Dr Alexander Fletcher
School of Mathematical and Physical Sciences
School Director of Research and Innovation
Professor of Mathematical Biology
a.g.fletcher@sheffield.ac.uk
+44 114 222 3846
+44 114 222 3846
G15, Hicks Building
Full contact details
Dr Alexander Fletcher
School of Mathematical and Physical Sciences
G15
Hicks Building
Hounsfield Road
Sheffield
S3 7RH
School of Mathematical and Physical Sciences
G15
Hicks Building
Hounsfield Road
Sheffield
S3 7RH
- Profile
-
- 2022 - 2024: Senior Lecturer, School of Mathematics and Statistics, University of Sheffield
- 2019 - 2022: Lecturer, School of Mathematics and Statistics, University of Sheffield
- 2015 - 2019 : Vice-Chancellor's Fellow, School of Mathematics and Statistics, University of Sheffield
- 2011 - 2015 : Research Fellow in Computational Science, Mathematical Institute, University of Oxford
- 2008 - 2015 : Stipendiary Lecturer in Mathematics, St Hugh's College, University of Oxford
- 2008 - 2011 : Postdoctoral Research Assistant, Mathematical Institute, University of Oxford
- 2005 - 2010 : DPhil, Mathematical Institute, University of Oxford
- Research interests
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I develop and apply mathematical models to study complex biological systems. Techniques range from discrete and continuous models of temporal dynamics to more computationally intensive individual-based and multiscale simulations. Major applications include mechanisms underlying tissue homeostasis and their disruption in cancer formation and progression, and the orchestration of cell-level processes such as proliferation, death, adhesion and migration to give correct tissue-level proportions in embryos.
- Publications
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Featured publications
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All publications
Journal articles
- The mechanical influence of densification on epithelial architecture. PLOS Computational Biology, 20(4), e1012001-e1012001.
- insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology. Biology Open, 12(9).
- In-silico and in-vitro morphometric analysis of intestinal organoids. PLOS Computational Biology, 19(8). View this article in WRRO
- Polychaetoid/ZO-1 strengthens cell junctions under tension while localizing differently than core adherens junction proteins. Molecular Biology of the Cell, 34(8), ar81.
- The Mechanical Influence of Densification on Initial Epithelial Architecture.
- ChemChaste : simulating spatially inhomogeneous biochemical reaction–diffusion systems for modeling cell–environment feedbacks. GigaScience, 11(2022).
- Adhesion-regulated junction slippage controls cell intercalation dynamics in an Apposed-Cortex Adhesion Model. PLoS Computational Biology, 18(1).
- The evolution of strategy in bacterial warfare via the regulation of bacteriocins and antibiotics. eLife, 10.
- Modelling of epithelial growth, fission and lumen formation during embryonic thyroid development : a combination of computational and experimental approaches. Frontiers in Endocrinology, 12.
- Seven challenges in the multiscale modeling of multicellular tissues. WIREs Mechanisms of Disease. View this article in WRRO
- Of mitogens and morphogens : modelling Sonic Hedgehog mechanisms in vertebrate development. Philosophical Transactions of the Royal Society B: Biological Sciences, 375(1809).
- Contemporary morphogenesis: Contemporary morphogenesis. Philosophical Transactions of the Royal Society B: Biological Sciences, 375(1809).
- Toward engineering biosystems with emergent collective functions. Frontiers in Bioengineering and Biotechnology, 8. View this article in WRRO
- Coupled differentiation and division of embryonic stem cells inferred from clonal snapshots. Physical Biology. View this article in WRRO
- Chaste: Cancer, Heart and Soft Tissue Environment. Journal of Open Source Software, 5(47), 1848-1848.
