Professor Peter Andrews

Peter AndrewsArthur Jackson Professor of Biomedical Science
Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Email: p.w.andrews@sheffield.ac.uk
Telephone: +44 (0) 114 222 4173
Room: E Floor Alfred Denny building

General

Career History

Department of Biomedical Science, University of Sheffield

  • Arthur Jackson Professor of Biomedical Science: 1992 - present
  • Chairman of Department 1995-2003

The Wistar Institute of Anatomy and Biology, Philadelphia:

  • Associate Professor: 1991 - 1992
  • Assistant Professor: 1983 - 1990
  • Research Associate: 1980 - 1982
  • Research Investigator: 1978 - 1979

Sloan-Kettering Institute, New York:

  • Research Fellow: 1976 - 1978

Institut Pasteur, Paris:

  • Research Fellow: 1974 - 1975

Research interests

The Biology of human Embryonic Stem Cells and their Malignant counterparts from Teratocarcinomas.

Activities and distinctions:

  • Chairman, Department of Biomedical Science, 1995 -2003.
  • Co-founder and Director, Axordia Ltd., A University Spin-out Company (now a subsidiary of Pfizer).
  • Director, Centre for Stem Cell Biology (CSCB)
  • Co-ordinator of ESTOOLS, a European FP6 Integrated Project  (2006 – 2010)

CSCB ESTOOLS

Other external activities

Current External Activities:

  • Editorial Boards:  Journal of. Anatomy, Stem Cells, Regenerative Medicine, Handbook of Stem Cells, Stem Cell Research, Stem Cells and Development.
  • Co-Director, Centre for Stem Cell Biology 2003 – present
  • Co-ordinator of the International Stem Cell Initiative 2003 – present
  • Director, Pluripotent Stem Cell Platform (a Hub under the UKRMP) 2014 - present
  • Member, UK Stem Cell Bank Advisory Board 2011 – present

Past:

  • 2008 Member MRC Translational Stem Cell Research Panel (July 2008 – 2013)
  • 2007 Member SAB for Stem Cells for Safer Medicines (SC4SM), a PPP company established by the DTI and the ABPI to develop applications of human ES cells in predictive toxicology (2007 – 2011).
  • 2010 SAB Bioprocessing Technology Institute, Biopolis, Singapore, 2010 - 2011.
  • 2009 Participant in MRC delegations to California (Jan 2009); to China (May 2009)
  • 2009 Member of INSERM review committee for INSERM Unit, I-Stem, Evry, Paris. Jan 2009
  • 2008 Invited Participant in UK FCO sponsored ‘Road Show on UK Human ES cell research, California, Feb 2008
  • 2007 Review panel for Canadian Stem Cell Network (Sept 2007).
  • 2007 Expert Review Panel for 21st Century Centre of Excellence Program, Kyoto University (Japan, June 2007)
  • 2006 Member Steering Committee for UK Toxicology Initiative July 2006 – 2007
  • 2006 Co-ordinated for MRC and CIRM a UK:California Stem Cell meeting, held in the UK Nov 2006.
  • 2006 Member, NIH National Stem Cell Bank, USA, 2006 - 2009
  • 2006 Elected Board Member, ISSCR, March 2006 to 2009
  • 2005 Member MRC Molecular Cell and Medicine Board April 2005- April 2010
  • 2005 Represented MRC in meeting with California Institute Regenerative Medicine, San Francisco April 2005

 Funding

  • European Union
  • UK Regenerative Medicine
  • MRC/International Stem Cell Forum

