WIMM PI
CURRICULUM VITAE
Name:
Nationality:
E-Mail:
Andrew J.H. Smith
British
andrew.smith@ed.ac.uk;
andrew.smith@blackberry.orange.co.uk
Current Position
1995 - present
2010 - present
Group Leader (Genome Engineering Group) and Supervisor of the
Gene Targeting Laboratory at the Institute for Stem Cell Research
[ISCR] (formerly Centre for Genome Research) and the MRC Centre
for Regenerative Medicine, university of Edinburgh; and Senior
Lecturer, School of Biological Sciences, University of Edinburgh.
Staff Scientist at MRC Molecular Haematology Unit, Weatherall
Institute of Molecular Medicine, Oxford University.
Previous Positions
1981-1984
SRC/NATO Post-doctoral research at Stanford University
Biochemistry Department.
1985-1989
MRC Staff Scientist position in PNAC Division of the MRC Laboratory of
Molecular Biology.
1989-1995
Senior Research Fellow in PNAC Division of the MRC Laboratory
of Molecular Biology, supported by the National Foundation for
Cancer Research (NFCR) and Association of International
Cancer Research (AICR).
Research Achievements
The research programme has been mainly concerned with the innovation of
strategies for the genetic modification of mouse embryonic stem cells and
generation of transgenic animals, for application in functional genetic analysis,
disease modelling and stem cell biology. The most notable achievement was the
development of a Cre recombinase-mediated chromosome engineering strategy in
mouse
ES cells for large-scale segmental genome replacement to enable 'humanisation'
of the mouse genome in regions of well conserved synteny. This has the potential to
allow accurate tests of functional equivalence between mouse and human
sequence in ES cells and mice, and to facilitate the generation of more precise
mouse models of human genetic diseases.
More recent work has applied genetic modification strategies to human ES cell lines.
This work, which was undertaken as a component of an EU FP6 consortium project
and involved collaboration with groups in Dresden (Francis Stewart and Konstantinos
Anastassiadis) and Bonn (Frank Edenhofer), has resulted in the production of
several human ES cell lines with reporter knock- in integrations to monitor pluripotency
and lineage-specific differentiation.
Future Aims
Further development of technologies for ES cell genetic modification will continue with
emphasis in the following areas: 1) testing more efficient strategies for
‘humanisation’ of mouse ES cells; 2) generating human ES cell lines with multiple
reporter gene and other effector gene knock-ins to monitor and manipulate their invitro differentiation; 3) generating human ES cells with gene targeted mutations to
recapitulate diseases in-vitro. A further area of investigation will be to devise
strategies for genetic manipulation of human somatic cells ex-vivo, for example
reporter gene knock-ins into haematopoietic stem or progenitor cells for lineage
analysis.
In addition, there are several ongoing internal collaborative projects in the MRC
Molecular Haematology Unit with groups requiring application of ES cell genome
engineering technologies. An important ongoing external collaboration with Peter
Andrews (Centre for Stem Cell Biology, Sheffield University) is concerned with
investigating potential lineage-affiliated sub-states in populations of self- renewing
human ES cells. Other collaborations will involve working with colleagues in the MRC
Centre for Regenerative Medicine, University of Edinburgh, focused on projects
exploiting human ES cell genetic modification capability for directed in-vitro
differentiation into several cell lineages.
Contribution To Understanding And Management Of Human Disease
Human disease models in transgenic mice and recapitulation of human diseases
using in-vitro differentiated genetically modified human ES cells will in combination
provide the best experimental approach for investigating cooperating genetic and
environmental factors involved in diseases, and eventually facilitate experimental
platforms for development of drug therapies. Looking towards the future, therapeutic
approaches for treating inherited human diseases by gene targeted correction of
genetic defects in-vivo, or in ex-vivo cultured cells that can be used for autologous
transplantation, may become a real possibility with improvements in the efficiency of
vector delivery and homologous recombination. Ongoing work to improve vector
designs and gene targeting efficiency will place WIMM research groups in an optimal
position to develop such therapeutic approaches.
Lay Summary
In the last twenty years application of the sciences of molecular biology and genetics
has enabled us to acquire considerable knowledge of the basis of many human
diseases. However, there is still much more to learn, in particular in the case of
complex diseases involving contributing environmental factors. Furthermore, the
attempt to develop and apply rational molecular and genetic treatments has only
been partially successful despite considerable funding and experimental efforts.
This research programme seeks to improve our capability to model human
diseases in order to provide suitable experimental platforms for more extensive and
accurate testing of drug therapies.
