Network models of biological complex systems

Abstract

This invention describes computer based systems and methods for modeling and simulation of complex biological systems from the cellular, or subcellular, to the organism and population level, for using said models to predict functions of components of the biological systems and to simulate physiological and pathological states at the various levels, and for using said models in drug development for testing in a computer system substances for possible use as therapeutics by simulating their effects on the physiological and pathological states.

128 . An interactive computer-implemented system for modelling a dynamic multi-variable biological system from the cellular, or subcellular, to the human or patient population level, wherein the biological system is controlled by a plurality of interrelated biologic processes defining functions occurring within the biological system, comprising: 
 a) a plurality of levels, each level comprising one or more distinct linkable entities representing biologic processes, and each level having a respective level of biologic complexity; and    b) a human interface for interacting with the plurality of levels to create an executable model of the dynamic multi-variable biological system.    
   
   
       129 . The interactive computer-implemented system of  claim 128 , wherein the plurality of levels comprise two or more levels having links between said levels for navigating information between said levels during execution of the model.  
   
   
       130 . The interactive computer-implemented system of  claim 128 , wherein the plurality of levels comprises two or more levels having links between levels for providing model information to the human interface.  
   
   
       131 . The interactive computer-implemented system of  claim 128 , wherein said entities comprise interactive graphical entities.  
   
   
       132 . The interactive computer-implemented system of  claim 128 , wherein said human interface includes an input mechanism for altering information used by the model.  
   
   
       133 . The interactive computer-implemented system of  claim 128 , wherein said human interface includes an output mechanism for viewing information from the model.  
   
   
       134 - 137 . (canceled)  
   
   
       139 . (canceled)  
   
   
       140 . A method for use in drug development, comprising the steps of: 
 a) developing an interactive computer-implemented system for modeling a dynamic multi-variable biological system from the cellular, or subcellular, to the human or patient population level, wherein the biological system is controlled by a plurality of interrelated biologic processes defining functions occurring within the biological system, wherein said computer-implemented system includes a plurality of levels, each level comprising one or more distinct linkable entities representing biologic processes, and each level having a respective level of complexity, and a human interface for interacting with one or more levels from the plurality of levels; and    b) applying said interactive computer-implemented system to drug development, wherein said interactive computer-implemented system considers the effects of a drug on biologic processes to identify appropriate applications for the drug.    
   
   
       143 . (canceled)  
   
   
       145 . A computer readable medium or media, comprising a computer executable model of a hierarchical biological system, the model for use with a computer system including a memory and a processor, the model comprising: 
 a) a plurality of biological modeling units stored in the memory, each biological modeling unit having: 
 i) at least one chemical level input representing a level of a chemical available to the biological modeling unit;  
 ii) at least one chemical production output representing a level of a chemical produced by the biological modeling unit and made available to other biological modeling units; and  
 iii) a chemical production function describing the production output of a chemical by the biological modeling unit as a function of the chemical level inputs; and  
   b) the plurality of biological modeling units organized into a plurality of levels, each level representing a different level of biological function, each biological modeling unit in any level providing its chemical production outputs to any number of other biological modeling units, receiving as its chemical level input, chemical levels from any number of other biological modeling units, and wherein execution of the model by the processor modifies the respective inputs and outputs of each of the biological modeling units.    
   
   
       146 . The computer readable medium or media of  claim 145 , wherein first and second biological modeling units represent first and second cell pools, each cell pool representing cells of a particular type or cells in particular state, the model further comprising: 
 a) a regulator biological modeling unit representing a regulator function comprising: 
 i) at least one chemical level input representing a level of a chemical available to the regulator biological modeling unit;  
 ii) at least one quantity input representing a quantity of a first type of biological modeling unit; and  
   b) regulator function describing a change in the first type of biological modeling unit as a function of the chemical level and quantity inputs, wherein execution of the model by the processor causes respective changes in the quantities of the first and second types of biological modeling units, and representing changes in the quantities of cells in the respective first and second cell pools.    
   
   
       147 . A computer readable medium or media, comprising a computer executable model of a hierarchical biological system, the model for use with a computer system including a memory and a processor, the model comprising: 
 a) a plurality of cell pool modeling units and one or more cell production modeling units stored in the memory, each cell pool modeling unit representing a quantity of cells having a particular cell type or a particular cell state, at least one of the cell production modeling unit having: 
 i) at least one chemical level input representing a level of a chemical in an environment containing the cells of a selected first cell pool modeling unit;  
 ii) at least one quantity input representing a quantity of cells of the selected first cell pool modeling unit; and  
 iii) at least one output representing a quantity of cells of a selected second cell pool modeling unit or a level of a chemical produced by the first or second cell pool modeling unit; and  
   b) at least one production function, executable by the processor, that generates said at least one output in response to the chemical level input and quantity input;    wherein execution of the model by the processor causes the production function of each cell production modeling unit to modify the at least one output.    
   
