HomeProfessor of Histopatholology |
Contact details:
| Tel: | +44 20 7882 8956 |
| Fax: | +44 20 7882 2186 |
| Email: | n.a.wright@qmul.ac.uk |
| Address: | Centre for Digestive Diseases, |
Biography
I graduated in medicine at the University of Durham and after house jobs went straight into pathology. I trained at the University of Newcastle in the Royal Victoria Infirmary, where I became senior lecturer in 1976. In 1977 I moved to a Clinical Readership at the University of Oxford , and was made Nuffield Reader in Pathology in 1978. In 1980 I was appointed to the Chair of Pathology at the Royal Postgraduate Medical School at Hammersmith Hospital , a position I held for 17 years. In 1987 I was seconded to the ICRF and moved my lab to Lincoln 's Inn Fields, where it has been since then. In 1992 I was appointed Director of Clinical Research at the ICRF and in 1994, when Charing Cross and the Hammersmith merged to form the Hammersmith hospitals NHS Trust, I was the first Clinical Director of Pathology. In 1997, when the RPMS joined Imperial College , I was appointed Dean of the RPMS and then Deputy Principal of the Imperial College School of Medicine. I moved to Barts and the London as Warden and Vice-Principal in 2001. I am a past-President of the Pathological Society of Great Britain and Ireland and of the British Society for Gastroenterology.
Research Activity
Our achievements include: that colorectal adenomas originate in the monocryptal adenoma and initial expansion is by crypt fission rather than top-down spread; that Cdx2-/- cells induce intercalations in chimaeric mouse gut, and that X-inactivation patch size in human female colon and others tissues confounds the assessment of tumour clonality. We have studied the earliest tubular adenomas in the colon to show that these develop initially following a bottom-up mode, and favour an origin in basally-sited mutated stem cells. We have used mtDNA mutations to demonstrate that basal crypt stem cells mutate and expend to fill colonic crypts: these expand to form monoclonal patches of crypts with the same genotype by the process of crypt fission. We have also shown that human gastric glands are clonal and contain multiple multipotential stem cells: they also undergo gland fission to give rise to patches of genotypically-identical glands. In the field of stem cell plasticity we have shown that bone-marrow-derived myofibroblasts and fibroblasts engraft into multiple organ in bone-marrow-transplanted mice; that bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion; that bone marrow contributes to tumour-associated myofibroblasts and fibroblasts; that there is a regenerative role for bone marrow following experimental colitis including a considerable contribution to neovasculogenesis (the formation of whole new vessels), that wild-type marrow ameliorates colitis in Il-10KO mice and that there is a significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. We have developed methods for analysing the function of these engrafted cells, demonstrating the Y chromosome as a bone marrow marker, a lineage-specific marker such as a-smooth muscle actin and a lineage specific mRNA, such as pro-collagen 1a chain, and also for demonstrating proliferative activity, all in the same section. We have also shown that bone marrow contributes to renal parenchymal turnover and regeneration, that proliferation of bone marrow-derived cells contributes to regeneration after folic acid-induced acute tubular injury, and that bone marrow cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport's syndrome.
In the future, we will follow three related programmes: (i) gastrointestinal stem cells in relationship to the origins of colorectal cancer: (ii) lineage infidelity in bone marrow stem cells and (ii) in gut biology. We intend to exploit our use of mtDNA mutations in human gastrointestinal crypt stem cells, to study the clonal expansion of mutated clones, and to analyse cell lineages in the human gut and to study early tumour formation. We will first of all attempt to establish the habitus of mutated colonic crypts and gastric glands to assess their relationship to normal crypts, and then to measure the rate of expansion of mutated clones and patches in the human colon, measuring the densities of mutation events in large tissue blocks. Serial section analysis of partially-mutated crypts will allow the assessment of clonal expansion within crypts, and by combining lineage markers with enzyme histochemistry we believe that we will be able to trace cell lineages in the human gut from the stem cells. We hope to study clonality of premalignant lesions in the gut using a variety of techniques, including colorectal acdenomas and dysplasia in ulcerative colitis, to analyse the spread of mutations in Barrett's oesophagus and LKB-1 mutation in Peutz-Jeghers polyposis, study de novo crypt formation in flat adenomas, the TFF2/MUC6-secreting cell lineage in the stomach in relation to intestinal metaplasia, to examine the proposal that colonic stem cells do not protect their genome by selective segregation of template DNA strands, and to critically assess whether side populations are a marker of stem cell habitus. In our studies of lineage infidelity in bone marrow stem cells we hope to continue our work on bone marrow contribution to vascular cell lineages in experimental colitis and in tumours, with special reference to the role of integrins, on the bone marrow contribution to epidermal cell lineages, asking whether bone marrow cells from animals genetically modified to produce skin tumours can do so after transplantation, on the bone marrow contribution to myofibroblast populations in tumour stroma and on the bone marrow contribution to renal cell lineages.
Key Publications
• Greaves LC, Preston SL , Tadrous PJ, Taylor RW, Barron MJ, Oukrif D, Leedham SJ, Deheragoda M , Sasieni P, Novelli MR, Jankowski JA, Turnbull DM, Wright NA , McDonald SA (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proceedings of the National Academy of Sciences USA 103: 714-9
• Brittan M , Braun KM, Reynolds LE, Conti FJ, Reynolds AR , Poulsom R, Alison MR, Wright NA , Hodivala-Dilke KM (2005) Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion. Journal of Pathology 205, 1-13
• Preston S, Wong R, Poulsom R, Jeffery R, Goodlad R, Mandir N, Elia G, Novelli M, Bodmer W, Tomlinson I, Wright N (2003) Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Research 63, 3819-25
• Poulsom R, Forbes SJ , Hodivala-Dilke K, Ryan E , Wyles S, Navaratnarasah S, Jeffery R, Hunt T, Alison MR , Cook T, Pusey C, Wright NA (2001) Bone marrow contributes to renal parenchymal turnover and regeneration. Journal of Pathology 193, 1-7
• Direkze NC, Jeffery R, Hodivala-Dilke K, Hunt T, Playford RJ, Elia G, Poulsom R, Wright NA, Alison MR (2006) Bone marrow-derived stromal cells express lineage-related messenger RNA species. Cancer Research 66, 1265-9
