WO2001057775A2 - System and method for modelling genetic, biochemical, biophysical and anatomical information - Google Patents
System and method for modelling genetic, biochemical, biophysical and anatomical information Download PDFInfo
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- WO2001057775A2 WO2001057775A2 PCT/US2001/001988 US0101988W WO0157775A2 WO 2001057775 A2 WO2001057775 A2 WO 2001057775A2 US 0101988 W US0101988 W US 0101988W WO 0157775 A2 WO0157775 A2 WO 0157775A2
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
- G16B50/20—Heterogeneous data integration
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
- Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
Definitions
- the present invention relates to a computer-implemented system of constructing databases and modeling biological processes; and more particularly to mathematical, informational, and computational processes and procedures for automatically generating computer-based models that integrate biological information from the subcellular to the cellular, tissue and organ level.
- Sequence Data Library (a.k.a. GenBank) and NAD for nucleic acid sequences; SWISS-PROT for protein sequences; PDB for protein structures and the like.
- Other databases are organism specific and include GDB and OMIM for human; MGD for mouse, PigBASE for pig; ATDB for Arabidopsis; ECDC for E. Coli, and many others.
- Still other databases contain information on particular areas of interest, such as specific databases for individual genes, databases about specific protein families, and databases of transcription factors.
- Biochemical databases contain information regarding coupled biochemical reactions and feedback signals which take place within the cell. Additionally, proprietary databases such as the availability of entire genomic sequences due to improved high throughput gene sequencing, available from the large data production houses, have been created and are expanding with technology.
- bioinformatics is unable to simulate these complex, highly nonlinear dynamic interactions that occur between each gene or gene product, and other components of the network they are a part of.
- bioinformatics researchers do not, at present, have the necessary tools to obtain a complete representation of subcellular and cellular processes, as well as the effect of these processes on tissues and organs.
- the Virtual Cell project has developed a framework for organizing, modeling, simulating, and visualizing cell structure and physiology.
- these projects lack an overall ability to link to existing genetic, protein and structural data bases.
- these projects have not defined procedures for modeling biological systems using information stored in local or distributed databases. As such, detailed and accurate representations of the many different simultaneous subcellular and cellular processes and the effect of these processes on cellular systems which occur at any given time are not presently possible.
- the system comprises: (a) at least one database containing biological information which is used to generate at least one data structure having at least one attribute associated therewith; (b) a user interface for interactively viewing and editing attributes the data structure to create at least one hierarchical description of subcellular, cellular, tissue or organ function; (c) an equation generation engine operative to generate at least one mathematical equation from at least one hierarchical description; and (d) a computational engine operative on at least one mathematical equation to model dynamic biological behavior.
- the system of the present invention can access and tabulate genetic information contained within proprietary and nonproprietary databases, combine this with functional information on the biochemical and biophysical role of gene products and based on this information; formulate, solve and analyze computational models of genetic, biochemical and biophysical processes within cells and higher order biological systems.
- the system of the invention therefore provides a dynamic tool for quantitative understanding of biological processes, identifying new drug targets for therapeutic intervention and predicting the outcome of drug screening. This is accomplished by the accurate modeling and simulation of highly complex nonlinear dynamic interactions that occur between each gene or gene product.
- a method modeling biological information that accounts for multiple time frames inherent in biological processes comprising: (a) at least one database containing biological information which is used to generate a plurality of data structures, each having at least one attribute associated therewith; (b) a user interface for viewing, editing or linking the plurality of data structures to generate at least one hierarchical description of a biological system; (c) a correlation engine operative on at least one hierarchical description of a biological system to generate a simplified system of equations; and (d) a computational engine operative to solve the simplified system of equations to create a model of a dynamic biological process.
- the models created in accordance with this method integrate biological knowledge across all levels of analysis ranging from that of the gene to that of the cell, tissue and organ to provide a detailed and accurate representation of heterogeneous systems.
