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Draft:Bryan Paul Morgan

From Wikipedia, the free encyclopedia

Bryan Paul Morgan known as Paul Morgan, is a Welsh immunologist, medically trained clinical biochemist and academic. His research focuses on the complement system and its roles in inflammatory, degenerative and neurological disease. He is Professor of Immunology at Cardiff University and a Group Leader at the UK Dementia Research Institute at Cardiff. He has held senior academic leadership positions at Cardiff, including Dean of Medicine, Head of the School of Medicine, and Centre Director of the UK Dementia Research Institute at Cardiff. Morgan's research has examined the structure, function and regulation of the membrane attack complex (MAC), including work showing that MAC is not restricted to cell lysis but can induce sublytic cellular signalling and inflammatory responses. His research has also investigated cellular recovery from sub-lytic MAC attack, regulation of MAC formation by CD59, inherited variation in complement proteins, and the involvement of complement in diverse diseases including multiple sclerosis and Alzheimer's disease. Morgan was elected a Fellow of the Academy of Medical Sciences in 1999 and a Fellow of the Learned Society of Wales in 2011. He served as President of the International Complement Society and chaired the European Complement Network. In 2022 he received the European Complement Network Medal for lifetime achievement in complement research.

Early life and education

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Morgan was born in Llanelli, Wales. He studied medical biochemistry and medicine at the Welsh National School of Medicine, receiving a first-class BSc in Medical Biochemistry in 1977 and graduating in medicine in 1980. Following early medical training in Cardiff, he specialised in clinical biochemistry and completed a PhD in 1984 on the biochemistry and pathology of complement component C9. From 1984 to 1985, Morgan was a Medical Research Council Travelling Fellow at the Johns Hopkins School of Medicine in Baltimore and the University of Florida in Gainesville. He subsequently returned to Wales and took up a lectureship in clinical biochemistry.

Academic career

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In 1987, Morgan returned to Wales to take up a Wellcome Trust Senior Clinical Research Fellowship, which he held for 15 years. He was appointed professor in 1995 and became Head of Medical Biochemistry and Immunology at the University of Wales College of Medicine in 2001. Following the merger of the University of Wales College of Medicine with Cardiff University, Morgan served as Dean of Medical Research in the School of Medicine from 2007. He subsequently served as Dean of Medicine and Head of the School of Medicine from April 2009 until December 2014. Morgan served on the Council of the Academy of Medical Sciences from 2005 to 2008 and was appointed to the Council of the Medical Research Council in 2011. He was awarded a Spinoza Professorship at the University of Amsterdam in 2012 and was elected to Academia Europaea in 2015. His later research at Cardiff has focused increasingly on complement in brain diseases, particularly Alzheimer's disease.

Research

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Complement membrane attack complex (MAC)

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A major focus of Morgan's research group has been the complement membrane attack complex (MAC), the terminal complex generated upon complement activation. His early work investigated how nucleated cells respond to complement MAC attack. Morgan showed that human neutrophils could survive MAC attack by removing membrane attack complexes through endocytosis and exocytosis.[1] This contributed to understanding that MAC on nucleated cells does not invariably result in cell lysis and that cells can recover following complement attack. Morgan subsequently investigated non-lytic effects of the MAC. His work demonstrated that MAC-mediated calcium flux can activate the NLRP3 inflammasome.[2] He later contributed to structural studies of the MAC, including a 2016 cryo-electron microscopy study that defined its stoichiometry and molecular organisation and provided insight into the mechanism of membrane disruption.[3]

CD59 and regulation of complement

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Morgan has also studied mechanisms that protect host cells from MAC-mediated membrane damage, particularly the endogenous MAC inhibitor, CD59. His research showed that CD59 inhibits complement-mediated lysis by interfering with C9 incorporation during assembly of the membrane attack complex.[4] Further work investigated the functional site of CD59 involved in inhibition of MAC assembly.[5] Morgan's group generated CD59-deficient mice. The animals showed increased susceptibility to complement-mediated damage and spontaneous intravascular haemolysis.[6] CD59-deficient models were subsequently used to investigate the contribution of terminal complement activation to inflammatory and autoimmune disease. In an experimental model of multiple sclerosis, CD59a deficiency increased disease severity, demyelination and axonal injury.[7]

