Levon Khachigian

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Levon Michael Khachigian (born 6 March 1964 in Beirut, Lebanon) [1] is an Australian medical research scientist notable for his work in vascular cell and molecular biology. [2] He is a Professor in the Faculty of Medicine at the University of New South Wales. [3]

Contents

Khachigian is known for his studies in the area of transcriptional control and for translating basic discoveries into potential novel therapeutics. He is the inventor of the experimental drug Dz13, which may help treat a range of common diseases or complications including skin cancer, post-angioplasty restenosis, macular degeneration and asthma. [1] [2] [4]

Early life and education

Khachigian was born to Armenian parents who served as evangelical protestant missionaries in the Middle East [5] and migrated to Australia at age 18 months. He was raised in Naremburn, New South Wales, Australia [1] and attended Naremburn Public School and later Crows Nest Boys' High School. [6]

Khachigian obtained a B.Sc. with first-class honours in biochemistry in 1986 and Ph.D. in growth factor biochemistry and cell biology in 1993 from the University of New South Wales. He performed doctoral research at the School of Medicine, St George Hospital (Sydney), Division of Biomolecular Engineering, Commonwealth Scientific and Industrial Research Organisation and Department of Haematology, Prince of Wales Hospital (Sydney). He obtained a D.Sc. in vascular biology and transcriptional control in 2004 from the University of New South Wales. [2] [3]

Research

Khachigian is a vascular biologist with a strong focus on "bench to bedside" translational research. His research has centered mainly on interrogating the roles of immediate-early genes (such as Egr1 and c-Jun) as molecular switches in the pathogenesis of disease. He and his collaborators have uncovered regulatory networks underpinning waves of transcriptional change in cellular activation in a range of single gene [7] [8] [9] [10] [11] and systems-based approaches. [12] [13] Khachigian has developed a range of interventional approaches to target key regulatory genes for the development of novel therapeutics, particularly catalytic DNA. [14]

Khachigian invented Dz13, a molecule that targets the transcription factor c-Jun, implicated in a range of common proliferative, occlusive and inflammatory diseases. In 1999 Khachigian reported the first use of catalytic DNA as new experimental drugs in an animal model of any kind. [15] In 2013 he reported the first clinical use of catalytic DNA in human subjects. [16] This was later followed by numerous other independent, some multi-center, clinical trials evaluating DNAzymes in humans, including DNAzymes targeting EBV-LMP1 in patients with nasopharyngeal cancer [17] and DNAzymes targeting another nuclear transcription factor GATA3 in patients with allergic asthma [18] demonstrating DNAzyme efficacy and safety. Targeted catalytic DNA-based molecular therapy may represent a novel, effective and less invasive therapeutic approach in humans. [19]

Career

After obtaining his Ph.D. and with the support of a CJ Martin Research Fellowship from the National Health and Medical Research Council of Australia and Fulbright Program, Khachigian studied vascular biology and transcriptional control with Professor Tucker Collins [20] at Brigham and Women’s Hospital, Harvard Medical School, Boston USA. On returning to Australia in 1996 he established the Transcription Laboratory within the Centre for Vascular Research, Faculty of Medicine at the University of New South Wales. [6] He has been supported by an NHMRC RD Wright Fellowship, Principal Research Fellowship, Senior Principal Research Fellowship and the Australia Fellowship. [3] In 2004 Khachigian was appointed Professor in Medicine and in 2009 appointed Director of the Centre for Vascular Research, succeeding its Foundation Director Scientia Professor Colin Chesterman AO. [2] [21]

Service

Khachigian has a strong record of service to international and national scientific societies and has been at the helm of numerous international conferences in vascular biology, drug design and discovery, and interdisciplinary health and medical research, including the International Vascular Biology Meeting and Congress of the International Society on Thrombosis and Haemostasis. [2] He has served as president of the Australian Society for Medical Research and president of the Australian Vascular Biology Society. [1] [3] He is a member of the Faculty of 1000. [22]