- Close encounters of the cell kind: The impact of contact inhibition on tumour growth and cancer models. Bulletin of Mathematical Biology, 82(2). View this article in WRRO
- Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts : insights from an agent-based model. Computational and Structural Biotechnology Journal, 18, 230-240. View this article in WRRO
- The tricellular vertex-specific adhesion molecule sidekick facilitates polarised cell intercalation during drosophila axis extension. PLOS Biology, 17(12). View this article in WRRO
- Conserved gene signalling and a derived patterning mechanism underlie the development of avian footpad scales. EvoDevo, 10(1). View this article in WRRO
- Inferring tumour proliferative organisation from phylogenetic tree measures in a computational model. Systematic Biology, 0, 1-41. View this article in WRRO
- The devil is in the mesoscale: Mechanical and behavioural heterogeneity in collective cell movement. Seminars in Cell and Developmental Biology, 93, 46-54. View this article in WRRO
- Experimental and theoretical evidence for bidirectional signaling via core planar polarity protein complexes in Drosophila. iScience, 17, 49-66. View this article in WRRO
- Quantification of crypt and stem cell evolution in the normal and neoplastic human colon. Cell Reports, 27(8), 2524-2524. View this article in WRRO
- Recasting the Cancer Stem Cell Hypothesis: Unification Using a Continuum Model of Microenvironmental Forces. Current Stem Cell Reports, 5(1), 22-30. View this article in WRRO
- Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation. Cell Death & Disease, 10. View this article in WRRO
- Tissue tension and not interphase cell shape determines cell division orientation in the Drosophila follicular epithelium. EMBO Journal, 38(3). View this article in WRRO
- An ancient Turing-like patterning mechanism regulates skin denticle development in sharks. Science Advances, 4(11). View this article in WRRO
- Chronic TNFα-driven injury delays cell migration to villi in the intestinal epithelium.. Interface, 15(145). View this article in WRRO
- Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis. Journal of Mathematical Biology, 76(7), 1673-1697. View this article in WRRO
- Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues.. Journal of Theoretical Biology, 443, 66-81. View this article in WRRO
- Numerical Analysis of the Immersed Boundary Method for Cell-Based Simulation. SIAM Journal on Scientific Computing, 39(5), B943-B967. View this article in WRRO
- Integrating planar polarity and tissue mechanics in computational models of epithelial morphogenesis. Current Opinion in Systems Biology, 5, 41-49. View this article in WRRO
- Impact of implementation choices on quantitative predictions of cell-based computational models. Journal of Computational Physics, 345, 752-767. View this article in WRRO
- A hierarchical Bayesian model for understanding the spatiotemporal dynamics of the intestinal epithelium. PLoS Computational Biology, 13(7). View this article in WRRO
- Morphological Plant Modeling: Unleashing Geometric and Topological Potential within the Plant Sciences. Frontiers in Plant Science, 8. View this article in WRRO
- Mechanocellular models of epithelial morphogenesis. Philosophical Transactions of the Royal Society B: Biological Sciences, 372(1720). View this article in WRRO
- Comparing individual-based approaches to modelling the self-organization of multicellular tissues.. PLoS Computational Biology, 13(2). View this article in WRRO
- An extended model for culture-dependent heterogenous gene expression and proliferation dynamics in mouse embryonic stem cells. npj Systems Biology and Applications, 3(1). View this article in WRRO
- Robust cell tracking in epithelial tissues through identification of maximum common subgraphs. Interface, 13(124). View this article in WRRO
- Unipolar distributions of junctional Myosin II identify cell stripe boundaries that drive cell intercalation throughout Drosophila axis extension. eLife, 5. View this article in WRRO
- A Computational Modeling Approach for Deriving Biomarkers to Predict Cancer Risk in Premalignant Disease. Cancer Prevention Research, 9(4), 283-295. View this article in WRRO
- Multiscale modelling of intestinal crypt organization and carcinogenesis. Mathematical Models and Methods in Applied Sciences, 25(13), 2563-2585. View this article in WRRO
- Migration and horizontal gene transfer divide microbial genomes into multiple niches. Nature Communications, 6(1). View this article in WRRO
- Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance. PLoS Computational Biology, 11(9). View this article in WRRO
- A parallel implementation of an off-lattice individual-based model of multicellular populations. Computer Physics Communications, 192, 130-137. View this article in WRRO
- Models, measurement and inference in epithelial tissue dynamics. Mathematical Biosciences and Engineering, 12(6), 1321-1340. View this article in WRRO
- Oxygen consumption dynamics in steady-state tumour models. Royal Society Open Science, 1(1), 140080-140080. View this article in WRRO
- Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon. Cell Reports, 8(4), 940-947.
- Modelling and analysis of bacterial tracks suggest an active reorientation mechanism in
Rhodobacter sphaeroides. Journal of The Royal Society Interface, 11(97), 20140320-20140320.