Selected Publications since 2014

  1. Isasi R, Andrews PW, Baltz JM, Bredenoord AL, Burton P, Chiu IM, Hull SC, Jung JW, Kurtz A, Lomax G, Ludwig T, McDonald M, Morris C, Ng HH, Rooke H, Sharma A, Stacey GN, Williams C, Zeng F, Knoppers BM.  2014 
    Identifiability and privacy in pluripotent stem cell research. 
    Cell Stem Cell.  14: 427-430
  2. Barbaric, I., Biga, V., Gokhale, P.J., Jones, M., Stavish, D., Glen,G., Coca, D., Andrews, P.W.  2014 
    Time-lapse analysis of human embryonic stem cells reveals multiple bottlenecks restricting colony formation and their relief upon culture adaptation. 
    Stem Cell Reports.  3: 142-155
  3. Ben-David U, Gal Arad1, Maimon A, Mandefro B, Weissbein U, Golan-Lev T, Narwani K, Clark AT, Andrews PW, Benvenisty N, Biancotti JC.  2014 
    Trisomy 12 induces profound changes in the global gene expression signature, cellular proliferation and tumorigenicity of human pluripotent stem cells. 
    Nature Communications 5: 4825
  4. Sutiwisesak R, Kitiyanant N, Kotchabhakdi N, Felsenfeld G, Andrews PW, Wongtrakoongate P.  2014 
    Induced pluripotency enables differentiation of human nullipotent embryonal carcinoma cells N2102Ep. 
    Biochim Biophys Acta. 1843: 2611-2619.
  5. Isasi R, Andrews PW, Baltz JM, Bredenoord AL, Burton P, Chiu IM, Hull SC, Jung JW, Kurtz A, Lomax G, Ludwig T, McDonald M, Morris C, Ng HH, Rooke H, Sharma A, Stacey GN, Williams C, Zeng F, Knoppers BM.  2014 
    Identifiability and privacy in pluripotent stem cell research. 
    Cell Stem Cell. 14: 427-30.
  6. Na J, Baker D, Zhang J, Andrews PW, Barbaric I.  2014 
    Aneuploidy in pluripotent stem cells and implications for cancerous transformation. 
    Protein Cell. 8: 569 -579
  7. 7Andrews P.W., Cavanagro J., Deans R., Feigel E., Horowitz E ., Keating A., Rao M., Turner M., Wilmut I.,  Yamanaka S.  2014 
    Harmonizing standards for producing clinical-grade therapies from pluripotent stem cells
    Nature Biotechnology 8: 724 – 726.
  8. Gokhale PJ, Au-Young JK, Dadi S, Keys DN, Harrison NJ, Jones M, Soneji S, Enver T, Sherlock J, Andrews PW  2015 
    Culture adaptation alters transcriptional hierarchies among single human embryonic stem cells reflecting altered patterns of differentiation. 
    PLoS One, 10:e0123467
  9. Jones, AJ, Gokhale, PJ, Allison, TF, Sampson, B, Athwal, S, Grant, S, Andrews, PW, Allen, ND, C Patrick Case, CP.  2015 
    Evidence for bystander signalling between human trophoblast cells and human embryonic stem cells.
    Sci Rep. 5: 11694.
  10. Andrews P, Baker D, Benvinisty N, Miranda B, Bruce K, Brüstle O, Choi M, Choi YM, Crook J, de Sousa P, Dvorak P, Freund C, Firpo M, Furue M, Gokhale P, Ha HY, Han E, Haupt S, Healy L, Hei Dj, Hovatta O, Hunt C, Hwang SM, Inamdar M, Isasi R, Jaconi M, Jekerle V, Kamthorn P, Kibbey M, Knezevic I, Knowles B, Koo SK, Laabi Y, Leopoldo L, Liu P, Lomax G, Loring J, Ludwig T, Montgomery K, Mummery C, Nagy A, Nakamura Y, Nakatsuji N, Oh S, Oh SK, Otonkoski T, Pera M, Peschanski M, Pranke P, Rajala K, Rao M, Ruttachuk R, Reubinoff B, Ricco L, Rooke H, Sipp D, Stacey G, Suemori H, Takahashi T, Takada K, Talib S, Tannenbaum S, Yuan BZ, Zeng F, Zhou Q.  2015 
    Points to consider in the development of seed stocks of pluripotent stem cells for clinical applications: International Stem Cell Banking Initiative (ISCBI). 
    Regen Med. 10(2 Suppl):1-44
  11. Heslop JA, Hammond TG, Santeramo I, Tort Piella A, Hopp I, Zhou J, Baty R, Graziano EI, Proto Marco B, Caron A, Sköld P, Andrews PW, Baxter MA, Hay DC, Hamdam J, Sharpe ME, Patel S, Jones DR, Reinhardt J, Danen EH, Ben-David U, Stacey G, Björquist P, Piner J, Mills J, Rowe C, Pellegrini G, Sethu S, Antoine DJ, Cross MJ, Murray P, Williams DP, Kitteringham NR, Goldring CE, Park BK. 2015 
    Concise Review: Workshop Review: Understanding and Assessing the Risks of Stem Cell-Based Therapies. 
    Stem Cells Transl Med. 4:389-400
  12. Desmarais JA, Unger C, Damjanov I, Meuth M, Andrews P  2016 
    Apoptosis and failure of checkpoint kinase 1 activation in human induced pluripotent stem cells under replication stress. 
    Stem Cell Research & Therapy 7:17-23
  13. Hoff AM, Alagaratnam S, Zhao S, Bruun J, Andrews PW, Lothe RA, Skotheim RI.  2016 
    Identification of Novel Fusion Genes in Testicular Germ Cell Tumors.
    Cancer Res. 76:108-116
  14. Burns AJ, Goldstein AM, Newgreen DF, Stamp L, Schäfer KH, Metzger M, Hotta R, Young HM, Andrews PW, Thapar N, Belkind-Gerson J, Bondurand N, Bornstein JC, Chan WY, Cheah K, Gershon MD, Heuckeroth RO, Hofstra RM, Just L, Kapur RP, King SK, McCann CJ, Nagy N, Ngan E, Obermayr F, Pachnis V, Pasricha PJ, Sham MH, Tam P, Berghe PV.  2016 
    White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. 
    Dev Biol on line April 2016.
  15. Baker D, Hirst AJ, Gokhale PJ, Juarez M, Williams S, Wheeler M, Bean K, Allison TF, Moore HD, Andrews PW, Barbaric I.  2016 
    Detecting genetic mosaicism in cultures of human pluripotent stem cells. 
    Stem Cell Reports, in press
  16. Damjanov I and Andrews PW  2016 
    Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice.  A histopathology atlas. 
    Int. J. Devel. Biology (special Issue) In Press

