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Multi-Layer Modeling in Systems Biology Sriram Iyengar, PhD, Associate Professor, School of Biomedical Informatics Associate Professor, School of Biomedical

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  • Multi-Layer Modeling in Systems Biology Sriram Iyengar, PhD, Associate Professor, School of Biomedical Informatics Associate Professor, School of Biomedical Informatics University of Texas, Houston Biological processes involved in diseases and disease progression require integration of multiple types of knowledge.
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  • 2 A goal of Systems Biology t = time Functionality(t) = (y1,y2,y3,..,t) = f(x1,x2,x3,, t) Other goals, maybe on the way to achieving the above: Enhance detailed understanding of biological processes
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  • 3 Biology is complex Biology is complex! Interactome - Protein-protein Interaction Map - The Scientist 2004, 18(12):18
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  • 4 What can systems biology do for medicine and patient care Develop accurate specific and personalized models of actual biological processes based on tissue samples and individual genetics Generate hypotheses for disease presence and disease progression Support personalized medicine Develop targeted therapies. Support translational medicine
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  • 5 The biological cell: Natures canonical object in the sense of Object oriented programming The fundamental unit of life is the biological cell and hence should be the focus for current research in digital biology - Sidney Brenner, 2002 Nobel laureate in medicine Cellular process modeling is now an active research area - E-cell project (Japan) - Virtual cell project (National Resource for Cell Analysis and Modeling, USA) Create in-silico digital cell
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  • 6 But: Biological cells are extremely intricate ~500 types of cells - red blood cells, neurons, and more >60 billion cells in the human body - >100 billion Symbiotic bacteria 30,000 proteins expressed at any given time by a cell Thats only a fraction of what a cell does, or what it looks like A cubic cm of the human brain can contain 50 million neurons, each supported by 10 glial cells and connected to many other neurons
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  • 7 In silico cell modeling The challenge - Creating an executable software description of a biological cell is an extremely formidable task The computer science response - Reduce complexity Use artificial Intelligence and software engineering methods
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  • 8 Why do this? Morphoproteomics Development of malignant tumors depends on - Timing Cell cycle phase - Location Interactions in cell - Pathways Signal cell proliferation - Crosstalk Messages sent across multiple signaling pathways Robert Brown, MD, Deputy Chief of Pathology, Univ. Texas, Houston
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  • 9 Morphoproteomics visual analysis of stained tumor cells
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  • 10 Glioblastoma multiforme
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  • 11 Implications for cancer therapy Multidimensional approach required to analyze - Timing - Location - Signals - Crosstalk Cell morphology - Where are particular signal transduction events taking place? - How does intracellular morphology, eg cytoskeleton, impact signaling, cross-talk and ultimately, disease progression?
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  • 12 Techniques to reduce complexity Abstraction - Capture the essential or defining attributes of a body of knowledge Modularity - Divide and conquer Reduce complex problems into simpler sub-problems Solve each sub-problem by domain specialists
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  • 13 Model Abstraction & Assembly Abstraction - Simplify the system in such a way that the properties of interest are preserved - Einstein: Make the abstracted system as simple as possible, but no simpler Assemble the sub-problems - Glue via a suite of interfaces (APIs - Application Programming Interfaces) Create a multi-layer model: what criteria? Physical scale? Functional behavior? Injection of humility: remember that All models are wrong, but some are useful GEP Box (a statistician)
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  • 14 Example Multi-layer model ISO-OSI - International Standards Organization - Open Systems Interconnect - Used to model and create systems for data communications - Email, web, file transfer
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  • 15 ISO-OSI model for Data Communications
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  • 16 Multi-layer Modeling benefits Complex problem reduced to tractable sub-problems - Data homogeneous within a layer Each layer can be dealt with by appropriate specialists - Problems in the physical layer differ from those in the application layer - Different skills needed - No one person must be expert in several disciplines (layers) Universal focus in thought and discussion - TCP belongs to transport layer Everyone knows what TCP does and does not do
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  • 17 Building multi-layer models to support Systems Biology How can this be done? Lets consider one aspect at a time - Simplify the system via divide & conquer Define the sub-problems and their interfaces - Data - Processes - Interactions Goal - To create a model based on the synthesis of heterogeneous knowledge Biological cell seems to be a good place to start
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  • 18 Multi-layer Cell Model ____Metabolism / Signaling ____Physical Structure ____Symbolic Biochemistry ____Biochemistry____Functionality ____Molecular Morphology
