336, 688-690. doi:10.1038/336688a0
• Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Schöler, H. & Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell, 95, 379-391. doi:10.1016/S0092-8674(00)81769-9
• Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S. & Smith, A.G. (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655. doi:10.1016/S0092-8674(03)00392-1.
• Ying, Q.L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P. & Smith, A.G. (2008) The ground state of embryonic stem cell self-renewal. Nature 453, 519-523 doi:10.1038/nature06968.
• Takashima, Y. , Guo, G., Loos, R., Nichols, J., Ficz, G., Krueger, F., Oxley, D., Santos, F., Clarke, J., Mansfield, W., Reik, W., Bertone, P. & Smith, A. (2014) Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human. Cell 158, 1254-1269. doi:10.1016/j.cell.2015.06.052.

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External Engagement and Impact

Awards and Honours

• 2000    Pfizer Academic Award, 'For pioneering work in the field of stem cell science'
• 2002    Ellison-Cliffe Medal, Royal Society of Medicine
• 2003    Fellow of the Royal Society of Edinburgh
• 2003    Medical Research Council Professor
• 2004    Member of the European Molecular Biology Organisation
• 2006    Fellow of the Royal Society of London
• 2010    Prix Louis-Jeantet de médicine
• 2010    Member of Academia Europaea
• 2016    McEwen Award for Innovation, International Society for Stem Cell Research

Editorships and Editorial Boards

• Development, Editor, 2006-2018
• EMBO Molecular Medicine, Editorial Board, 2009-2015 
• The EMBO Journal, Editorial Board, 2011- present
• Stem Cell Reports, Editorial Board, 2013-present

Expert Groups

• Royal Society Working Group on Stem Cell Research and Therapeutic Cloning, 2000
• Academy of Medical Sciences Working Group on Interspecies Chimaeras, 2007
• EMBL Council Working Group on Human Embryonic Stem Cells and Embryo Research, 2020-21

Funding Panels

• The Wellcome Trust Molecular and Cell Panel (2000 – 2003)

Scientific Advisory Boards

• RIKEN Center for Developmental Biology, Kobe, Japan (2000 – 2015); Chair from 2007-2015
• University of Lund BMC Biomedical Centre, Lund, Sweden (2002-08)
• Ontario Institute for Cancer Research, Cancer Stem Cell Program, Toronto, Canada (2008-13)
• Global Center of Excellence (G-COE), Kyoto University, Japan (2009, 2012)
• RIKEN Advisory Council (RAC), Tokyo, Japan (2009, 2014, 2017, 2019).
• Stem Cell Institute for Regenerative Medicine, Erasmus University, Netherlands (2010)
• REVIVE Stem Cell Network, Paris, France (2011- present)
• Cell Fate and Cancer Programme, Centre for Genomic Regulation, Barcelona, Spain (2012)
• Wellcome Trust Sanger Institute Cellular Genetics Programme, Hinxton, UK (2014)
• Cell Therapy Catapult Academic Advisory Board, London, UK (2014-2018)
• Izmir Biomedicine and Genome Center, Dokuz Eylul University, Turkey (2015-2018)

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Teaching

BIO4041 - Stem cell biology lecture

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