Research Overview

res01.jpgHuman embryonic stem cells (HESCs) are derived from the inner cell mass of the early embryo; the cells are genetically normal and retain in vitro both the ability to self renew and also to differentiate into each of the cell types found in the adult body. Such a system offers an in vitro model of human embryogenesis. Thus, a powerful resource now exists for the investigation of human developmental biology, the testing of candidate drugs for toxicology and efficacy and ultimately, tissue engineering for regenerative medicine.

The sensitivity of HESCs to biologically active factors and their developmental plasticity are attributes that confer upon them such great potential, but also present significant obstacles to their exploitation.

Many of these issues derive from an inadequate understanding of how HESCs regulate their self renewal and commitment to differentiation, and how these processes may be affected by the environment in which the cells are maintained.

Adaptation of Human embryonic Stem Cells to in vitro culture

In human ES cells, after prolonged culture, repetitive karyotypic changes have been noted (1, 2). These repetitive karyotypic changes are strikingly similar to the karyotypic abnormalities observed in Embryonal Carcinoma (EC) cells, which are the malignant stem cells of germ cell tumours.

Culture adapted ES cells may also show higher proliferative and cloning ability than their `normal´ early passage counterparts. Pluripotent ES cells in culture are subject to continual selection for genetic variants that increase the probability of `self-renewal´ and decrease the probability of differentiation or apoptosis. It also seems likely that EC cells in germ cell tumours are subject to similar selection pressures. Thus understanding the nature of the karyotypic and other genetic changes that occur in human ES cells in culture may give insights, not only into the genetic and molecular mechanisms that control self-renewal and commitment in these cells, but also give insights into the processes of cancer development and progression in germ cell tumours.

