The Garvan Institute of Medical Research was founded in 1963 by the Sisters of Charity. Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with approximately 650 scientists, students and support staff. The current director is Prof John Mattick.Garvan's research is focused on the major diseases that affect today's society: cancer, diabetes, osteoporosis, Alzheimer's disease, Parkinson's disease; as well as eating disorders, and autoimmune and inflammatory conditions such as rheumatoid arthritis and asthma. It specialises in genetic and molecular technologies, and emphasises collaborative research.In 2014 the Institute became one of only three organisations in the world – and the only one outside the United States – able to sequence the human genome at a base cost below $US1,000 each when it purchased the next generation of genome sequencing equipment, which is capable of sequencing 350 genomes a week . Wikipedia.
Garvan Institute of Medical Research | Date: 2017-07-26
The present disclosure provides methods and reagents for the diagnosis, prognosis or the monitoring of breast cancer, including various subtypes of breast cancer including, for example, estrogen receptor (ER) negative breast cancer, ER positive breast cancer, triple negative breast cancer (TNBC) and other subtypes of breast cancer.
Morris K.V.,University of New South Wales |
Morris K.V.,Scripps Research Institute |
Mattick J.S.,Garvan Institute of Medical Research |
Mattick J.S.,University of New South Wales
Nature Reviews Genetics | Year: 2014
Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective. © 2014 Macmillan Publishers Limited. All rights reserved.
Vissel B.,Garvan Institute of Medical Research
Acta neuropathologica communications | Year: 2014
The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aβ) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of Aβ deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aβ oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for Aβ in AD. We conclude it is essential to expand our view of pathogenesis beyond Aβ and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.
Mercer T.R.,Garvan Institute of Medical Research |
Mattick J.S.,Garvan Institute of Medical Research
Genome Research | Year: 2013
An expansive functionality and complexity has been ascribed to the majority of the human genome that was unanticipated at the outset of the draft sequence and assembly a decade ago. We are now faced with the challenge of integrating and interpreting this complexity in order to achieve a coherent view of genome biology. We argue that the linear representation of the genome exacerbates this complexity and an understanding of its three-dimensional structure is central to interpreting the regulatory and transcriptional architecture of the genome. Chromatin conformation capture techniques and high-resolution microscopy have afforded an emergent global view of genome structure within the nucleus. Chromosomes fold into complex, territorialized three-dimensional domains in concert with specialized subnuclear bodies that harbor concentrations of transcription and splicing machinery. The signature of these folds is retained within the layered regulatory landscapes annotated by chromatin immunoprecipitation, and we propose that genome contacts are reflected in the organization and expression of interweaved networks of overlapping coding and noncoding transcripts. This pervasive impact of genome structure favors a preeminent role for the nucleoskeleton and RNA in regulating gene expression by organizing these folds and contacts. Accordingly, we propose that the local and global three-dimensional structure of the genome provides a consistent, integrated, and intuitive framework for interpreting and understanding the regulatory and transcriptional complexity of the human genome. © 2013, Published by Cold Spring Harbor Laboratory Press.
Cannons J.L.,Human Genome Research Institutes |
Tangye S.G.,Garvan Institute of Medical Research |
Schwartzberg P.L.,Human Genome Research Institutes
Annual Review of Immunology | Year: 2011
The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia. SAP consists almost entirely of a single SH2 protein domain that interacts with the cytoplasmic tail of SLAM and related receptors, including 2B4, Ly108, CD84, Ly9, and potentially CRACC. SLAM family members are now recognized as important immunomodulatory receptors with roles in cytotoxicity, humoral immunity, autoimmunity, cell survival, lymphocyte development, and cell adhesion. In this review, we cover recent findings on the roles of SLAM family receptors and the SAP family of adaptors, with a focus on their regulation of the pathways involved in the pathogenesis of XLP and other immune disorders. © 2011 by Annual Reviews. All rights reserved.
Barry G.,Garvan Institute of Medical Research
Molecular Psychiatry | Year: 2014
Regulatory RNA is emerging as the major architect of cognitive evolution and innovation in the mammalian brain. While the protein machinery has remained largely constant throughout animal evolution, the non protein-coding transcriptome has expanded considerably to provide essential and widespread cellular regulation, partly through directing generic protein function. Both long (long non-coding RNA) and small non-coding RNAs (for example, microRNA) have been demonstrated to be essential for brain development and higher cognitive abilities, and to be involved in psychiatric disease. Long non-coding RNAs, highly expressed in the brain and expanded in mammalian genomes, provide tissue- and activity-specific epigenetic and transcriptional regulation, partly through functional control of evolutionary conserved effector small RNA activity. However, increased cognitive sophistication has likely introduced concomitant psychiatric vulnerabilities, predisposing to conditions such as autism and schizophrenia, and cooperation between regulatory and effector RNAs may underlie neural complexity and concomitant fragility in the human brain. © 2014 Macmillan Publishers Limited.
Mercer T.R.,University of Queensland |
Mattick J.S.,Garvan Institute of Medical Research
Nature Structural and Molecular Biology | Year: 2013
Genomes of complex organisms encode an abundance and diversity of long noncoding RNAs (lncRNAs) that are expressed throughout the cell and fulfill a wide variety of regulatory roles at almost every stage of gene expression. These roles, which encompass sensory, guiding, scaffolding and allosteric capacities, derive from folded modular domains in lncRNAs. In this diverse functional repertoire, we focus on the well-characterized ability for lncRNAs to function as epigenetic modulators. Many lncRNAs bind to chromatin-modifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modulating chromatin states and impacting gene expression. Considering this regulatory potential in combination with the abundance of lncRNAs suggests that lncRNAs may be part of a broad epigenetic regulatory network. Copyright © 2013 Nature America, Inc.
Cole A.R.,Garvan Institute of Medical Research
FEBS Journal | Year: 2013
The dominant genetic and environmental causes of mood disorders and schizophrenia have not been forthcoming, so alternative approaches are required to elucidate the mechanisms underlying these diseases and to develop improved treatments for use in the clinic. Pharmacological evidence implicates glycogen synthase kinase 3 (GSK3) as a key target of current therapeutics, and this is well supported by genetic studies in animal models. Several upstream regulators of GSK3 are also genetically associated with mood disorders and schizophrenia, further suggesting convergence on GSK3 signalling. Whereas pathways upstream of GSK3 are being elucidated, relatively little progress has been made in identifying targets downstream of GSK3 that mediate its functional effects. This is important, because these substrates themselves could become next-generation therapeutic targets that are more potent and specific than current therapeutics targeting GSK3. Here, a few likely candidates and their connection to mood disorders and schizophrenia are discussed. Glycogen synthase kinase 3 (GSK3) and its upstream regulators are strongly implicated in mood disorders and Schizophrenia. However, relatively little progress has been made on identifying its pathogenic targets in these disorders. These could become next generation therapeutic targets that are more potent and specific than current drugs. Possible candidates and their connection to mood disorders and Schizophrenia are discussed. © 2013 FEBS.
Berglund L.J.,Garvan Institute of Medical Research
Blood | Year: 2013
B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common γ chain (γc)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21.
Garvan Institute of Medical Research | Date: 2016-12-14
The present disclosure provides an isolated protein comprising an antibody light chain variable domain (V_(L)) comprising at least one negatively charged amino acid positioned between residues 49 to 56 according to the numbering system of Kabat, the protein capable of binding specifically to an antigen.