- Vertex Models of Epithelial Morphogenesis. Biophysical Journal, 106(11), 2291-2304.
- Metabolic Alterations During the Growth of Tumour Spheroids. Cell Biochemistry and Biophysics, 68(3), 615-628.
- A filter-flow perspective of haematogenous metastasis offers a non-genetic paradigm for personalised cancer therapy. European Journal of Cancer, 50(17), 3068-3075.
- Implementing vertex dynamics models of cell populations in biology within a consistent computational framework. Progress in Biophysics and Molecular Biology, 113(2), 299-326.
- Mechanisms and mechanics of cell competition in epithelia. Nature Reviews Molecular Cell Biology, 14(9), 581-591.
- The effect of sampling rate on observed statistics in a correlated random walk. Journal of the Royal Society Interface, 10(85).
- Toward a quantitative understanding of the Wnt/β
-catenin pathway through simulation and experiment. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 5(4), 391-407.
- A theoretical investigation of the effect of proliferation and adhesion on monoclonal conversion in the colonic crypt. Journal of Theoretical Biology, 312, 143-156.
- A PHABULOSA/Cytokinin Feedback Loop Controls Root Growth in Arabidopsis. Current Biology, 22(18), 1699-1704.
- Mathematical modeling of monoclonal conversion in the colonic crypt. Journal of Theoretical Biology, 300, 118-133.
- Modelling the role of the basement membrane beneath a growing epithelial monolayer. Journal of Theoretical Biology, 298, 82-91.
- Comparing a discrete and continuum model of the intestinal crypt. Physical Biology, 8(2), 026011-026011.
- A hybrid approach to multi-scale modelling of cancer. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 368(1930), 5013-5028.
- An integrative computational model for intestinal tissue renewal. Cell Proliferation, 42(5), 617-636.
- Chaste: A test-driven approach to software development for biological modelling. Computer Physics Communications, 180(12), 2452-2471.
- Accurate staging of chick embryonic tissues via deep learning of salient features. Development.
- Spatial Metrics of Tumour Vascular Organisation Predict Radiation Efficacy in a Computational Model. PLOS Computational Biology, 12(1), e1004712-e1004712. View this article in WRRO
- Capabilities and Limitations of Tissue Size Control through Passive Mechanical Forces. PLOS Computational Biology, 11(12), e1004679-e1004679. View this article in WRRO
- Patterning of wound-induced intercellular Ca2+flashes in a developing epithelium. Physical Biology, 12(5), 056005-056005. View this article in WRRO
- Evidence of a role for radiation-induced lysosomal damage in non-targeted effects: an experimental and theoretical analysis.
- Capabilities and Limitations of Tissue Size Control Through Passive Mechanical Forces.
- Ten Simple Rules for a Successful Cross-Disciplinary Collaboration. PLOS Computational Biology, 11(4), e1004214-e1004214. View this article in WRRO
- Modelling and analysis of bacterial tracks suggest an active reorientation mechanism inRhodobacter sphaeroides.
- Ten Simple Rules for Effective Computational Research. PLoS Computational Biology, 10(3), e1003506-e1003506. View this article in WRRO
- Novel Methods for Analysing Bacterial Tracks Reveal Persistence in Rhodobacter sphaeroides. PLoS Computational Biology, 9(10), e1003276-e1003276. View this article in WRRO
- Chaste: An Open Source C++ Library for Computational Physiology and Biology. PLoS Computational Biology, 9(3), e1002970-e1002970. View this article in WRRO
- A computational study of discrete mechanical tissue models. Physical Biology, 6(3), 036001-036001.
- MultiCellDS: a community-developed standard for curating microenvironment-dependent multicellular data. View this article in WRRO
- Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi. FASEB Journal. View this article in WRRO
Chapters
- Mathematical Modeling of the Metastatic Process, Experimental Metastasis: Modeling and Analysis (pp. 189-208). Springer Netherlands
- Multiscale Cancer Modeling CRC Press
Conference proceedings papers
- A multidisciplinary approach to studying crypt-villus homeostasis and regeneration in the intestinal epithelium. FEBS JOURNAL, Vol. 281 (pp 217-218)
Preprints
- Donor embryonic stem cells impede host epiblast specification in 8-cell stage chimeras by crowding and FGF4 signalling, Cold Spring Harbor Laboratory.
