Professor Dean Nizetic, MD, PhD

Professor of Molecular Medicine

Email: d.nizetic@ntu.edu.sg
Principal Investigator, Mechanisms of Ageing and Diseases via Studying
Down Syndrome Laboratory

Introduction
Prof Dean Nizetic was born in Split, Croatia in 1959. He obtained his M.D. at the Faculty of
Medicine, University of Zagreb, Croatia, in 1982. He performed the experimental work for his
PhD thesis in Molecular Biology at the Max-Planck-Institute for Biology in Tuebingen,
Germany. He was a postdoc at the ICRF Genome Analysis Department in London (1987-1994).
From 1994, he is an independent group leader at Centre for Applied Molecular Biology, School
of Pharmacy, University of London (today UCL) where he becomes a Reader in 2000. From July
2001, he obtained a Chair in Cellular and Molecular Biology at Barts and The London School of
Medicine, Queen Mary University of London, and from February 2014 he starts in the position
of Professor of Molecular Medicine at Lee Kong Chian School of Medicine.
Prof Nizetic has become one of the leading researchers and opinion-makers in molecular
research into Down Syndrome (DS), in particular its relation to stem cell biology and cancer
(Nature Rev. Cancer 2012). Several results by Prof Nizetics group have produced paradigm
shifts in the definition of key pathogenic molecules and therapeutic targets in DS -associated
childhood leukaemia, (Lancet 2003, BJH 2004, Blood 2005, Oncogene 2010, Blood 2013). His
team also discovered the earliest molecular changes of DS in embryonic stem cells causing the
deregulation embryonic stem cell fate (Am J Hum Genet 2008, Mol Cell Proteomics 2009). This
work attracted media-attention including Press, live TV and Radio interviews, and support from
the UK National DS Association (see http://news.bbc.co.uk/1/hi/health/7597761.stm). Prof
Nizetic coordinated a work package on embryonic stem cell modelling within the 12 million
EU-FP6-Integrated Project "AnEUploidy.
Research Focus
Down syndrome: accelerated ageing and high incidence/severity of common diseases
Most phenotypic components that make up the clinical picture of DS or trisomy 21 (T21) occur
as separate important diseases in the general population, but have a markedly increased incidence
and severity in people with DS. From the geneticists/biologists point of view, studying trisomy
21 could in theory provide a back door entry into mechanisms and therapeutic targets for
cognitive impairment, ageing, Alzheimers Disease, diabetes, epilepsy, tumour suppression (but
susceptibility to childhood leukaemia), neuronal synapse plasticity, heart development,

immunodeficiency and other pathophysiological processes through the identification of specific

chromosome 21 genes (and mechanisms) whose dose imbalance cause these diseases.
New therapeutic concepts to help people with DS
For individuals with DS, until now, impaired cognition and later decline was considered
untreatable, but recently this view has changed radically as several research groups (including
Prof Nizetics), have started to dissect DS biology, showing that pathological phenotypes in
cellular models, and cognitive deficits in mouse models, can be treated using chemical
compounds. This has resulted in the first clinical trials in adults with DS for the improvement of
cognitive functions, such as the cognitive enhancement with GABA-A5 inverse agonists,
memantine and EGCG (alkaloid extracted from green tea). Deeper understanding of mechanisms
could lead to innovative therapeutic concepts for dementia in general population which is an
important public health domain. For example, in Singapore general population, impaired
cognition and dementia are on the rise, as increasing number of people reaches >65 age cohort,
and some studies predict prevalence of dementia to approximately double every 10 years
(http://www.alz.org.sg/about-dementia/statistics ).
Inter-disciplinary approach to study disease mechanisms via Downs syndrome (DS)
Recently, Prof Nizetic was one of the initiators of a worldwide-first-of-a-kind interdisciplinary
translational research consortium The London Downs syndrome Consortium (LonDownS): An
integrated system to study the development and therapeutic amelioration of cognition and
dementia, including UKs leading childhood and adult psychiatrist DS-specialists, mouse model
and human geneticists, as well as a representative of the DS associations. This consortiums
ambition is to make a significant transformative impact in understanding cognition in DS, by
studying the developmental roots of cognitive phenotypes in infants and study neuro-ageing in
young and older adults in order to explore the origins of Alzheimers dementia in DS. The
LonDownS consortium was awarded a 2.5 million Strategic Funding Award by The Wellcome
Trust in 2012 (http://www.ucl.ac.uk/londowns).
Prof Nizetic recently pioneered the concept of the developmental disturbance of embryonic stem
cell fate, accelerated cellular ageing, and specific actions of chromosome 21 genes for deeper
understanding of DS patho-mechanisms, causing dysbalance in availability of somatic stem cells
in foetal development and adult life (Am J Hum Genet 2008, Oncogene 2010, Nature Rev
Cancer 2012). The challenge for future research is to understand better how these and other
mechanisms cause co-morbidity and inverse co-morbidity between DS-associated diseases:
neurodevelopmental defects, Alzheimers dementia, susceptibility to childhood leukaemia (but
protection from other common childhood and adult cancers), diabetes, auto-immune diseases,
epilepsy, autism.
Prof Nizetic recently generated isogenic induced-pluripotent-Stem-cells (iPSC) by reprogramming the skin fibroblasts from an adult individual with mosaic DS, and then cloning