Furthermore, a long term goal is to develop sophisticated genetic technologies to
enable correction of some genetic defects in human patients.
PUBLICATIONS OVER THE PAST 5 YEARS:
Vernimmen D, Marques-Kranc F, Sharpe JA, Sloane-Stanley JA, Wood WG,
Wallace HA, Smith AJH, Higgs DR. (2009). Chromosome looping at the human
alpha globin locus is mediated via the major upstream regularory element (HS 40). Blood 114: 4253-4260
Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI,
Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS,
Smith AJH, Batterham RL, Ashford MLJ, Vanhaesebroeck B, Withers D. (2009).
Dominant role of the p110β isoform of PI3K over p110α in energy homeostasis
regulation by POMC and AgRP neurons. Cell Metabolism 10: 343-354.
Meek, S., Buehr, M,. Sutherland, L., Thomson, A., Mullins, J.J., Smith, A.J.H. &
Burdon T. (2010) Efficient gene targeting by homologous recombination in rat ES
cells. PLoS One 5: e14225.
Lynch, M.D., Smith, A.J.H., De Gobbi, M., Flenley, M., Hughes, J.R., Vernimmen,
D., Ayyub, H., Sharpe, J.A., Sloane-Stanley, J.A., Sutherland, L., Meek, S.,
Burdon, T., Gibbons, R.J., Garrick, D. & Higgs, D.R. (2011) An interspecies
analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate
Polycomb complex recruitment. EMBO J, 31: 317-329.
Vernimmen D, Lynch M, De Gobbi, M., Garrick, D., Sharpe, J.A., Sloane-Stanley,
J.A,. Smith A.J.H. & Higgs, D.R (2011) Polycomb eviction as a new distant
enhancer function. Genes Dev, 25: 1583-1588.
Nowell, C.S., Bredenkamp, N., Tetélin, S., Jin, X., Tischner, C., Vaidya, H,.
Sheridan, J.M., Stenhouse, F.H., Heussen, R., Smith, A.J.H., Blackburn, C.C.
(2011) Foxn1 regulates lineage progression in cortical and medullary
thymic epithelial cells but
is dispensable for medullary sublineage
divergence. PLoS 7: e1002348
Devoy, A., Bunton-Stasyshyn, R.K.A., Tybulewicz, V.L.J., Smith A.J.H. & Fisher,
E.M.C. (2012) Genomically humanized mice: technologies and promise. Nature
Reviews Genetics 13: 14-20.
Rostovskaya, M.. Fu, J., Obst, M., Baer, I., Weidlich, S., Wang, H., Smith, A.J.H.,
Anastassiadis, K., Stewart, A.F. (2012) Transposon-mediated BAC transgenesis
in human ES cells. Nucleic Acids Research 40:e150.
Davies, O.R., Lin, C.Y., Radzisheuskaya, A., Zhou, X., Taube, J., Blin, G., Waterhouse, A.,
Smith, A.J.H., Lowell, S. (2013) Tcf15 primes pluripotent cells for differentiation. Cell
Reports 3: 472-484.
Zhou, X., Smith A.J.H., Waterhouse, A., Blin, G., Malaguti, M., Lin, C.Y., Osorno, R.,
Chambers, I., Lowell, S. (2013) Hes1 desynchronises differentiation of pluripotent cells by
modulating STAT3 activity. Stem Cells 31: 1511-1522.
10 KEY CAREER PUBLICATIONS:
Anderson, S., Bankier, A.T., Barrell, B.G., de Bruijn, M.H.L., Coulson, A.R., Drouin, J.,
Eperon, I.C., Nierlich, D.P., Roe, B.A., Sanger, F., Schreier, P.H., Smith, A.J.H.,
Staden, R. and Young, I.G. (1981). Sequence and organization of the human
mitochondrial genome. Nature 290: 457-465.
Warren, A.J., Colledge, W.H., Carlton, M.B.L., Evans, M.J., Smith, A.J.H. and Rabbitts,
T.H. (1994). The oncogenic cysteine-rich LIM domain protein Rbtn2 is essential for
erythroid development. Cell 78:45-57.
Nehls, M., Kyewski, B., Messerle, M., Waldschütz, R., Schüddekopf, K., Smith, A.J.H.
and Boehm, T. (1996). Two genetically separable steps in the differentiation of
thymic epithelium. Science 272: 886-889.