- a method for creating a model of biological information for use with a computer system comprising: (a) accessing at least one database containing biological information; (b) generating a plurality of data structures, each having at least one attribute associated therewith; (c) interactively viewing editing or linking the plurality of data structures to generate at least one hierarchical description of a biological system; and (d) utilizing a at least one computational engine to mathematically generate at least one model of a biological system reflective of the multiple time frames inherent in biological processes.
- a method for linking models of subcellular and cellular processes to systems processes comprising: (a) generating at least one hierarchical description of subcellular function from at least one database containing biological information, the hierarchical description generated from a data structure having at least one attribute associated therewith; (b) generating at least one hierarchical description of cellular function by linking a plurality of attributes of subcellular function from the hierarchical description of subcellular function; (c) generating at one least hierarchical description of system function by linking a plurality of attributes of cellular function from the hierarchical description of cellular function; and (d) utilizing at least one computational engine to mathematically generate at least one model of a biological system reflective of a biological system.
- this allows for the creation of highly complex models of biological systems.
- FIG. 1 is a schematic diagram illustrating the overall flow of operations through the system of the present invention
- FIG. 2 is a Pathway Data Structure depicting the topology of the pyruvate dehydrogenase reaction in which pyruvate is converted to acetyl- CoA;
- FIG. 3 is a block diagram illustrating the flow of information to produce hierarchical descriptions of subcellular and cellular function in which EDS defines an elementary structure, BDS defines a binary data structure, and PDS defines a pathway data structure;
- FIG. 4 depicts a Binary Data Structure;
- FIG. 5 illustrates a Binary Data Structure modeling a biophysical process
- FIG. 6 illustrates a Binary Data Structure representing a gene regulatory network
- FIG. 7 is a schematic diagram illustrating the flow of information used to generate structural, finite-element cell models;
- FIG. 8 illustrates a biochemical reaction network;
- FIG. 9a illustrates a naive (quiescent) signal transduction pathway for PI 3 kinase in Tcells
- FIG. 9b illustrates activation of a signal transduction pathway for P13 kinase in Tcells
- FIG. 9c illustrates inhibition of a signal transduction pathway for P13 kinase in Tcells
- FIG. 10 sets forth a model of Tcell differentiation in rheumatoid arthritis
- FIG. 11 sets forth a model of inhibition of Tcell differentiation in rheumatoid arthritis as a result of TNF- ⁇ therapy
- FIG. 12a sets forth a model of Tcell differentiation from TO to
- FIG. 12b sets forth a model of Tcell differentiation from TO to
- FIG. 13 provides an example of a descriptive report generated by the system of the invention in response to a specific modeling query
- FIG. 14 provides an illustrative graphical model output for the dynamic change in concentrations or levels in a T-cell that is characteristic of the behavior of that cell, and is characteristic of the signaling within the T-cell.
- FIG. 15 illustrates the various reaction pathways involved during the activation of Tcells
- the present invention provides a multidimensional computational tool capable of integrating biological knowledge across all levels of analysis ranging from that of the gene to that of the cell, tissue and organ. This is accomplished by a system and method which incorporates at least one database that stores biological information, an interface which displays, links, organizes and modifies that information, and computational engines which operate on the information contained in the database to automatically formulate, solve and analyze computational models of biochemical reaction networks, biophysical mechanisms, and in general dynamic processes at the subcellular, cellular, tissue, and organ level.
- the present invention is an interactive computer-implemented system for mathematically modeling biological information from the subcellular to the cellular, tissue, and organ level comprising: (a) at least one database containing biological information which is used to generate a plurality of data structures having at least one attribute associated therewith; (b) a user interface for interactively viewing and linking together attributes the plurality of data structures to create at least one hierarchical description of subcellular, cellular, tissue or organ function; (c) an equation generation engine operative to generate at least one mathematical equation from at least one hierarchical description; and (d) a computational engine operative on at least one mathematical equation to model dynamic biological behavior.