separately the genetically identical T21 and euploid (D21) iPSC lines. Prof Nizetic is leading the
iPSCcellular
modelling
stream
within
the
LonDownS
consortium
(see
http://www.ucl.ac.uk/londowns/research-themes/cellular). The focus of research in Singapore
will be to form an interdisciplinary consortium focussing on specific aspects of DS,
understanding basic mechanisms of developmental defects, but also involving clinicians and
other basic scientists, and propose to identify and involve in the study (with the help of local
associations that help people with DS) the individuals with DS that are characterized for
presence/absence of frequent DS disease components. One of the aims will be the development
of cellular tools/assays for screening for chemical compound that reverse/ameliorate the cellular
pathologies as a basis for therapeutic developments.
Key Publications
1. Aoife Murray, Audrey Letourneau, Claudia Canzonetta, Elisavet Stathaki, Stefania Gimelli,
Frederique Sloan-Bena, Robert Abrehart, Pollyanna Goh, Shuhui Lim, Chiara Baldo, Franca
Dagna-Bricarelli, Saad Hannan, Martin Mortensen, David Ballard, Denise Syndercombe Court,
Noemi Fusaki, Mamoru Hasegawa, Trevor G. Smart, Cleo Bishop, Stylianos E. Antonarakis,
Jrgen Groet*, and Dean Nizetic*
*co-corresponding, shared senior authors Isogenic induced pluripotent stem cell lines from an
adult with mosaic Down Syndrome model accelerated neuronal ageing and neurodegeneration.
Stem Cells, In Press 2015 Feb 19. doi: 10.1002/stem.1968. [Epub ahead of print] PMID:
25694335 [https://www.youtube.com/watch?v=MoMwXg2azGo]
2. Sergey I Nikolaev, Marco Garieri, Federico Santoni, Emilie Falconnet, Pascale Ribaux,
Michel Guipponi, Aoife Murray, Jrgen Groet, Emanuela Giarin, Giuseppe Basso, Dean Nizetic*
and Stylianos E Antonarakis*Sergey I Nikolaev, Marco Garieri, Federico Santoni, Emilie
Falconnet, Pascale Ribaux, Michel Guipponi, Aoife Murray, Jrgen Groet, Emanuela Giarin,
Giuseppe Basso, Dean Nizetic* and Stylianos E Antonarakis*
*co-corresponding, shared senior authors Frequent cases of RAS-mutated Down syndrome acute
lymphoblastic leukaemia lack JAK2 mutations. Nature Communications 5, Article number:
4654 doi:10.1038/ncomms5654, 8 August 2014. Sniffing out clues in Down syndrome The
Sunday Times, page 44 (feature article with photo of Prof Nizetic)
3. Dean Nizetic and Jurgen Groet; Tumorigenesis in Downs syndrome: big lessons from a small
chromosome.
Nature Reviews Cancer, October; 12(10):721-732 (2012). PMID: 22996602
Given a public interview on this subject for the free web series Faculti Media (see
http://facultimedia.com/medicine-tumorigenesis-in-downs-syndrome/
4. Serena De Vita, Claudia Canzonetta, Claire Mulligan, Frederic Delom, Jurgen Groet, Chiara
Baldo, Lesley Vanes, Franca Dagna-Bricarelli, Alex Hoischen, Joris Veltman, Elizabeth M. C.