De Felipe, C., Herrero, J.F., O'Brien, J.A., Palmer, J.A., Doyle, C.A., Smith, A.J.H.,
Laird, J.M.A., Belmonte, C., Cervero, F. and Hunt, S.P. (1998). Altered nociception,
analgesia and aggression in mice lacking the receptor for substance P. Nature
392: 394-397.
Souslova, V., Cesare, P., Ding, Y., Akopian, A.N., Stanfa, L., Suzuki, R., Carpenter,
K., Dickenson, A., Boyce, S., Hill, R., Nebenius-Oosthuizen, Smith, A.J.H., Kidd, E.,
Wood, J.N. (2000). Warm- coding deficits and aberrant inflammatory pain in mice
lacking P2X3 receptors. Nature 407: 1015-1017.
Okkenhaug, K., Bilancio, A., Farjot, G., Priddle, H., Sancho, S., Peskett, E., Pearce,
W., Meek, S.E., Salpekar, A., Waterfield, M.D., Smith, A.J.H., Vanhaesebroeck, B.
(2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase
mutant mice. Science 297: 1031-1034.
Foukas, L.C., Claret, M., Pearce, W., Okkenhaug, K., Meek, S., Peskett, E.,
Sancho, S., Smith, A.J.H., Withers, D.J., Vanhaesebroeck, B. (2006). Critical role
for the p110alpha phosphoinositide-3- OH kinase in growth and metabolic
regulation. Nature 441: 366-370.
Wallace, H. A. C., Marques-Kranc, F., Richardson, M., Luna-Crespo, F., Sharpe, J.
A., Hughes, J., Wood, W. G., Higgs, D. R., Smith, A. J. H. (2007). Manipulating the
mouse genome to engineer precise functional syntenic replacements with
human sequence. Cell 128: 197-209.
Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ,
Pearce W, Meek S, Millan J, Cutillas PR, Smith AJH, Ridley AJ,
Gerhardt H, Vanhaesebroeck B. (2008). Angiogenesis selectively
p110C isoform of PI3K to control endothelial cell migration. Nature.
Salpekar A,
Ruhrberg C,
requires the
453: 662-6.
Devoy A, Bunton-Stasyshyn RKA, Tybulewicz VLJ, Smith AJH, Fisher EMC (2012).
Genomically humanised mice: technologies and promises. Nature Reviews
Genetics 13: 14-20.
Markers of Esteem
PATENTS
Co-inventor on European patent 'Methods for producing members for specific binding
pairs' filed 15/5/92 by Cambridge Antibody Technology Limited.
Winter,G.P., Johnson,K.S., Griffiths,A.D., & Smith,A.J.H. (1999) L.G.B.Medical
Research Council & M.G.B.Cambridge Antibody Technology Limited. Methods for
producing members of specific binding pairs. US Patent. 5,858,657. 480,006,
#13231
Patent application on ‘Humanisation’ of animals’. General publication ref
WO2008/081197; currently being prosecuted at national phase in EP and US territories.
Both in the examination phase (EP08701746.3 and US12/522235). Exclusively licensed on
a royalty bearing commercial basis to Taconic Farms Inc for the duration of the patent life.
Effective date 10th Mar 2011.
LICENSING INCOME
Income (~ £10,000 per annum) received from commercial licensing of p110 delta
kinase knock-in mutant mice (generated by ISCR Gene Targeting Lab in
collaboration with Ludwig Institute for Cancer Research).
ADMINISTRATION
Acting Head of ISCR 2005 - 2008.
RESEARCH COORDINATION
Workpackage Leader (WP3 - Recombination Tools and Genetic Switches) in
ESTOOLS EU FP6 consortium project ‘Advances with human embryonic stem cells’
2006 -2010
CONFERENCE ORGANISATION
Co-organised Company of Biologists Workshop ‘New technologies and applications
for genome engineering’ March 2012.
INVITED PARTICIPATION IN INTERNATIONAL TEACHING COURSES
Course Instructor on British Council sponsored practical course in Sao Paulo,
Brazil ‘ES cells as a model system for development’ February 2009.
Invited Lecturer on Wellcome Trust Advanced Course at Sanger Centre, Hinxton
‘Genetic Manipulation of ES cells’ November 2009, 2010.
Course Instructor on British Council sponsored practical course in Cuernavaca,
Mexico ‘ES cells as a model system for development’ March 2011.
Invited Lecturer on Eurosystems Summer School at Hydra September 2011
Current Research Grants
MRC award to MRC Molecular Haematology Unit for ‘Resource for innovation and
application of genetic engineering strategies in embryonic stem cells’ (reference MCUU-12009/10) initiated in April 2012 until 2100.