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  • 19 Molecular Morphology Bio-molecular structure & form Molecular modeling Molecular dynamics - UIUC group, www.ks.uiuc.edu Protein folding, conformation Interactions at molecular level - UTH -www.biomachina.org
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  • 20 Biochemistry (Thermodynamics) View cell as a dynamic chemical machine Use reaction kinetics, rate constants Michaelis-Menten equation Set multiple equilibria Identify bio-chemical minutiae by which organic molecules interact with each other Examples Plateki (www.biokin.com) Determines inhibition constants from plate-reader data
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  • 21 Symbolic biochemistry Abstract symbolic models of biochemical assemblies from components - DNA as an assembly of A, G, C, T - Proteins as assemblies of amino acids Genetic code - Human genome project Algorithms: Smith-Waterman, Hidden Markov models
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  • 22 Metabolism Cells convert nutrients into energy via metabolic pathways & processes Symbolic models facilitate understanding of cells Quality of life Is cell functioning at 100% energy efficiency? Examples - Biocyc projects - E-cell project
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  • 23 Signaling Processes by which cell communicates with external entities and intra-cellular components Signal transduction pathways Examples - Pathway Logic - Pi Calculus - Rewriting Logic and Protein Functional Domains
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  • 24 Physical Structure Cell Morphology Cell Assembly - anatomic components 3-D shapes 3-D spatial relationships Physical characteristics of cell components - Texture - Permeability Specialized components - Axons, Dendrons etc Cytoview Project: In collaboration with Indian Inst of Science Journal of Biosciences, v32 #5 Cytoview: Development of a cell modeling framework.
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  • 25 Cytoview: Ontology of components
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  • 26 Relationship Matrix
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  • 27 Functionality What does cell do? - Use mathematical and software idealizations - Black box, systems approach - Like ISO-OSI application layer Examples - McCulloch-Pitts model of neuron - Models of optical cells The challenge of in silico cell modeling - How to relate functionality to rest of cell
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  • 28 Interfaces Receptors & other chemical entities - Enable signaling - Serve as interfaces among pathway segments Receptors - From computing / communications view Receptors are control hubs They determine topologies of signaling and metabolic pathways - Receptor chemistry is an important discipline in itself Symbolic descriptions of signaling interfaces help define cell processes
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  • 29 Multi-layered synthesis of heterogeneous knowledge It is most likely impossible that - The complete story From functionality down to the molecular layer - Can be expressed by a set of mathematical equations But it is possible that - Algorithmic procedures encoded in software can do so The layered model is intended to provide a framework for developing software & underlying knowledge bases - Morphoproteomics - Other applications ???
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  • 30 Example Firing of neuron can be represented as - A cascade of events & processes across layers Depending on desired level of detail, a multi-layer software model of neuron firing may - instantiate objects, databases, & software from several levels Functionality is clearly dependent on physical structure - Axons, dendrites
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  • 31 Example Neurons continued existence & wellness depends on metabolism Control behavior is mediated by signal transduction - Biochemical neural signals at input synapses Biochemistry & molecular dynamics mediate actual passage of electrical signals (Hodgkin-Huxley)
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  • 32 Layered model tasks Define overall - Application Programming Interfaces, or rather meta- APIs, which describe how layers should communicate with each other Define for each layer - Uniform standards for representations of knowledge - Standards for databases and database access Note: above tasks are simplified since there is greater homogeneity of knowledge within a layer Interactions between layers: eg, can results derived from reasoning in the symbolic biochemistry layer be used to reduce dimensionality or enhance computational tractability in the biochemistry layer
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  • 33 Summary Bio-molecular complexity may be reduced by - Abstraction - Modularization The goal of creating an in silico complex biological objects, eg, biological cell, may be facilitated by means of the layered model described Multi-layer model as an organizing principle to guide discussion, research, development?
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  • 34 Challenges To date most methods have been used for analysis of interactions within a single cell In reality, cells work together - or aqainst each other - in biological processes Cancer involves millions of cells and inter-cellular interactions (metastasis) Computer science can offer tools to solve these challenging problems Morphoproteomics, with its depth of heterogeneous knowledge, is a unique application area that bridges bench to bedside : Translational, personalized medicine
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  • 35 Acknowledgements Mary McGuire, MS, PhD, UT Houston Jack W Smith, MD, PhD, UT Houston Robert Brown, MD, UT Houston Pat Lincoln, PhD, SRI Carolyn Talcott, PhD, SRI David Mercer, MD, University of Nebraska Suma Chandra, PhD, Indian Institute of Science N. Balakrishnan,PhD, Indian institute of Science