Complement genetics and human disease

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Morgan's research has examined how inherited variation in complement proteins influences complement activity and susceptibility to disease. His team demonstrated that common functional polymorphisms in C3, factor B and factor H interact to influence systemic complement activation.[8] The study introduced the concept of a functional complotype, in which combinations of inherited complement variants collectively influence complement activity and susceptibility to disease. Morgan investigated complement genetics and biomarkers in human disease. This included work linking increased circulating factor H-related protein 4 (FHR4) to age-related macular degeneration.[9] His later work showed that Alzheimer's disease-associated variants in complement genes influence circulating concentrations of their encoded proteins.[10]

Neurological disease and neurodegeneration

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Morgan has had a long-standing research interest in the role of complement in neurological disease. His work on multiple sclerosis has examined complement activation, microglial responses, demyelination and terminal complement pathway activation in experimental models and human disease.[11] His work demonstrated a C3-dependent mechanism of microglial priming relevant to multiple sclerosis.[12] His research has also examined complement proteins and activation products in multiple sclerosis tissue and the potential use of circulating complement proteins as biomarkers of disease state.[13] His later research has focused particularly on Alzheimer's disease and other neurodegenerative diseases. His programme at the UK Dementia Research Institute combines human genetics, complement biomarkers, neuropathology and experimental models to investigate how complement dysregulation contributes to neuroinflammation and synaptic loss. Morgan showed that activation of the terminal complement pathway contributes to synaptic loss in experimental models of Alzheimer's disease.[14] Subsequent studies examined how an Alzheimer's disease-associated variant of complement receptor 1 (CR1) affects glial phagocytosis[15] and investigated complement dysregulation in tauopathies.[16]

Complement therapeutics

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Building on his mechanistic and biomarker studies, Morgan's research has extended into the development of therapeutic approaches to control complement activation, including strategies to inhibit the terminal complement pathway within the central nervous system. In work published in Brain, Morgan and Zelek developed and evaluated a brain-penetrant C7-blocking antibody in a mouse model of Alzheimer's disease. Systemic administration of the brain-penetrant C7-blocking antibody for three months reduced complement activation, synapse loss and inflammatory markers, and improved cognitive performance in the experimental model.[17] Morgan and Zelek are named inventors on a patent covering antibodies and antibody fragments that inhibit C7 protein.[18] During the COVID-19 pandemic, Morgan led studies investigating complement dysregulation in acute and long COVID.[19][20] Work published in 2024 identified persistent complement dysregulation in long COVID and investigated its potential as a therapeutic target. Morgan is a Director of Acionna Therapeutics, a biotechnology company incorporated in 2025.

Honours and professional service

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Morgan was elected a Fellow of the Academy of Medical Sciences in 1999 and served on its Council from 2005 to 2008. He was elected a Fellow of the Learned Society of Wales in 2011 and to Academia Europaea in 2015. He chaired the European Complement Network from 2002 to 2007 and served as President of the International Complement Society from 2011 to 2014. In 2022, Morgan received the European Complement Network Medal, which recognises lifetime achievement in complement research. His other academic roles have included membership of the Medical Research Council and a Spinoza Professorship at the University of Amsterdam.