- Polychaetoid/ZO-1 strengthens cell junctions under tension while localizing differently than core adherens junction proteins, Cold Spring Harbor Laboratory.
- In-silicoandin-vitromorphometric analysis of intestinal organoids, Cold Spring Harbor Laboratory.
- Seven Challenges in the Multiscale Modelling of Multicellular Tissues, MDPI AG.
- Towards Engineering Biosystems with Emergent Collective Functions, MDPI AG.
- Coupled differentiation and division of embryonic stem cells inferred
from clonal snapshots, arXiv.
- Multiscale modelling of intestinal crypt organization and carcinogenesis, arXiv.
- Models, measurement and inference in epithelial tissue dynamics, arXiv.
- A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy, arXiv.
- Mathematical modeling of the metastatic process, arXiv.
- Bespoke data augmentation and network construction enable image classification on small microscopy datasets, Cold Spring Harbor Laboratory.
- insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology, Cold Spring Harbor Laboratory.
- ChemChaste: Simulating spatially inhomogenous biochemical reaction-diffusion systems for modelling cell-environment feedbacks, Cold Spring Harbor Laboratory.
- Competition Between Cell-Cell and Cell-Substrate Adhesion Determines Epithelial Monolayer Architecture in Culture, Cold Spring Harbor Laboratory.
- Adhesion dynamics regulate cell intercalation behaviour in an active tissue, Cold Spring Harbor Laboratory.
- The tricellular vertex-specific adhesion molecule Sidekick facilitates polarised cell intercalation during Drosophila axis extension.
- Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: insights from an agent-based model.
- Inferring Tumour Proliferative Organisation from Phylogenetic Tree Measures in a Computational Model. View this article in WRRO
- Chronic inflammation delays cell migration to villi in the intestinal epithelium, Cold Spring Harbor Laboratory.
- Information Flow in Planar Polarity.
- Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues, Cold Spring Harbor Laboratory.
- Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis, Cold Spring Harbor Laboratory.
- MultiCellDS: a standard and a community for sharing multicellular data.
- Impact of implementation choices on quantitative predictions of cell-based computational models, Cold Spring Harbor Laboratory.
- Harnessing the lymphocyte meta-phenotype to optimize adoptive cell therapy.
- QuickStitch for seamless stitching of confocal mosaics through high-pass filtering and recursive normalization.
- Morphological plant modeling: Unleashing geometric and topological potential within the plant sciences, Cold Spring Harbor Laboratory.
- Comparing Individual-Based Approaches to Modelling the Self-Organization of Multicellular Tissues, Cold Spring Harbor Laboratory.
- A hierarchical Bayesian framework for understanding the spatiotemporal dynamics of the intestinal epithelium, Cold Spring Harbor Laboratory.
- Numerical Analysis of the Immersed Boundary Method for Cell-Based Simulation, Cold Spring Harbor Laboratory.
- Robust cell tracking in epithelial tissues through identification of maximum common subgraphs, Cold Spring Harbor Laboratory.
- Spatial metrics of tumour vascular organisation predict radiation efficacy in a computational model, Cold Spring Harbor Laboratory.
- A computational modelling approach for deriving biomarkers to predict cancer risk in premalignant disease, Cold Spring Harbor Laboratory.
- Exploiting evolutionary non-commutativity to prevent the emergence of bacterial antibiotic resistance, Cold Spring Harbor Laboratory.
- A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy, Cold Spring Harbor Laboratory.
- The mechanical influence of densification on epithelial architecture. PLOS Computational Biology, 20(4), e1012001-e1012001.
- Research group
- Grants
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Current grants, as Principal Investigator: Inferring epithelial tissue mechanics through data-efficient multi-fidelity modelling BBSRC Understanding self-organised tissue patterning across scales EPSRC Chaste: developing sustainable software for computational biology BBSRC Current grants, as Coinvestigator: Hypothalamic development from self-organising progenitors Wellcome Trust Past grants, as Coinvestigator: How do the atypical cadherins Fat and Dachsous integrate growth and patterning during development? BBSRC
- Teaching activities
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MAS116 Mathematical Investigation Skills
MAS2007 Mathematics and Statistics in Action