- the system of the present invention uses computer-implemented tools to link genetic and molecular information to the topological and kinetic properties of biochemical and biophysical processes within cells, tissues and organs, to provide functional information on the biochemical and physiological role of gene products, and the effect thereof on biological systems.
- This information is coupled to computational engines that can automatically formulate, interconnect, solve and analyze properties of computational models of genetic, biochemical and biophysical processes within biological systems.
- computational engines can automatically formulate, interconnect, solve and analyze properties of computational models of genetic, biochemical and biophysical processes within biological systems.
- it is possible to address the functional role played by each molecular/genetic component from which a model is composed, to identify optimal points of therapeutic intervention within these models and to "numerically screen" lead compounds for functional effects on these models.
- Fig. 1 a schematic diagram illustrating the overall flow of operations of the system of the present invention.
- the system includes database 1 1 , data structure 17, graphical user interface 23 for interactive contact with the information generated by the system, equation generation engine 24 and a computational engine 22
- Database 1 1 encompasses both internal and external databases. External refers to databases designed to store and organize biological information, but which were not designed explicitly to be coupled with the subcellular, cellular, tissue and organ modeling, simulation, and analysis tools described herein. Internal refers to databases with a specific structure (to be described in subsequent sections) which are designed explicitly to support the formulation, simulation, and analysis of subcellular, cellular and systems models. Internal and external databases include those containing gene and protein sequences, biochemical and biophysical processes, descriptions of cellular, tissue and organ physical structure, experimentally validated models of biochemical and physiological processes, or models previously generated by the system.
- database 1 1 may contain one or any number of the foregoing databases.
- Any means for accessing and searching external and internal databases may be used in the present invention.
- these would include: commercial database front-ends with SQL queries, web-based solutions such as Perl scripts and Java-based tools for accessing remote databases, as well as cross-platform software tools . available, for example, from Genomica Corp. (Boulder, CO), Pangea Systems, Inc. (Oakland. CA) and NetGenics Inc. (Cleveland, OH).
- Internal databases include those that have been generated from the data extracted from the external databases as well as data added by users via the graphical user interface. Such data may include experimental data including, for example, new descriptions of biochemical and physiological processes, or it may be data generated as a result of computer modeling by the system. Data generated and stored by the internal databases are manipulated using commercially available object-relational or relational database management systems such as Oracle Corp. (Redwood City, CA), Sybase, Inc. (Emeryville, CA), or Informix (Menlo Park, CA), or using markup languages such as SGML or XML, all of which are well known to the skilled artisan. Most importantly, the internal databases store information on the (a) topology; (b) kinetics; and (c) interconnectivity between various genetic and biochemical reaction networks (BRN'S) within cells. These are generically referred to as internal biochemical databases herein.
- topology refers to the pattern of interactions within a specific genetic or biochemical reaction network
- kinetics refers to the reaction rate constants that, in conjunction with the laws of mass action, determine the dynamic behavior of such reaction network processes
- interconnectivity refers to the specific points of coupling between different genetic and biochemical reaction networks within the cell which results in cellular behavior.
- the internal biochemical databases store the interconnection topology, including the rate constants associated therewith, for each BRN.
- the BRN for the pyruvate dehydrogenase reaction in which pyruvate is converted to acetyl- CoA is illustrated in FIG. 2.
- Information on this BRN which is stored in the internal biochemical databases includes each of the intermediates involved in the reaction, the enzymes involved in determining the rate at which the intermediates are formed (along with lists of co-factors influencing the reaction rate such as pH, temperature, and the like) and the reaction pathways connecting these intermediates.
- These databases also include qualitative data such as cell-cell, cell-molecule, molecule-molecule interactions, cell growth rates, binding constants, concentration effects of cells and molecules on cell- cell, cell-molecule, and molecule-molecule interactions and the like.