References

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  1. ↑ Morgan, B. P.; Dankert, J. R.; Esser, A. F. (1987-01-01). "Recovery of human neutrophils from complement attack: removal of the membrane attack complex by endocytosis and exocytosis". Journal of Immunology. 138 (1). Baltimore, Md. : 1950: 246–253. ISSN 0022-1767. PMID 3782799.{{cite journal}}: CS1 maint: location (link)
  2. ↑ Triantafilou, Kathy; Hughes, Timothy R.; Triantafilou, Martha; Morgan, B. Paul (2013-07-01). "The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation". Journal of Cell Science. 126 (Pt 13): 2903–2913. doi:10.1242/jcs.124388. ISSN 1477-9137. PMID 23613465.
  3. ↑ Serna, Marina; Giles, Joanna L.; Morgan, B. Paul; Bubeck, Doryen (2016-02-04). "Structural basis of complement membrane attack complex formation". Nature Communications. 7: 10587. doi:10.1038/ncomms10587. ISSN 2041-1723. PMC 4743022. PMID 26841837.{{cite journal}}: CS1 maint: article number as page number (link)
  4. ↑ Meri, S.; Morgan, B. P.; Davies, A.; Daniels, R. H.; Olavesen, M. G.; Waldmann, H.; Lachmann, P. J. (1990-09). "Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers". Immunology. 71 (1): 1–9. ISSN 0019-2805. PMC 1384213. PMID 1698710. {{cite journal}}: Check date values in: |date= (help)
  5. ↑ Bodian, D. L.; Davis, S. J.; Morgan, B. P.; Rushmere, N. K. (1997-02-03). "Mutational analysis of the active site and antibody epitopes of the complement-inhibitory glycoprotein, CD59". The Journal of Experimental Medicine. 185 (3): 507–516. doi:10.1084/jem.185.3.507. ISSN 0022-1007. PMC 2196035. PMID 9053451.
  6. ↑ Holt, D. S.; Botto, M.; Bygrave, A. E.; Hanna, S. M.; Walport, M. J.; Morgan, B. P. (2001-07-15). "Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria". Blood. 98 (2): 442–449. doi:10.1182/blood.v98.2.442. ISSN 0006-4971. PMID 11435315.
  7. ↑ Mead, Richard James; Neal, James William; Griffiths, Mark Raymond; Linington, Christopher; Botto, Marina; Lassmann, Hans; Morgan, Bryan Paul (2004-01). "Deficiency of the complement regulator CD59a enhances disease severity, demyelination and axonal injury in murine acute experimental allergic encephalomyelitis". Laboratory Investigation; a Journal of Technical Methods and Pathology. 84 (1): 21–28. doi:10.1038/labinvest.3700015. ISSN 0023-6837. PMID 14631387. {{cite journal}}: Check date values in: |date= (help)
  8. ↑ Heurich, Meike; Martínez-Barricarte, Ruben; Francis, Nigel J.; Roberts, Dawn L.; Rodríguez de Córdoba, Santiago; Morgan, B. Paul; Harris, Claire L. (2011-05-24). "Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk". Proceedings of the National Academy of Sciences of the United States of America. 108 (21): 8761–8766. doi:10.1073/pnas.1019338108. ISSN 1091-6490. PMC 3102398. PMID 21555552.
  9. ↑ Cipriani, Valentina; Lorés-Motta, Laura; He, Fan; Fathalla, Dina; Tilakaratna, Viranga; McHarg, Selina; Bayatti, Nadhim; Acar, İlhan E.; Hoyng, Carel B.; Fauser, Sascha; Moore, Anthony T.; Yates, John R. W.; de Jong, Eiko K.; Morgan, B. Paul; den Hollander, Anneke I. (2020-02-07). "Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration". Nature Communications. 11 (1): 778. doi:10.1038/s41467-020-14499-3. ISSN 2041-1723. PMC 7005798. PMID 32034129.
  10. ↑ Veteleanu, Aurora; Stevenson-Hoare, Joshua; Keat, Samuel; Daskoulidou, Nikoleta; Zetterberg, Henrik; Heslegrave, Amanda; Escott-Price, Valentina; Williams, Julie; Sims, Rebecca; Zelek, Wioleta M.; Carpanini, Sarah M.; Morgan, Bryan Paul (2023-07-21). "Alzheimer's disease-associated complement gene variants influence plasma complement protein levels". Journal of Neuroinflammation. 20 (1): 169. doi:10.1186/s12974-023-02850-6. ISSN 1742-2094. PMC 10362776. PMID 37480051.
