Professor Dean Nizetic

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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

Laboratory Staff

  • Ms Yeap Yee Jie, MSc, Research Associate
  • Dr Reinhard Brunmeir, Senior Research Fellow
  • Dr Xiaowei Shao, PhD, Research Fellow
  • Dr Aoife Murray, PhD, William Harvey Res Institute Academy Fellow
  • Dr David Koschut, PhD, Research Fellow
  • Dr Ivan Alic, PhD, Research Fellow
  • Mr Wu Kanxing, Research Fellow
  • Aaron Lal Zo Thanga, MBBS, NTU-RSS PhD student
  • Gillian Gough, PhD student
  • Xiaomeng Xu, MD, PhD student

 

Competitive Research Grants Awarded

  • MOE T1 [2014-T1-001-173]
  • MOE T2 [2015-T2-1-023]
  • NTU-RSS PhD studentship [FY15030TIER2LCKMDN]
  • NMRC-CSIRG [2015-CIRG15may040]
  • MOE T2 [2015-T2-2-119]
  • William Harvey Research Institute Academy Fellowship (to Dr. A.Murray)

 

Introduction

Professor 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, 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 started 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 Nizetic’s 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, Nature Comm. 2014). 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. 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 Down’s syndrome (DS)

Recently, Prof Nizetic was one of the initiators of a worldwide-first-of-a-kind interdisciplinary translational research consortium “The London Down’s syndrome Consortium (LonDownS): An integrated system to study the development and therapeutic amelioration of cognition and dementia”, including UK’s leading childhood and adult psychiatrist DS-specialists, mouse model and human geneticists, as well as a representative of the DS associations. This consortium’s 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 Alzheimer’s 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 generated isogenic induced-pluripotent-Stem-cells (iPSC) by re-programming the skin fibroblasts from an adult individual with mosaic DS, and then cloning separately the genetically identical T21 and euploid (D21) iPSC lines (Stem Cells 2015). Prof Nizetic is leading the iPSC–cellular modelling stream within the LonDownS consortium(see http://www.ucl.ac.uk/londowns/research-themes/cellular). The challenge for future research is to understand better how trisomy 21 driven mechanisms cause co-morbidity and inverse co-morbidity between DS-associated diseases: neurodevelopmental defects, Alzheimer’s dementia, susceptibility to childhood leukaemia (but protection from other common childhood and adult cancers), diabetes, auto-immune diseases, epilepsy, autism.
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. 

  

 
 

 LKCMedicine Research Spotlight

 
 

Key Publications

  1. Murray, A., Letourneau, A., Canzonetta, C., Stathaki, E., Gimelli, S., Sloan-Bena, F., Abrehart, R., Goh, P., Lim, S., Baldo, C., Dagna-Bricarelli, F., Hannan, S., Mortensen, M., Ballard, D., Syndercombe Court, D., Fusaki, N., Hasegawa, M., Smart, T. G., Bishop, C., Antonarakis, S. E., Groet, J.* and Nizetic, D.* (2015), Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration. Stem Cells, 33: 2077–2084. doi:10.1002/stem.1968 [https://www.youtube.com/watch?v=MoMwXg2azGo]
  2. Nikolaev, S.I., Garieri, M., Santoni, F.,  Falconnet,  E.,  Ribaux,  P., Guipponi, M.,  Murray,  A., Groet,  J., Giarin, E., Basso, G., Nizetic, D.*, Antonarakis,  S.E.* Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nature Communications  5, 4654 doi: 10.1038/ncomms5654, 8 August 2014;  PMID: 25105841. “Sniffing out clues in Down syndrome” The Sunday Times, page 44 (feature article with interview and photo of Prof Nizetic)
     
  3. Nizetic, D. and Groet,  J. and Jurgen Groet; Tumorigenesis in Down’s 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. De Vita, S., Canzonetta, C., Mulligan C., Delom, F., Groet, J., Baldo, C., Vanes, L., Dagna-Bricarelli, F., Hoischen, A., Veltman, J., Fisher, E.M., Tybulewicz, VL. and Nizetic, D. 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, 6099–6101.
  5. Canzonetta C, Mulligan C, Deutsch S, Ruf S, O'Doherty A, Lyle R, Borel C, Lin-Marq N, Delom F, Groet J, Schnappauf F, De Vita S, Averill S, Priestley JV, Martin JE, Shipley J, Denyer G, Epstein CJ, Fillat C, Estivill X, Tybulewicz VL, Fisher EM, Antonarakis SE, Nizetic D. 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. Groet J, Mulligan C, Spinelli M, Serra A, McElwaine S, Cotter FE, Dagna-Bricarelli F, Saglio G, Basso G, Nizetic D. 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. O'Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TV, Henderson DJ, Nizetic D, Tybulewicz VL, Fisher EM. 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. Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE, Nizetic D. Acquired mutations in GATA1 in neonates with Down syndrome with Transient Myeloid Disorder. Lancet, 361:1617-1620 (2003).
  9. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML; Chromosome 21 mapping and sequencing consortium.;   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. Groet J, Ives JH, South AP, Baptista PR, Jones TA, Yaspo ML, Lehrach H, Potier MC, Van Broeckhoven C, Nizetic D. Bacterial contig map of the 21q11 region associated with Alzheimer’s disease and abnormal myelopoiesis in Down syndrome. Genome Research, 8:385-398 (1998).