Opportunities and Challenges in Building a Spatiotemporal Multi-scale Model of the Human Pancreatic β Cell

The construction of a predictive model of an entire eukaryotic cell that describes its dynamic structure from atomic to cellular scales is a grand challenge at the intersection of biology, chemistry, physics, and computer science. Having such a model will open new dimensions in biological research and accelerate healthcare advancements. Developing the necessary experimental and modeling methods presents abundant opportunities for a community effort to realize this goal. Here, we present a vision for creation of a spatiotemporal multi-scale model of the pancreatic β-cell, a relevant target for understanding and modulating the pathogenesis of diabetes.

[1]  Alois Knoll,et al.  The Human Brain Project: Creating a European Research Infrastructure to Decode the Human Brain , 2016, Neuron.

[2]  Jie Liang,et al.  Challenges in structural approaches to cell modeling. , 2016, Journal of molecular biology.

[3]  Derek N. Macklin,et al.  The future of whole-cell modeling. , 2014, Current opinion in biotechnology.

[4]  Adrian H. Elcock,et al.  Diffusion, Crowding & Protein Stability in a Dynamic Molecular Model of the Bacterial Cytoplasm , 2010, PLoS Comput. Biol..

[5]  Wei Wei,et al.  Single cell proteomics in biomedicine: High‐dimensional data acquisition, visualization, and analysis , 2017, Proteomics.

[6]  Torsten Schwede,et al.  The SWISS-MODEL Repository: new features and functionalities , 2005, Nucleic Acids Res..

[7]  Min Xu,et al.  De Novo Structural Pattern Mining in Cellular Electron Cryotomograms. , 2015, Structure.

[8]  David S. Goodsell,et al.  3D molecular models of whole HIV-1 virions generated with cellPACK , 2014, Faraday discussions.

[9]  T. Bartol,et al.  Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J C Schaff,et al.  Virtual Cell modelling and simulation software environment. , 2008, IET systems biology.

[11]  B. Chait,et al.  Determining the architectures of macromolecular assemblies , 2007, Nature.

[12]  V. Golubovskaya,et al.  CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth , 2017, Cancers.

[13]  Reza Kalhor,et al.  Genome architectures revealed by tethered chromosome conformation capture and population-based modeling , 2011, Nature Biotechnology.

[14]  Halit Ongen,et al.  Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome , 2013, Genome research.

[15]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[16]  Jonathan R. Karr,et al.  A Whole-Cell Computational Model Predicts Phenotype from Genotype , 2012, Cell.

[17]  Lorraine Brennan,et al.  Metabolomic analysis of pancreatic beta cells following exposure to high glucose. , 2013, Biochimica et biophysica acta.

[18]  Ryohei Yasuda,et al.  High-Throughput, High-Resolution Mapping of Protein Localization in Mammalian Brain by In Vivo Genome Editing , 2016, Cell.

[19]  Douglas A. Melton,et al.  Generation of stem cell-derived β-cells from patients with type 1 diabetes , 2016, Nature Communications.

[20]  Jonathan Schug,et al.  Human islets contain four distinct subtypes of β cells , 2016, Nature Communications.

[21]  J. Vissers,et al.  Quantitative proteomics of rat and human pancreatic beta cells , 2015, Data in brief.

[22]  R. Horwitz,et al.  Integrated, multi-scale, spatial-temporal cell biology--A next step in the post genomic era. , 2016, Methods.

[23]  H. Terai,et al.  A case of congenital dyserythropoietic anemia type II associated with hemochromatosis. , 1992, Internal medicine.

[24]  T. Ideker,et al.  The cancer cell map initiative: defining the hallmark networks of cancer. , 2015, Molecular cell.

[25]  M. Aronova,et al.  Quantitative analysis of mouse pancreatic islet architecture by serial block-face SEM. , 2015, Journal of structural biology.

[26]  J. Shaw,et al.  Global estimates of diabetes prevalence for 2013 and projections for 2035. , 2014, Diabetes Research and Clinical Practice.

[27]  Bonny Jain,et al.  Towards a whole-cell modeling approach for synthetic biology. , 2013, Chaos.

[28]  R. Aebersold,et al.  Visual proteomics of the human pathogen Leptospira interrogans , 2009, Nature Methods.

