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Dean Nizetic




Professor Dean Nizetic
MD, PhD
Professor of Molecular Medicine
Principal Investigator, Mechanisms of Ageing and Diseases via Studying Down Syndrome Laboratory
Research Programme: Neuroscience & Mental Health​
 

Team

  • Ms Yeap Yee Jie, MSc, Research Associate
  • 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
  • Aaron Lal Zo Thanga, MBBS, NTU-RSS PhD student
  • Gillian Gough, PhD student
  • Xiaomeng Xu, MD, PhD student​


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 was an independent group leader at Centre for Applied Molecular Biology, School of Pharmacy, UCL, where he became 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.,.He assumed his current position of Professor of Molecular Medicine at Lee Kong Chian School of Medicine in February 2014.
 
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 here). Prof Nizetic coordinated a work package on embryonic stem cell modelling within the €12 million EU-FP6-Integrated Project "AnEUploidy”.​

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)​
    MOE T3 [2017-T3-1-002] (Co-I)


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.
 
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 (see here).

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 here). 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.

Isogenic induced pluripotent stem cell.jpgHuman cerebral organoids grown in vitro from an isogenic induced pluripotent stem cell (iPSC) model of trisomy 21 developed by the Nizetic Lab  showing both neurons (Map2+) and astrocytes (GFAP+) in the cortical layer of the organoid. These organoids are currently used to understand the pathogenesis of Alzheimer’s dementia.
​ 

Selected Publications

Nizetic D, Chen CL, Hong W, et al. (2015). Inter-dependent mechanisms behind cognitive dysfunction, vascular biology and Alzheimer’s dementia in Down syndrome: multi-faceted roles of APP. Frontiers in Behavioural Neuroscience. Dec 1;9:299.

Murray A., Letourneau A., ... Nizetic D. (2015). IsogenicInduced Pluripotent Stem Cell Lines From an Adult With Mosaic Down SyndromeModel Accelerated Neuronal Ageing and Neurodegeneration. Stem Cells. 33(6): 2077–84. [More here.]

Nikolaev SI, Garieri M, ...Nizetic D*, & Antonarakis SE* (2014). Frequent casesof RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2mutations. Nature Communications. 5, 4654. (*Shared senior authors) [Featured in The Sunday Times, p44: Sniffing out clues in Down syndrome]

Nizetic D, & Groet J. (2012). Tumorigen​esis in Down’s syndrome: big lessons from a smallchromosome. Nature Reviews Cancer. 12(10):721-32.

De Vita S, Canzonetta C, ... Nizetic, D. (2010). Trisomic dose of several chromosome 21 genesperturbs haematopoietic stem and progenitor cell differentiation in Down Syndrome. Oncogene. 29(46):6102-14. [Highlighted in Oncogene Editorial: “Trisomy 21 leukemias: Finding the hits that matter.” Oncogene. 29:6099–101.]

Canzonetta C, Mulligan C, ... Nizetic D. (2008). DYRK1A dosage imbalanceperturbs NRSF/REST levels de-regulating pluripotency and embryonic stem cellfate in Down syndrome. American Journal of Human Genetics.  83(3):388-400. [More here.]


O'Doherty A, Ruf S, ... Nizetic D, et al. (2005). An Aneup​loid Mouse Strain Carrying HumanChromosome 21 with Down Syndrome Phenotypes. Science. 309(5743):2033-2037. [Chosen as top scientific breakthrough of the year by The Guardian.]

Groet J, McElwaine S, ... Nizetic D. (2003). Acquired mutations in GATA1 in neonates with Down syndrome with Transient MyeloidDisorder. The Lancet. 361:1617-1620.

Hattori M, Fujiyama A, ... Nizetic D &, Chromosome 21 Mapping and Sequencing Consortium (2000). The DNA sequence of human chromosome 21Nature. 405:311- 9.
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