Embryonal Carcinoma (EC) Cells and Germ Cell Tumours

EC cells are the malignant stem cells of teratocarcinomas, a subset of germ cell tumours which occur predominantly as testicular cancers and are the most common cancers of young men. (3). EC cells are malignant counterparts of ES cells derived from human blastocysts. Human EC cells share some features in common with mouse ES and EC cells (e.g. expression of the transcription factors Oct4 and Nanog, and high levels of alkaline phosphatase) but they differ in other respects such as their distinct patterns of surface marker antigen expression. Neverthelesss, just as mouse EC and ES cells resemble the inner cell mass cells of the early mouse embryo at the blastocyst stage, so human EC cells resemble human ES cells and inner cell mass cells of early human blastocysts (4).

Over many years we have used EC cell lines as surrogates for the study of plurotent human ES cells and have used them to define a series of marker antigens for defining the undifferentiated EC phenotype (5) and for monitoring differentiation (6). These antigens are now widely used in the study of human ES cells (7). Human EC cell lines also remain relatively simple models for further studies with ES cells, since they can readily be grown in large numbers without the need for feeder cells or expensive media additives. Widely used lines include relatively nullipotent lines such as 2102Ep, useful in defining the phenotype of undifferentiated human EC and ES cells, and NTERA2 which differentiates extensively into neurons and other cells types when induced by agents such as retinoic acid (8). Studies in NTERA2 provided the first evidence of the dosage dependence of retinoic acid induction of HOX gene expression, in a way that appears to reflect the pattern of HOX gene expression along the anterior posterior axis of the developing embryo (9). In a different area of research, differentiatial susceptibility of undifferentiated and differentiated NTERA2 EC cells to replication of human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV) provides tools for investigating the interaction of these pathogenic viruses with human cells (10, 11).

Signalling pathways that contribute to the self-renewal and differentiation of human embryonic stem cells

Multiple signalling pathways contribute to maintenance of the undifferentiated state of ES cells and to controlling their commitment to differentiation. Relatively little is known about how specific pathways interact with each other in ES cells, but it is becoming evident that the relative importance of particular pathways may differ substantially between mouse and human ES cells. We are currently using a variety of approaches, including comparative studies of `normal´ and `adapted´ ES cells, as well as studies of human EC cells to identify particular signalling systems that contribute to self renewal and differentiation in human ES cells. Our specific areas of interest include the Notch and Wnt pathways as well as the role of TGFbeta superfamily members. Our techniques include the use of RNAi to modulate gene expression Using the latter technique , for exampole, we demomnstrated that, indeed, human EC and ES cells require the expression of Oct4 to maintain their undifferentiated state and that if its expression is knocked-down, differentiation towards trophectoderm ensues (12).

Differentiation of Human ES cells

Pluripotency of human ES cells is their property that offers such great potential for future applications. Human ES cells will spontaneously differentiate into a wide range of cell types but this process is difficult to control. Eventual applications will depend on understanding the mechanisms that control lineage selection once the cells commit to differentiate and developing protocols to make use of that knowledge. In our group we are specifically focussing on the mechanisms that regulate neural differentiation and differentiation toward pancreatic cells. Eventually these cell types could be used in regenerative medicine to treat a range of neurodegenerative diseases and diabetes. However, it is important to recognise that considerable research and development will be necessary before these goals can be realised.

The Centre for Stem Cell Biology

The Centre for Stem Cell Biology (CSCB), directed by Professors Peter W Andrews and Harry D Moore, brings together researchers in the University of Sheffield interested in the biology of human ES cells and in developing applications that involve these cells. Within the CSCB, we have derived six new human ES cell lines and are building a new cGMP facility that will enable us to derive new lines in the future to meet standards required for their future clinical applications. The CSCB also runs an annual training course in the culture of human ES cells, and can provide assistance to others who wish to establish human ES cell research in their own laboratories. For this we have specific funding from the MRC to operate a `Human ES Cell Resesource Centre´ to assist development of human ES cell research throughout the UK. As well as a variety of human ES cell lines, we also maintain various facilities such as a recently installed state-of-the-art Dakocytomation cell sorter.

The International Stem Cell Initiative (ISCI)

The ISCI is a study being carried out under the auspices of the International Stem Cell Forum. It includes a comparative study of surface antigen markers and gene expression patterns of up to 75 human ES cell lines from some 15 laboratories and 10 countries worldwide (13). It is expected to complete its work and issue a report by the end of 2005.