Fisher, Victor L.J. Tybulewicz and Dean Nizetic. Trisomic dose of several chromosome 21 genes
perturbs haematopoietic stem and progenitor cell differentiation in Down Syndrome. Oncogene
Nov 18;29(46):6102-14 (2010). Highlighted in an Oncogene Editorial: Trisomy 21 leukemias:
Finding the hits that matter Oncogene (2010) 29, 60996101.
5. Claudia Canzonetta, Claire Mulligan, Samuel Deutsch, Sandra Ruf, Aideen ODoherty, Robert
Lyle, Christelle Borel, Nathalie Lin-Marq, Frederic Delom, Jrgen Groet, Felix Schnappauf,
Serena De Vita, Sharon Averill, John V. Priestley, Joanne E Martin, Janet Shipley, Gareth Denyer,
Charles J. Epstein, Cristina Fillat, Xavier Estivill, Victor L. J. Tybulewicz, Elizabeth M. Fisher,
Stylianos E. Antonarakis & Dean Nizetic
DYRK1A dosage imbalance perturbs NRSF/REST levels de-regulating pluripotency and
embryonic stem cell fate in Down syndrome. American Journal of Human Genetics Volume
83(3), 388-400, (2008).
Multiple interviews and articles in the media, see http://news.bbc.co.uk/1/hi/health/7597761.stm
6. Jrgen Groet, Claire Mulligan, Monica Spinelli, Anna Serra, Suzanne McElwaine, Finbarr E.
Cotter, Franca Dagna-Bricarelli, Giuseppe Saglio, Giuseppe Basso and Dean Nizetic.
Independent clones at separable stages of differentiation, bearing different GATA1 mutations in
the same TMD patient with Down Syndrome.
Blood, 106(5):1887-1888 (2005).
7. Aideen O Doherty, Sandra Ruf, Claire Mulligan, Victoria Hildreth, Mick L. Errington, Sam
Cooke, Abdul Sesay, Sonie Modino, Lesley Vanes, Diana Hernandez, Jacqueline M. Linehan,
Paul T. Sharpe, Sebastian Brandner, Timothy V.P. Bliss, Deborah J. Henderson, Dean Nizetic,
Victor L.J. Tybulewicz, Elizabeth M.C. Fisher Aideen O Doherty, Sandra Ruf, Claire Mulligan,
Victoria Hildreth, Mick L. Errington, Sam Cooke, Abdul Sesay, Sonie Modino, Lesley Vanes,
Diana Hernandez, Jacqueline M. Linehan, Paul T. Sharpe, Sebastian Brandner, Timothy V.P.
Bliss, Deborah J. Henderson, Dean Nizetic, Victor L.J. Tybulewicz, Elizabeth M.C. Fisher. An
Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes.
Science, 309(5743):2033-2037, 23rd September (2005).
Chosen as top scientific breakthrough of the year by The Guardian
http://www.theguardian.com/science/2005/dec/30/research.stemcells
8. Jrgen Groet, Suzanne McElwaine, Monica Spinelli, Andrea Rinaldi, Ingo Burtscher, Claire
Mulligan, Afua Mensah, Simona Cavani, Franca Dagna-Bricarelli, Giuseppe Basso, Finbarr E
Cotter, Dean Nizetic; Acquired mutations in GATA1 in neonates with Down syndrome with
Transient Myeloid Disorder. Lancet, 361:1617-1620 (2003).
9. M. Hattori, A. Fujiyama, T. D. Taylor, H. Watanabe, T. Yada, H.-S. Park, A. Toyoda, K. Ishii,
Y. Totoki, D.-K. Choi, E. Soeda, M. Ohki, T. Takagi, Y. Sakaki, S. Taudien, K. Blechschmidt, A.
Polley, U. Menzel, J. Delabar, K. Kumpf, R. Lehmann, D. Patterson, K.Reichwald, A. Rump, M.

Schillhabel, A. Schudy, W. Zimmermann, A. Rosenthal, J. Kudoh, K. Shibuya, K. Kawasaki, S.

Asakawa, A. Shintani, T. Sasaki, K. Nagamine, S. Mitsuyama, S. E. Antonarakis, S. Minoshima,
N. Shimizu, G. Nordsiek, K. Hornischer, P. Brandt, M. Scharfe, O. Schn, A. Desario, J.
Reichelt, G. Kauer, H. Blcker, J. Ramser, A. Beck, S. Klages, S. Hennig, L. Riesselmann, E.
Dagand, S. Wehrmeyer, K. Borzym, K. Gardiner, D. Nizetic, F. Francis, H. Lehrach, R.
Reinhardt & M.-L. Yaspo;
The DNA sequence of human chromosome 21. Nature 405, 311 - 319 (2000).
The second human chromosome to be completely sequenced. D.Nizetic is the only co-author
from the UK on the work.
10. Juergen Groet, Jane H.Ives, Andrew P.South, Pedro R. Baptista, Tania A. Jones, Marie-Laure
Yaspo, Hans Lehrach, Marie-Claude Potier, Christine Van Broeckhoven & Dean Nizetic;
Bacterial contig map of the 21q11 region associated with Alzheimers disease and abnormal
myelopoiesis in Down syndrome. Genome Research, 8:385-398 (1998).