- more than one BRN may be linked together to provide a more complex representation of subcellular, cellular and system behavior.
- the internal biochemical databases store genetic and biochemical reaction network data in a way that makes possible the hierarchical construction of mathematical and computational models of these networks from their underlying components.
- Equation generation engine 24 - U " transforms each genetic and biochemical entity within the internal biochemical database into a group of symbolic equations and numerical subroutines associated therewith which are stored as attributes of these entities. As discussed in more detail later, use of these attributes allows the user to simulate and view functional behavior of this entity (based on the genetic/biochemical properties of interest) by way of graphical user interface 23, and computational engine 22. In this way, the system makes it possible to link genetic and molecular information to functional information regarding subcellular, cellular and system processes.
- each of these attributes associated with the genetic and biochemical entities also includes time delays in process through implicit time constants that are functions of kinetic rates.
- the biochemical reaction networks can be compartmentalized, i.e., a set of BRNs can be gathered into different compartments each of which can have different attributes such as surface area, internal volume, geometry among others. This can create representations of different cells that have specific reactions and molecules that interact by crossing the compartment boundary.
- a reaction carries a molecule from inside a compartment (cell) to its outside, and that molecule is then taken into another compartment (cell), the cells are communicating with each other and is one aspect of a tissue model.
- a molecule can sit on one compartment boundary and attach to another molecule sitting on another compartment and this represents cell-cell contact and is another aspect of a tissue model.
- This process can be built up by including all the cell types and their quantitative numbers and thus build a complete tissue.
- the tissue compartments can then be used to create whole organs.
- databases are presently available or are currently being developed, see e.g., Popel et al., 7Vze Microcirculation Physiome Project, 26 Annals of Biomedical Engineering 91 1 -913 (1998). These databases can be created and organized by known software tools which help users build and organize databases such as, for example, those available from Oracle Corp. (Redwood City, CA). Software tools for designing and viewing, interactive graphical representations via graphical user interface 23 of these databases are also well known and readily available.
- the internal databases will also represent and store information regarding biophysical processes within cells, tissues and organs. These internal biophysical databases contain information on the physical properties of biological processes required to formulate mathematical and computational models of these processes; for example, ion channels and currents, membrane transport systems such as pumps and exchangers, membrane receptors and signal transduction pathways for a given cellular process.
- each physical property stores as attributes a group of symbolic equations and numerical subroutines associated therewith which allow the user to simulate and view cell function (based on the biophysical properties of interest) via graphical user interface 23, equation generation engine 24 and computational engine 22.
- these attributes may also include time delay in processes, enabling the incorporation of multiple time frames.
- Internal databases also comprise internal structural databases which contain information on the physical structure and spatial relationship between various organelles within a given cell, as well as the relationships between cells in tissues and organs.
- this information is in the form of three-dimensional image data obtained from different modalities (e.g. electron micrograph serial sections, confocal serial sections, two-photon laser scanning serial sections, magnetic resonance images, position emission tomography images and the like.
- the three-dimensional image data may be further transformed into structural finite-element models describing cell, tissue and organ shape and spatial placement of organelles and/or cells therewithin via an optional computational modeling engine which will be discussed in greater detail below.
- Structural models generated from the three-dimensional data are also stored in the structural databases.
- the structural databases thus contain information on anatomical subcellular, cellular, tissue and organ structure and spatial relationships which, in conjunction with the molecular, biochemical and biophysical databases, provides the data necessary to produce a complete model of subcellular, cellular, tissue and organ function.
- the structural databases may be publicly available or it may consist of a novel or proprietary database.
- the precise geometry of and the spatial relationship between cardiac T-tubules and their associated L-type calcium (“Ca”) channels and ryanodine-sensitive Ca release channels in the sarcoplasmic reticulum membrane provides information on the properties of calcium-induced calcium release, and therefore mechanical force generation in cardiac muscle cells.