  11. ↑ Prineas, J. W.; Kwon, E. E.; Cho, E. S.; Sharer, L. R.; Barnett, M. H.; Oleszak, E. L.; Hoffman, B.; Morgan, B. P. (2001-11). "Immunopathology of secondary-progressive multiple sclerosis". Annals of Neurology. 50 (5): 646–657. doi:10.1002/ana.1255. ISSN 0364-5134. PMID 11706971. {{cite journal}}: Check date values in: |date= (help)
  12. ↑ Ramaglia, Valeria; Hughes, Timothy R.; Donev, Rossen M.; Ruseva, Marieta M.; Wu, Xiaobo; Huitinga, Inge; Baas, Frank; Neal, James W.; Morgan, B. Paul (2012-01-17). "C3-dependent mechanism of microglial priming relevant to multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America. 109 (3): 965–970. doi:10.1073/pnas.1111924109. ISSN 1091-6490. PMC 3271873. PMID 22219359.
  13. ↑ Ingram, Gillian; Hakobyan, Svetlana; Hirst, Claire L.; Harris, Claire L.; Pickersgill, Trevor P.; Cossburn, Mark D.; Loveless, Sam; Robertson, Neil P.; Morgan, Bryan Paul (2010-06). "Complement regulator factor H as a serum biomarker of multiple sclerosis disease state". Brain: A Journal of Neurology. 133 (Pt 6): 1602–1611. doi:10.1093/brain/awq085. ISSN 1460-2156. PMID 20421219. {{cite journal}}: Check date values in: |date= (help)
  14. ↑ Carpanini, Sarah M.; Torvell, Megan; Bevan, Ryan J.; Byrne, Robert A. J.; Daskoulidou, Nikoleta; Saito, Takashi; Saido, Takaomi C.; Taylor, Philip R.; Hughes, Timothy R.; Zelek, Wioleta M.; Morgan, B. Paul (2022-07-06). "Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models". Acta Neuropathologica Communications. 10 (1): 99. doi:10.1186/s40478-022-01404-w. ISSN 2051-5960. PMC 9258209. PMID 35794654.
  15. ↑ Daskoulidou, Nikoleta; Shaw, Bethany; Zelek, Wioleta Milena; Morgan, Bryan Paul (2025-07). "The Alzheimer's disease-associated complement receptor 1 variant confers risk by impacting glial phagocytosis". Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 21 (7): e70458. doi:10.1002/alz.70458. ISSN 1552-5279. PMC 12238831. PMID 40631443. {{cite journal}}: Check date values in: |date= (help)CS1 maint: article number as page number (link)
  16. ↑ Nimmo, Jacqui; Daskoulidou, Nikoleta; Van Pottelberge, Sophie; De Muynck, Louis; Morgan, B. Paul (2026-06-10). "Dysregulation of complement at the synapse in P301S mice and human tauopathies". Acta Neuropathologica Communications. 14 (1): 175. doi:10.1186/s40478-026-02347-2. ISSN 2051-5960. PMC 13495216. PMID 42271460.
  17. ↑ Zelek, Wioleta M.; Bevan, Ryan J.; Nimmo, Jacqui; Dewilde, Maarten; De Strooper, Bart; Morgan, Bryan Paul (2025-03-06). "Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model". Brain: A Journal of Neurology. 148 (3): 941–954. doi:10.1093/brain/awae278. ISSN 1460-2156. PMC 11884734. PMID 39215579.
  18. ↑ WO2021032860A3, Morgan, Bryan Paul & ZELEK, Wioleta Milena, "Anti-c7 antibody or antibody fragment", issued 2021-04-15
  19. ↑ Baillie, Kirsten; Davies, Helen E.; Keat, Samuel B. K.; Ladell, Kristin; Miners, Kelly L.; Jones, Samantha A.; Mellou, Ermioni; Toonen, Erik J. M.; Price, David A.; Morgan, B. Paul; Zelek, Wioleta M. (2024-03-08). "Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID". Med. 5 (3). New York, N.Y.: 239–253.e5. doi:10.1016/j.medj.2024.01.011. ISSN 2666-6340. PMID 38359836.
  20. ↑ Siggins, Matthew K.; Davies, Kate; Fellows, Rosie; Thwaites, Ryan S.; Baillie, J. Kenneth; Semple, Malcolm G.; Openshaw, Peter J. M.; Zelek, Wioleta M.; Harris, Claire L.; Morgan, B. Paul; ISARIC4C Investigators (2023-03). "Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19". Immunology. 168 (3): 473–492. doi:10.1111/imm.13585. ISSN 1365-2567. PMC 9537932. PMID 36175370. {{cite journal}}: Check date values in: |date= (help)CS1 maint: numeric names: authors list (link)
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