[29]  Matthew P. Jacobson,et al.  A New Coarse-Grained Model for E. coli Cytoplasm: Accurate Calculation of the Diffusion Coefficient of Proteins and Observation of Anomalous Diffusion , 2014, PloS one.

[30]  Robert F Murphy,et al.  CellOrganizer: Image-derived models of subcellular organization and protein distribution. , 2012, Methods in cell biology.

[31]  Andrej Sali,et al.  Uncertainty in integrative structural modeling. , 2014, Current opinion in structural biology.

[32]  Elijah Roberts,et al.  Cellular and molecular structure as a unifying framework for whole-cell modeling. , 2014, Current opinion in structural biology.

[33]  Min Xu,et al.  Template-free detection of macromolecular complexes in cryo electron tomograms , 2011, Bioinform..

[34]  R. Miura,et al.  A Model of β -Cell Mass, Insulin, and Glucose Kinetics: Pathways to Diabetes , 2000 .

[35]  P. Aloy,et al.  Interactome3D: adding structural details to protein networks , 2013, Nature Methods.

[36]  Peter J. Meikle,et al.  A comprehensive lipidomic screen of pancreatic β-cells using mass spectroscopy defines novel features of glucose-stimulated turnover of neutral lipids, sphingolipids and plasmalogens , 2016, Molecular metabolism.

[37]  N. Slavov,et al.  SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation , 2017, Genome Biology.

[38]  W. Baumeister,et al.  Cryo-EM single particle analysis with the Volta phase plate , 2016, eLife.

[39]  R. Horwitz,et al.  Whole cell maps chart a course for 21st-century cell biology , 2017, Science.

[40]  Dale L. Greiner,et al.  Novel Observations From Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets , 2015, Diabetes.

[41]  Torsten Schwede,et al.  The SWISS-MODEL Repository and associated resources , 2008, Nucleic Acids Res..

[42]  Henning Hermjakob,et al.  The Reactome pathway knowledgebase , 2013, Nucleic Acids Res..

[43]  Felix J. B. Bäuerlein,et al.  Focused ion beam micromachining of eukaryotic cells for cryoelectron tomography , 2012, Proceedings of the National Academy of Sciences.

[44]  Jeffrey Skolnick,et al.  BROWNIAN DYNAMICS SIMULATION OF MACROMOLECULE DIFFUSION IN A PROTOCELL. , 2011, Quantum bioinformatics IV : from quantum information to bio-informatics : Tokyo University of Science, Japan, 10-13 March 2010.

[45]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[46]  Joanna Trylska,et al.  Diffusion in crowded biological environments: applications of Brownian dynamics , 2011, BMC biophysics.

[47]  Zheng Yuan,et al.  Prediction of protein B‐factor profiles , 2005, Proteins.

[48]  Christoph Bock,et al.  Single‐cell transcriptomes reveal characteristic features of human pancreatic islet cell types , 2015, EMBO reports.

[49]  Clinton S Potter,et al.  Conformational states of the full-length glucagon receptor , 2015, Nature Communications.

[50]  Masaru Tomita,et al.  E-CELL: software environment for whole-cell simulation , 1999, Bioinform..

[51]  Alvis Brazma,et al.  The BioStudies database , 2015, Molecular Systems Biology.

[52]  Yasuteru Urano,et al.  Real-time measurements of protein dynamics using fluorescence activation-coupled protein labeling method. , 2011, Journal of the American Chemical Society.

[53]  John M. Hancock,et al.  A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic β cells , 2007, Mammalian Genome.

[54]  Jean-Charles Sanchez,et al.  Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism , 2017, PloS one.

[55]  Jessica R Gooding,et al.  Metabolomics applied to the pancreatic islet. , 2016, Archives of biochemistry and biophysics.

[56]  Louis H Philipson,et al.  Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis , 2016, PloS one.

[57]  Andrej Sali,et al.  Integrative Structural Biology , 2013, Science.

[58]  Robert B Russell,et al.  The hard cell: From proteomics to a whole cell model , 2007, FEBS letters.

[59]  Victor O. Leshyk,et al.  The 4D nucleome project , 2017, Nature.

[60]  Kurt Wüthrich,et al.  Biased Signaling Pathways in β2-Adrenergic Receptor Characterized by 19F-NMR , 2012, Science.

[61]  Matthias Braun,et al.  Mathematical Modeling of Heterogeneous Electrophysiological Responses in Human β-Cells , 2014, PLoS Comput. Biol..