- information about the physical location of Ca-channels and Ca-modulated potassium channels in auditory hair cells provides information about the electrical tuning of these cells or knowledge of the spatial location of subcellular processes in specific cell organelles, e.g. mitochondrial respiration, provides the information necessary for a complete and accurate model of the entire cell.
- External databases used in the present invention may be accessible through known commercial channels or the Internet. Typically, these databases contain gene sequence, protein sequence and three dimensional structural data on each constituent of a biochemical reaction network within a given cell or larger biological system, but certainly any type of data useful to develop models of subcellular, cellular, tissue and organ function is within the scope of the present invention. External databases such as those on the Internet are becoming increasingly standardized so that access to a variety of diverse databases is possible in a single application. See e.g., Markowitz et al., Characterizing Heterogeneous Molecular Biology Database Systems, 2 J. Comput. Biol. 547-556 (1995).
- the system of the present invention accesses and utilizes data from the external databases during model creation. Alternatively, the system may transfer the information from these databases into another database (not identified) in the system for later use.
- the information in internal database 1 1 is organized into and stored as at least one data structure which is used to construct at least one model of subcellular, cellular, or systems processes.
- the data structure comprises either a group of hierarchical description of subcellular, cellular and system function 17.
- the data structure comprises anatomical data structures describing the physical organization and structure of biological cells, tissues and organs.
- Data structure refers to a group of interdependent data generated from information obtained from literature, experiments, expert information and internal information.
- data structures are constructed by means of the graphical user interface and the information available in the database 1 1. They may also be retrieved from previously defined data structures residing in database 1 1, or generated from biological inputs (e.g., experimental data) into the system.
- Graphical user interfaces and databases can in turn be developed using software tools such as those available from Microsoft (Redmond, WA) or Oracle Corporation (Redwood City, CA).
- data structure 17 comprises elementary data structure 16, binary data structure 19 and pathway data structure 2 with the binary 19 and pathway 20 data structure formed from the lower level data structures.
- the lowest level data structure is the elementary data structure ("EDS") 17.
- EDS 17 may comprise either a protein i.e., an entity coded by a gene, or a variable.
- a variable refers to anything other than a gene, which defines interdependencies in cell processes as for example, elements or ions important to cell function such as K + , Na + , Ca + , H + , organic or inorganic compounds such as ATP, ADP, P i?
- each EDS is associated with an extensive set of attributes. For example, attributes associated with a protein might describe the organism in which the protein is found, the specific cell in which the protein is found, the specific gene coding for the protein, the sequence of the gene coding for the gene and so forth.
- the attributes describing each EDS are defined and hierarchically arranged by means of the graphical user interface 23.
- These hierarchical description attributes thus comprise a grouping of pointers to specific portions in database 1 1 in which specific information associated with each attribute is found.
- the attributes associated with a given protein could be arranged as Organism: Cell:Gene:State:Sequence:Structure:Location:Model.
- the attribute "Organism” is a pointer to the appropriate gene database in which a gene which codes for the protein exists.
- the attribute "Cell” points to the specific cell type within that database in which the gene is expressed.
- the attribute "Gene” is a pointer to the specific gene in the database.
- the attribute "State” identifies the state of the Organism:Cell:Gene triplet and may be anything that might effect expression of the protein such as an age-related parameter, the presence of a particular disease in the organism, a particular time in the progression of a disease, or the like. Therefore, the attribute "State” is a pointer identifying which particular subset of the Organism:Cell:Gene database to search.
- the attribute "Sequence” is a pointer to sequence data in the structure of the gene coding for the protein.
- the attribute “Structure” is a pointer to the three-dimensional structure of the protein coded by that gene, if known.
- the attribute "Model” is a pointer to a database in which functional models of the protein coded by that gene are stored.
- Binary data structure (“BDS”) 19 is formed as a composition of more than one EDS. As more specifically illustrated in FIG. 4, BDS 19 comprises separate EDS's with arcs denoting the transitions between these EDS'S.