Awards

Khachigian has received numerous prestigious national and international awards including the Commonwealth Health Minister's Award for Excellence in Health and Medical Research, GlaxoSmithKline Award for Research Excellence, [23] Gottschalk Medal from the Australian Academy of Science, Khwarizmi International Award for Science and Technology, and 3 separate Eureka Prizes from the Australian Museum for scientific research, medical research and international scientific collaboration. [3]

Investigations

The University of New South Wales investigated matters involving Khachigian in accordance with the Australian Code for the Responsible Conduct of Research. Khachigian maintained there was no wrongdoing [24] [25] and a trial involving Dz13 was put on hold “to err on the side of caution”. [26] Six research articles co-authored by Khachigian have been retracted and one corrected. [27] None of the multiple different, independent external expert panels of inquiry or investigations conducted under the Australian Code made any finding of research misconduct on the part of Khachigian and concluded that breaches arose from genuine error or honest oversight. [26] [28] [29] In 2017, a fifth independent external expert panel, set up following the Australian Research Integrity Committee’s review of all previous independent external expert investigations came to the same conclusion that there was no finding of research misconduct. [30] This decision was discussed in a news article by the Australian Broadcasting Corporation in October 2019. [30]

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics are stable heritable traits that cannot be explained by changes in DNA sequence, and the study of a type of stable change in cell function that does not involve a change to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

<span class="mw-page-title-main">DNA methyltransferase</span> Class of enzymes

In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

<span class="mw-page-title-main">EGR1</span> Protein-coding gene in the species Homo sapiens

EGR-1 also known as ZNF268 or NGFI-A is a protein that in humans is encoded by the EGR1 gene.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

Deoxyribozymes, also called DNA enzymes, DNAzymes, or catalytic DNA, are DNA oligonucleotides that are capable of performing a specific chemical reaction, often but not always catalytic. This is similar to the action of other biological enzymes, such as proteins or ribozymes . However, in contrast to the abundance of protein enzymes in biological systems and the discovery of biological ribozymes in the 1980s, there is only little evidence for naturally occurring deoxyribozymes. Deoxyribozymes should not be confused with DNA aptamers which are oligonucleotides that selectively bind a target ligand, but do not catalyze a subsequent chemical reaction.

<span class="mw-page-title-main">NF-κB</span> Nuclear transcriptional activator that binds to enhancer elements in many different cell types

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

<span class="mw-page-title-main">Transcription factor Sp1</span> Protein-coding gene in the species Homo sapiens

Transcription factor Sp1, also known as specificity protein 1* is a protein that in humans is encoded by the SP1 gene.

Dz13 is an experimental treatment developed by scientists at the University of New South Wales. The drug aims to combat a range of illnesses, including skin cancer, restenosis, arthritis and macular degeneration. Trials of Dz13 were suspended in 2013.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">TOP2B</span> Protein-coding gene in the species Homo sapiens

DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2B gene.

<span class="mw-page-title-main">STK11</span> Protein-coding gene in the species Homo sapiens

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

<span class="mw-page-title-main">HDAC9</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.

<span class="mw-page-title-main">Vpr</span> Group of transport proteins

Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication and enhanced gene expression from provirus in dividing or non-dividing cells such as T cells or macrophages. Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.

Merlin Crossley, is an Australian molecular biologist, university teacher and administrator. In 2016, he was appointed as Deputy Vice-Chancellor (Academic) at the University of New South Wales.

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H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