[62]  Amy E Herr,et al.  Single-Cell Western Blotting. , 2015, Methods in molecular biology.

[63]  Gerry McDermott,et al.  Mesoscale imaging with cryo‐light and X‐rays: Larger than molecular machines, smaller than a cell , 2017, Biology of the cell.

[64]  Chris de Graaf,et al.  Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators , 2017, Nature.

[65]  Brad J Marsh,et al.  Expedited approaches to whole cell electron tomography and organelle mark-up in situ in high-pressure frozen pancreatic islets. , 2008, Journal of structural biology.

[66]  Philip Miller,et al.  BiGG Models: A platform for integrating, standardizing and sharing genome-scale models , 2015, Nucleic Acids Res..

[67]  Lori Sussel,et al.  Heterogeneity of the Pancreatic Beta Cell , 2017, Front. Genet..

[68]  J. Kendrew Myoglobin and the structure of proteins. , 1963, Science.

[69]  Michael Krauss,et al.  Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins , 2014, Science.

[70]  R. Murphy Building cell models and simulations from microscope images. , 2016, Methods.

[71]  Y. Sugita,et al.  Biomolecular interactions modulate macromolecular structure and dynamics in atomistic model of a bacterial cytoplasm , 2016, eLife.

[72]  J Andrew McCammon,et al.  Accelerated Molecular Dynamics Simulations of Protein Folding , 2016, Journal of computational chemistry.

[73]  Min Xu,et al.  De Novo Structural Pattern Mining in Cellular Electron Cryotomograms. , 2015, Structure.

[74]  S. Bonner-Weir,et al.  β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance. , 2017, Cell metabolism.

[75]  Haruki Nakamura,et al.  Outcome of the First wwPDB Hybrid/Integrative Methods Task Force Workshop. , 2015, Structure.

[76]  The Uniprot Consortium UniProt: the universal protein knowledgebase , 2018, Nucleic acids research.

[77]  Jamie W Joseph,et al.  Metabolomic analysis of pancreatic β-cell insulin release in response to glucose , 2012, Islets.

[78]  Leslie M Loew,et al.  Spatial modeling of cell signaling networks. , 2012, Methods in cell biology.

[79]  Lukasz A. Kurgan,et al.  D2P2: database of disordered protein predictions , 2012, Nucleic Acids Res..

[80]  Pascal Benkert,et al.  QMEAN: A comprehensive scoring function for model quality assessment , 2008, Proteins.

[81]  Javier Carrera,et al.  Why Build Whole-Cell Models? , 2015, Trends in cell biology.

[82]  Yuji Sugita,et al.  Complete atomistic model of a bacterial cytoplasm for integrating physics, biochemistry, and systems biology. , 2015, Journal of molecular graphics & modelling.

[83]  John W Sedat,et al.  A distributed multi-GPU system for high speed electron microscopic tomographic reconstruction. , 2011, Ultramicroscopy.

[84]  Jonathan R. Karr,et al.  Accelerated discovery via a whole-cell model , 2013, Nature Methods.

[85]  Wolfgang Baumeister,et al.  A visual approach to proteomics , 2006, Nature Reviews Molecular Cell Biology.

[86]  M. Riel-Mehan,et al.  cellPACK: A Virtual Mesoscope To Model and Visualize Structural Systems Biology , 2015 .

[87]  Torsten Schwede,et al.  The SWISS-MODEL Repository—new features and functionality , 2016, Nucleic Acids Res..

[88]  Genji Kurisu,et al.  PDB-Dev: a Prototype System for Depositing Integrative/Hybrid Structural Models. , 2017, Structure.

[89]  Zaida Luthey-Schulten,et al.  Challenges of Integrating Stochastic Dynamics and Cryo-Electron Tomograms in Whole-Cell Simulations. , 2017, The journal of physical chemistry. B.

[90]  Louis H Philipson,et al.  Modeling of Ca2+ flux in pancreatic beta-cells: role of the plasma membrane and intracellular stores. , 2003, American journal of physiology. Endocrinology and metabolism.

[91]  Michael P H Stumpf,et al.  How to deal with parameters for whole-cell modelling , 2017, Journal of The Royal Society Interface.

[92]  James D. Johnson,et al.  Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells , 2014, Nature Biotechnology.