Denise Sheer Inaugural Lecture
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"From the Chromosome...Everything". My Inaugural Lecture at the Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London. 10th May 2010.
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Denise Sheer Inaugural Lecture
- 1. De Generatione Animalium On the Generation of Animals William Harvey, 1651 Ex ovo omnia From the egg, everything 1578-1657 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 2. From the chromosome… everything Denise Sheer Centre for Neuroscience & Trauma Denise Sheer ~ Inaugural Lecture 10th May 2010
- 3. Walther Flemming 1843-1905 Antonie van Leeuwenhoek 1632-1723 Polytene chromosomes in Chironomus Dividing cells Chick red blood cells Denise Sheer ~ Inaugural Lecture 10th May 2010
- 4. Cells behave as they do because of their genes Cell nucleus 46 chromosomes GenesDNA Denise Sheer ~ Inaugural Lecture 10th May 2010
- 5. Where do genes map onto chromosomes? What is the architecture of the chromosome? Which genetic abnormalities are involved in cancer? Denise Sheer ~ Inaugural Lecture 10th May 2010
- 6. A path travelled well…. Denise Sheer ~ Inaugural Lecture 10th May 2010
- 7. Dr Jenni Tsafrir Genetics of eye colour What was known then about chromosomes? 1965 - Barbara McClintock, Cornell University-Aspects of Gene Control in Higher Organisms “mechanisms related to.. .the chromosomes…and the highly organized nuclei”. Down Syndrome Denise Sheer ~ Inaugural Lecture 10th May 2010
- 8. 1969-1973 University of the Witwatersrand Johannesburg B.Sc - Zoology & Embryology BSc (Hons) - Zoology Prof Barry FabianProf Boris Balinsky Professor Barry Fabian nature Lifetime Mentoring Award 2007 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 9. Hamburger & Hamilton 1951 Balinsky 1925 Amabis & Cabral 1970 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 10. 1974-1975 South African Institute of Medical Research Anti-Snake Venom Primate Research Prof Trefor Jenkins Diagnostic genetics Genetic counselling Chromosome banding “Effects of dagga on primate chromosomes” Down Syndrome Denise Sheer ~ Inaugural Lecture 10th May 2010
- 11. Supervisor: Dr Martin Bobrow 1976-1980 University of Oxford D.Phil. Sir Walter Bodmer Reproduced with kind permission of Juliet Wood X X x X Xx v vv vv v v vv v v v v vv v v vv v v vv X vv v v vv v v vv v vv v v vv v v vv x Human Cells Mouse Cells Gene 1 Gene 2 Gene 3 Human-Mouse Hybrid Cells Mapping genes onto chromosomes Denise Sheer ~ Inaugural Lecture 10th May 2010
- 12. Imperial Cancer Research Fund/ Cancer Research UK 1980-1982 Post-Doctoral Research Fellow with Dr. Ellen Solomon 1982-2006 Head: Human Cytogenetics Laboratory Mapping genes onto chromosomes Denise Sheer ~ Inaugural Lecture 10th May 2010
- 13. Mapping genes onto chromosomes LIMK1 TP53 XPG ERBA2 ERBA1 APC MHC KIR/ILT TOP2B FRAX EIF-5A NOS1 ELK3 NOS3 HOXB Denise Sheer ~ Inaugural Lecture 10th May 2010
- 14. Mapping the APC gene on chromosome 5 Adenomatous Polyposis Coli APC gene at 5q21 Bodmer et al 1987 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 15. Genetic abnormalities in cancer At the cellular level, cancer is a genetic disease Denise Sheer ~ Inaugural Lecture 10th May 2010
- 16. Acute Lymphoblastic Leukaemia Acute Myelomonocytic Leukaemia Acute Promyelocytic Leukaemia Breast Carcinoma Chronic Myeloid Leukaemia Colorectal Adenoma Congenital Fibrosarcoma Ewing’s Sarcoma Glioblastoma Krukenberg Tumour Neuroblastoma Ovarian Carcinoma Pancreatic Carcinoma Primitive Neuro-ectodermal Tumour Genetic abnormalities in cancer Ovarian Carcinoma Glioblastoma Neuroblastoma Breast Carcinoma Denise Sheer ~ Inaugural Lecture 10th May 2010
- 17. 15;17 identified in all cases of APL Mapping the breakpoints 15;17 chromosome translocation in Acute Promyelocytic Leukaemia X X x X Xx v Vv vv v v vv v v v v v Human Cells Mouse Cells vv v v vv v vv V Gene 1 vv v v vv v v vv x Gene 2 Sheer et al 1983 Sheer et al 1985 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 18. What is the architecture of the chromosome? “The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact” Thomas Henry Huxley (1870) Thomas & Marion Cremer Comings 1968 Cremer et al 1976 Chinese Hamster cells after focal laser UV irradiation Chromosome Territories Inter-Chromosome Domain Cremer et al 1993 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 19. Chromosomes occupy discrete territories Cremer & Cremer 2006Bolzer et al 2005 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 20. 6! TAP2 PSMB8 TAP1 PSMB9 C2 BF C4 HLA-F HLA-G HLA-A HLA-E HLA-C HLA-B MICB C6orf10 HLA-DRA HLA-DQA1,2 HLA-DQB1,2 HLA-DOB HLA-DMA HLA-DOA HLA-DPA1 RING1 HLA-DPB1 TAPBP TNF HSPA1 TNXB NOTCH4 HLA-DRB1,3,4,5 * * * * * * * * * * * ***** *** * * The Major Histocompatibility Complex - a perfect model MHC- Cell-Type Specific & Inducible Gene Activity Denise Sheer ~ Inaugural Lecture 10th May 2010