References

  1. 1 2 3 4 "To crack the maze (Sydney Morning Herald 27 April 2006)". 27 April 2006.
  2. 1 2 3 4 5 "Levon M. Khachigian: IJO Editorial Academy (September 2012)".
  3. 1 2 3 4 5 "LM Khachigian website".
  4. ↑ "Wide role for new drug targeting skin cancer gene (Sydney Morning Herald 7 May 2013)". 6 May 2013.
  5. ↑ "Gene result a touch of shear brilliance". Sydney Morning Herald. 14 August 2003.
  6. 1 2 Khachigian, Levon. "Tall Poppies in Flight" (PDF). Australian Institute of Policy and Science.
  7. ↑ Khachigian, LM; et al. (1996). "Egr-1-induced endothelial gene expression: a common theme in vascular injury". Science. 271 (5254): 1427–31. Bibcode:1996Sci...271.1427K. doi:10.1126/science.271.5254.1427. PMID   8596917. S2CID   36935337.
  8. ↑ Khachigian, LM (2006). "Early growth response-1 in cardiovascular pathobiology". Circ Res. 98 (2): 186–91. doi: 10.1161/01.res.0000200177.53882.c3 . PMID   16456111.
  9. ↑ Tan, NY; et al. (2009). "Sp1 phosphorylation and its regulation of gene transcription". Mol Cell Biol. 29 (10): 2483–2488. doi:10.1128/mcb.01828-08. PMC   2682032 . PMID   19273606.
  10. ↑ Zhang, N; et al. (2012). "Repression of PDGF-R-alpha after cellular injury involves TNF-alpha, formation of a c-Fos-YY1 complex, and negative regulation by HDAC". Am J Physiol Cell Physiol. 302 (11): C1590-8. doi:10.1152/ajpcell.00429.2011. PMID   22322974.
  11. ↑ Khachigian, LM (2016). "Early growth response-1 in the pathogenesis of cardiovascular disease". J Mol Med. 94 (7): 747–753. doi:10.1007/s00109-016-1428-x. PMID   27251707. S2CID   15905744.
  12. ↑ Forrest, AR; et al. (2014). "A promoter-level mammalian expression atlas". Nature. 507 (7493): 462–470. Bibcode:2014Natur.507..462T. doi:10.1038/nature13182. PMC   4529748 . PMID   24670764.
  13. ↑ Arner, E; et al. (2015). "Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells". Science. 347 (6225): 1010–1014. Bibcode:2015Sci...347.1010A. doi:10.1126/science.1259418. PMC   4681433 . PMID   25678556.
  14. ↑ Khachigian, LM (2000). "Catalytic DNAs as potential therapeutic agents and sequence-specific molecular tools to dissect biological function". J Clin Invest. 106 (10): 1189–95. doi:10.1172/jci11620. PMC   381443 . PMID   11086018.
  15. ↑ Santiago, FS; et al. (1999). "New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation and regrowth after injury". Nature Medicine. 5 (11): 1264–1269. doi:10.1038/15215. PMID   10545992. S2CID   9566888.
  16. ↑ Cho, EA; et al. (2013). "Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER)". The Lancet. 381 (9880): 1835–1843. doi:10.1016/s0140-6736(12)62166-7. PMC   3951714 . PMID   23660123.
  17. ↑ Krug, N; et al. (2015). "Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme". N Engl J Med. 372 (21): 1987–95. doi:10.1056/nejmoa1411776. hdl: 1854/LU-6862585 . PMID   25981191.
  18. ↑ Cao, Y; et al. (2014). "Therapeutic evaluation of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme for treating of nasopharyngeal carcinomas". Mol Ther. 22 (2): 371–7. doi:10.1038/mt.2013.257. PMC   3916047 . PMID   24322331.
  19. ↑ "Dz13 drug targets skin cancer in clinical trial (Asian Scientist 13 May 2013)". 13 May 2013.
  20. ↑ Khachigian, LM (2007). "Science never sleeps: Tucker Collins MD, PhD". Endothelium. 14 (4–5): 173–174. doi:10.1080/10623320701670026.
  21. ↑ "First class honours (UNSW 12 June 2007)". 12 June 2007.
  22. ↑ "F1000 Prime Drug Discovery & Design (14 June 2012)".
  23. ↑ "Novel and pioneering research offers hope for cardiovascular disease (2006)".
  24. ↑ "ABC News (18 April 2014)". Australian Broadcasting Corporation . 17 April 2014.
  25. ↑ "Khachigian statement (11 August 2013)" (PDF). Australian Broadcasting Corporation .
  26. 1 2 "UNSW statement (12 August 2013)". 12 August 2013.
  27. ↑ "Retraction Watch Database".
  28. ↑ "UNSW public statement (26 November 2015)".
  29. ↑ "UNSW clears Levon Khachigian of all allegations of research misconduct (22 December 2015)".
  30. 1 2 "UNSW skin cancer researcher Levon Khachigian". Australian Broadcasting Corporation . 16 October 2019.
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