- EDS 1 represents the elementary data structure corresponding to state 1 of the binary relationship
- EDS 2 represents an elementary data structure corresponding to state 2
- EDS 3 and EDS 4 are elementary data structures determining the forward and backward transition rates, respectively, of the reaction between state 1 and state 2.
- This binary representation is also known as a state transition diagram.
- BDS's are the first level data structures at which information on the topology and kinetics of biological reaction networks are represented. BDS's are generated from knowledge of biophysical and biochemical pathways within intra and intercellular systems.
- the binary relationship illustrated in FIG. 4 has many analogues in biological systems.
- the binary relationship may represent transitions between two intermediates within the complex biochemical network shown in FIG 2.
- EDS 1 could represent pyruvate (a variable)
- EDS 2 could represent Acetyl-CoA (a variable)
- EDS 3 could represent the catalytic enzyme pyruvate dehydrogenase (a protein)
- EDS 4 could represent the substrate NAD (a variable).
- the binary data structure could represent a simple two-state closed-open model of a cardiac ion channel, thus modeling a biophysical process as shown in FIG. 5.
- EDS 1 corresponds the closed state of an ion channel (a variable)
- EDS 2 corresponds to the open state of the ion channel (a variable)
- EDS 3 and 4 would be identical and equal to membrane potential V (variables).
- the functional dependence of the transition rate constants K12 and K21 on quantities such as temperature, pH, membrane potential, and in general variables and/or proteins as defined previously, on membrane potential may or may not be specified, but the fact that a dependence exists would be.
- a binary representation of a gene regulatory network is shown in FIG. 6.
- EDS I represents an RNA polymerase (protein)
- EDS 2 represents a closed RNA polymerase complex (variable)
- EDS 3 represents a promoter (protein).
- ⁇ BDS 19 is also associated with a number of attribute lists.
- the BDS in FIG. 4 may be represented by the list Input:Output:Frate:Brate wherein the attribute "Input” is associated with EDS 1 , the attribute "Output” is associated with EDS 2, the attribute “Frate” is associated with EDS 3 and describes the forward transition rate, and the attribute "Brate” is associated with EDS 4 and describes the backward transition rate.
- a graphical user interface 23, or an interface into existing biological databases 11. would be used to generate the linked attribute lists.
- BDS 19 retains the attributes of each EDS which it comprises.
- the linked attribute lists defining BSD 19 would incorporate multiple attributes reflective of the group of attributes associated with each EDS. Therefore, a BSD may have distinct attributes of the Organism:Cell: Gene:State:Sequence:Structure:Location:Model attribute list discussed previously, but would not contain the single "Gene", "Sequence” or "Structure” attribute each is associated with a single EDS.
- Pathway data structure represents the highest level of data structure and is generated as the composition of more than one BDS.
- An example of a PDS is the pyruvate dehydrogenase reaction depicted in FIG. 2.
- FIGS. 9a, 9b and 9c another example of a PDS would be detailed information pertaining to protein expression in three phases of a cell's existence: naive (quiescent), activated, and inhibited (for the naive or activated state).
- a PDS may comprise information regarding T-cell differentiation as is shown in FIG. 10.
- PDS 20 represents a more complex state transition diagram which retains the attributes of the EDS's and BDS's present in the pathway.
- PDS 20 is also associated with a number of attribute lists. Because PDS 20 retains the attributes of its constituents, the attribute list Organism:Cell:-Gene:State:-Sequence:Structure:Location:Model described above may be applied to PDS 20.
- the modeling tools used to organize the databases and generate the EDS'S, BDS's and their associated data may be used to generate the PDS'S.
- any biochemical reaction and physiological process can be arranged into an EDS, BDS and PDS and its associated attribute list.
- the data associated with the data structures is generated by a user either prior to or at the time of model construction, or may comprise an attribute list from database 1 1 which is edited by the user.