- 21. MHC Chr 6 Inac&ve Ac&ve Chromosome architecture is related to gene activity Volpi et al 2000 Inac&ve Ac&ve * * * * * * Ac&ve Denise Sheer ~ Inaugural Lecture 10th May 2010
- 22. 2006 Centre for Neuroscience & Trauma Blizard Institute of Cell & Molecular Science Barts & the London School of Medicine & Dentistry Queen Mary University of London What is the architecture of the chromosome? What are the molecular determinants? Which genetic abnormalities are involved in cancer? How do children’s brain tumours arise? Denise Sheer ~ Inaugural Lecture 10th May 2010
- 23. Chromosome architecture is dependent on signalling pathways Inac&ve Ac&ve Interferon Gamma JAK-STAT SIGNALLING Christova et al 2007 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 24. Chromosome architecture is related to gene activity Inac&ve Ac&ve Anchored sites Ottaviani et al 2008a,b Denise Sheer ~ Inaugural Lecture 10th May 2010
- 25. Genetic abnormalities in paediatric low grade astrocytoma SEERDenise Sheer ~ Inaugural Lecture 10th May 2010
- 26. Tiny duplication on chromosome 7 in pilocytic astrocytoma Denise Sheer ~ Inaugural Lecture 10th May 2010
- 27. Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010 Tiny duplication on chromosome 7 in pilocytic astrocytoma Denise Sheer ~ Inaugural Lecture 10th May 2010
- 28. KIAA1549 BRAF Genes duplicated on chromosome 7 Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010Denise Sheer ~ Inaugural Lecture 10th May 2010
- 29. KIAA1549 BRAF KIAA1549 BRAFKIAA1549- BRAF fusion Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010 Genes duplicated on chromosome 7 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 30. The MAP kinase signalling pathway BRAF MEK1/2 ERK1/2 RAS NF1 Signals from outside the cell Forshew et al 2009; Tatevossian et al 2010; Lawson et al 2010 Regulated Cell Division Denise Sheer ~ Inaugural Lecture 10th May 2010
- 31. BRAF MEK1/2 ERK1/2 RAS P P Regulated Cell Division NF1 Signals from outside the cell The MAP kinase signalling pathway Denise Sheer ~ Inaugural Lecture 10th May 2010
- 32. BRAF fusion causes cells to keep dividing MEK1/2 ERK1/2 RAS P P NF1 Signals from outside the cell BRAFKIAA1549 Increased Cell Division Denise Sheer ~ Inaugural Lecture 10th May 2010
- 33. MEK1/2 ERK1/2 RAS P P NF1 Signals from outside the cell BRAFKIAA1549 New opportunities for treatment for pilocytic astrocytoma Inhibitor Increased Cell Division Denise Sheer ~ Inaugural Lecture 10th May 2010
- 34. BRAF fusions: A microhomology mediated mechanism? microhomology insertion microhomology microhomology microhomology microhomology insertion Lawson, Hindley et alDenise Sheer ~ Inaugural Lecture 10th May 2010
- 35. BRAF fusions: A microhomology mediated mechanism? Denise Sheer ~ Inaugural Lecture 10th May 2010
- 36. Where to now? Where do genes map onto chromosomes? What is the architecture of the chromosome? Which genetic abnormalities are involved in cancer? Cremer et al 2006 Denise Sheer ~ Inaugural Lecture 10th May 2010
- 37. Centre for Neuroscience and Trauma Prof John Priestley ~ Prof Gavin Giovannoni Surinder Pal ~ Carol Brown Sir Nick Wright Prof Tom MacDonald Prof Mike Curtis Jo Kirner ~ Kerry Newbury Josie Dance BLIZARD INSTITUTE OF CELL AND MOLECULAR SCIENCE Denise Sheer ~ Inaugural Lecture 10th May 2010
- 38. Johan Aarum Pavel Bezecny Rossi Christova Tim Forshew Guy Hindley Gabriel Jamie Tania Jones Andrew Lawson Elliott Lever William Ogunkolade Diego Ottaviani Chris Pieri Jarek Szary Ruth Tatevossian Denise Sheer ~ Inaugural Lecture 10th May 2010
- 39. Jane Babbage Srinjan Basu Andi Bolzer Guiseppe Calabrese Edith Chevret Rossen Donev Ceri Edwards Luda Federova Rachel Gillingham Pat Gorman Vikki Groves Peter Johonnett Fiona Kiely Xin Mao Chiara Mazzanti Paul Mulholland Rosella Muresu Alistair Newall Rodger Palmer Ketan Patel Chrys Poulikas Sue Rider Rebecca Roylance Gabi Senger Carol Shiels Janet Shipley Petros Takousis Badmavady Segarane Clare Taylor Radost Vatcheva Emanuela Volpi Jayson Wang Sarah Williams Jill Williamson Pei Jun Wu Stephan Beck Walter Bodmer Marion Cremer Thomas Cremer Thomas Down David Ellison Thomas Jacques Chris Jones Gavin Kelly David Kelsell Steve Krawetz Mike Levin Andrew Lister Antony Michalski Richard Mitter Paul Mulholland Dean Nizetic Andrew Pearson Jon Pritchard Jiannis Ragoussis Peter Sasieni Janet Shipley Andrew Silver Jeremy Squire John Trowsdale Frank Uhlmann Bryan Young Denise Sheer ~ Inaugural Lecture 10th May 2010
- 40. Denise Sheer ~ Inaugural Lecture 10th May 2010