   
       148 . (canceled)  
   
   
       155 . (canceled)  
   
   
       175 - 177 . (canceled)  
   
   
       190 - 191 . (canceled)  
   
   
       205 - 206 . (canceled)  
   
   
       207 . (canceled)  
   
   
       216 - 217 . (canceled)  
   
   
       220 . (canceled)  
   
   
       223 . A method for testing a substance for possible use as a therapeutic by simulating its effect on the physiological state of one or more cells, comprising the steps of: 
 a) specifying a biochemical network of one or more cells;    b) simulating said network by specifying the components of said network, and representing relationships between said components in one or more mathematical equations and setting the quantitative parameters of said components;    c) solving the mathematical equations to simulate a first physiological state of the one or more cells;    d) modifying the simulated network created above by representing the relationships between said chosen substance and other cell components in mathematical equations and setting forth the quantitative parameters of said components;    e) solving the mathematical equations of said modified simulated network to simulate a second physiological state of the one or more cells; and    f) identifying the differences between said first and second physiological state, and therefore testing the potential effect of said substance as a therapeutic.    
   
   
       224 . A method as recited in  claim 223  further comprising perturbing the modified simulated network by deleting one or more components thereof, changing the concentration of one or more components thereof or modifying one or more mathematical equations representing relationships between one or more of said components.  
   
   
       228 - 229 . (canceled)  
   
   
       230 - 233 . (canceled)  
   
   
       236 . (canceled)  
   
   
       237 - 238 . (canceled)  
   
   
       239 . A method for predicting a function of a component, intrinsic or added to a biological system, comprising: 
 a) providing a data structure relating a plurality of biological system reactants to a plurality of biological system reactions, wherein a plurality of said reactions comprises a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product, wherein said component is a reactant in at least one of said reactions;    b) providing and aplying a constraint set for said plurality of reactions;    c) providing at least one reactant distribution that results in a desired state of the biological system when said constraint set is applied to said data structure; and    d) determining the effects of adding or deleting said component, or modifying the properties of said component, on the state of the biological system, thereby predicting a function in which said component participates.    
   
   
       265 - 267 . (canceled)  
   
   
       268 - 269 . (canceled)  
   
   
       394 . The method of  claim 223 , wherein said components include first components each representing one or more biological entities of a given type, each component comprising any type of information or data associated with the one or more biological entities of a given type or second components of said first components, or any combination thereof.  
   
   
       395 . The method of  claim 394 , wherein at least one of the biological entities is a cell or a protein.  
   
   
       396 . The method of  claim 394 , wherein at least one of said first components comprises or references a variable that represents an absolute or relative quantity of the one or more biological entities of a given type it represents.  
   
   
       397 . The method of  claim 223 , wherein said relationships comprise semi-quantitative relationships.  
   
   
       398 . The method of  claim 223 , comprising at least one relationship between said components of type selected from the group of conversion, association, translocation, activation, inhibition, modification and regulation.  
   
   
       399 . The method of  claim 223 , further comprising at least one relationship between said components of type selected from the group of downstream, upstream, composition, linkage and containment.  
   
   
       400 . The method of  claim 223 , further comprising selecting said components or the values of their attributes or variables from a database.  
   
   
       401 . The method of  claim 223 , further comprising using an inference engine for reasoning over said components or their relationships, or any combination thereof.  
   
   
       402 . The method of  claim 223 , wherein a rule set specifies how said components may be related to other components.  
   
   
       403 . The method of  claim 223 , further comprising dynamically simulating networks of genetic, metabolic or signal transduction pathways, or any combination thereof.  
   
   
       404 . The method of  claim 223 , wherein at least one subnetwork or component is reusable to compose at least other network or subnetwork.  
   
   
       405 . The method of  claim 223 , wherein at least one network is defined through modification of at least one attribute or variable of at least one component of a preexisting network.  
   
   
       406 . The method of  claim 223 , wherein at least one component is defined as a prototype that can be instantiated and configured dynamically.  
   
   
       407 . The method of  claim 223 , wherein the components are defined as a hierarchy representing an ontology of the different functional units of a biological domain.  
   
   
       408 . The method of  claim 223 , wherein at least one component is defined as a lumped parameter system or black-box system.  
   
   
       409 . The method of  claim 223 , wherein a plurality of components comprise at least one input element, output element, or regulator element.  
   
   
       410 . The method of  claim 223 , wherein a plurality of components comprise stoichiometric coefficients.  
   
   
       411 . The method of  claim 223 , wherein a plurality of components comprise symbolic parameters.  
   
   
       412 . The method of  claim 223 , wherein a plurality of components comprise each at least one variable which values over time are computed dynamically.  
   
   
       413 . The method of  claim 223 , wherein a plurality of subnetworks of said network form a hierarchical or tree-like structure.  
   
   
       414 . The method of  claim 223 , wherein a plurality of components have associated visual representations.  
   
   
       415 . The method of  claim 414 , wherein a plurality of said visual representations further comprise at least one associated rule or function that can be called programmatically or interactively to be executed.  
   
   
       416 . The method of  claim 414 , further comprising methods to generate and display multidimensional networks, wherein the nodes are said visual representations of the discrete components.  
   
   
       417 . The method of  claim 223 , wherein said components comprise variables with associated equations to compute their values, said network of components representing the topology of the complex biological network and the variables representing its behavior.  
   
   
       418 . The method of  claim 223 , wherein said components include first components each representing a biological process, each component comprising any type of information or data associated with the process or second components of said first components, or any combination thereof.  
   
   
       419 . The method of  claim 418 , wherein at least one biological process represented by said first components is of a type selected from the group of conversion, association, translocation, activation, inhibition, modification and regulation.  
   
   
       420 . The method of  claim 418 , wherein a plurality of said first components comprises or references a variable that represents the rate of said process.