- models are configured so that a user can interact with graphical user interface 23 to retrieve, view and edit any of the data associated with or generated by the data structures and their associated attribute lists to thereby create revised data structures and attribute lists.
- the structure of the attribute lists also permit a user to analyze multiple data structures to determine common and unique properties. With this information, a user can link attributes from more than one data structure to analyze common information or create detailed models of subcellular and cellular processes as well as of complex biological systems (e.g., organs).
- Data structure 17 may also comprise at least one anatomical data structure describing the physical organization and structure of biological cells, tissues and organs. These data structures may be in the form of sets of three-dimensional image data from structural database as previously discussed.
- the three-dimensional image data and the structural finite element cell models have specific attributes.
- these attributes are in the form Organsim:Cell:Organelle: Modality:lmageFormat, wherein the attributes "Organism” and “Cell” are as discussed above.
- Organsim:Cell:Organelle: Modality:lmageFormat wherein the attributes "Organism” and “Cell” are as discussed above.
- “Organelle” is a pointer to that part of the anatomical database defining structure
- “Modality” defines the type of anatomical data (such as a model derived from the three-dimensional image data or the three- dimensional image data itself)
- “ImageFormat” defines the structure of the anatomical data.
- the attribute "Organ” would be included.
- three-dimensional image data from structural database is defined by attribute lists 44.
- This three-dimensional image data may be further transformed by geometry modeling engine 42 into structural finite-element model 43 describing cell, tissue and organ shape and spatial placement of organelles and/or cells there within, which may be used to create additional list 45.
- Well known and readily available geometry modeling engines useful in the construction of these structural models include EnSight (available from CEI, Inc., Research Triangle Park, NC) and FIDAP (available from Fluent Inc., Riverside, NH).
- EnSight available from CEI, Inc., Research Triangle Park, NC
- FIDAP available from Fluent Inc., Lebanon, NH.
- Each of the three-dimensional image data or the finite element models may be stored in the system for later use or generated as necessary.
- anatomical data structure may be specifically tailored to subsequent model use.
- the EDS, BDS and PDS's may be updated via a database interface, such as the i-Base interface proprietary to Physiome
- a user can use the database interface to pose specific queries regarding biological processes to the system, analyze experimental data and hypothesize against known EDS's, BDS's and PDS's.
- computational engines transform the data structures into mathematical models of biochemical, physiological and structural subcellular, cellular, tissue and organ processes.
- the interconnection topology specified in each data structure permits the computational engine to automatically generate these biological models by applying the laws of mass action.
- Computational engine 22 includes an equation generation engine for generating symbolic models of biological processes as well as an engine for generating computational models of dynamic biological behavior based upon the symbolic models.
- the equation generation engine 24 automatically transforms each data structure into at least one system of equations describing a specific biologic process. This system of equations is referred to as a symbolic model.
- These symbolic models may be stored in the system for later use in modeling the same biologic process, or alternatively, the models may be coupled with other symbolic models generated by the system to model different biologic processes.
- any number of symbolic models may be coupled together to produce models of complex subcellular, cellular, tissue or organ process. In this way, complex models which link functional behavior to subcellular and cellular, as well as system processes may be derived.
- Equation generation engines 24 such as those which are a part of commercially available software tools such as Mathematica and Maple are well suited to the practice of the present invention.
- Computational engine 22 generates a computational model reflective of the biological process defined by the symbolic model.
- a computational model refers to a software procedure for numerical simulation of the behavior of the symbolic model.
- computational models are software procedures for numerical simulation of the behavior of the symbolic model.
- tools used to generate numerical simulations include those available from IMSL (International Mathematical and Statistical Library); NAG (Numerical Algorithm Group); and MATLAB (Mathematical Laboratory); and Visual Numerics and the like.
- the symbolic models may also be translated into computer code such as Fortran and C++ by conventional means readily available in the prior art.
- typeset equations expressed in markup languages such as TeX, LaTeX or HTML can be automatically derived from the symbolic models, thereby tremendously simplifying the process of model documentation.
- critical components of computational models for example, Jacobian matrices that are used by certain numerical integration algorithms can be derived in an automated fashion from the symbolic models.
- equation generation engine 24 automatically generates symbolic models in the form of coupled systems of differential equations from the information contained in the data structures.
- the models so generated will retain the attributes of every component of the data structures used to generate the model.
- the attributes Organism:Cell:State:Location:ModelType would contain the attributes "Organism”, "Cell”, “State”, and "Location” as previously discussed, with the equation that is simpler than the original component model (a lumped model).
- parameters of the new model component are adjusted to fit the behavior of the original model component over the range of interest to the user, using regression techniques available in software products such as MATLAB (Mathworks, Nattick, MA), IDL (Research Systems, Boulder, CO) and PV-WAVE (Visual Numerics, Inc., Houston, TX) and in numerical libraries from NAG, Ltd. (Numerical Algorithm Group), Visual Numerics and the like. These packages can also be configured to provide statistical goodness-of-fit estimates that can be used to determine the statistical significance of the resulting simulations.
- the fitted correlation function or lumped model component is then used in the place of the original when performing computational simulations.
- a hybrid solver must be used. For example, correlation functions often introduce algebraic constraints to systems of differential equations.
- HDMR High-Dimensional Model Representation
- practical differential equation solver packages use adaptive methods that switch automatically between explicit and implicit time stepping methods, providing marked speed improvements particularly useful for models which exhibit stiff behavior at least at one point in a simulation.
- software with adaptive solvers include the ODEPACK family of solvers from the Lawrence Livermore National Laboratory and DASSPK family of solvers by Linda Petzold of the University of Minnesota. These solvers have the ability to handle mixed continuous-discrete time and differential-algebraic systems. They also can take advantage of the natural sparsely of the system of equations, providing even larger performance gains.
- PDE partial differential equations
- coupled differential algebraic systems parallel algorithms are useful to solve the problems.
- multiple-processor codes use industry standard libraries to control algorithm and data flow. Examples of these libraries are the Message Passing Interface (MPI) and the Parallel Virtual Machine (PVM). Both allow a single simulation application to run on heterogeneous machines, and allow each process to work on different tasks. In this way, a heterogeneous problem can run simultaneously on a network consisting of one or more personal computers, workstations and supercomputers.
- MPI Message Passing Interface
- PVM Parallel Virtual Machine
- the symbolic and computational models define the time rate of change of the concentration of reaction intermediates, or of other state variables that effect subcellular, cellular or higher order processes.
- A, B, C, and D represent elementary data structures defining the pathway wherein "i” or "j" are generic representations for the various states such as A, B, C, or D (K ;i , K AB or K CA or ... ), and K ⁇ represents the transition rate between states i and j that are defined by the various Frate and Brate pointers.
- equations are completely defined by knowledge of the connectivity of the network, and knowledge of the various transition rate constants, and since these quantities are all stored in the databases, the equations may be generated automatically on computer. They may also be integrated in time, or be analyzed using the numerical methods described herein.
- (E, + I) ' is the enzyme-inhibitor complex.
- This zero order qualitative model can be used to develop more complex structured models.
- the most detailed BRN model possible is a description of the temporal variance of every species within the cell.
- M i5 can be involved in several processes that contribute to its net formation and consumption. These processes can be transported across an organelle with the cytoplasm, synthesized or consumed in a chemical reaction and transport across a cell membrane.
- the basic mass balance for such a system can be represented by the following mathematical relationship: — '- ⁇ ⁇ 's v. , Where, s is the stoichiometric coefficient dt j associated with each flux v,. Each flux v is some function of the metabolite concentrations, i.e., v
- S is the stoichiometric matrix and v is the vector of metabolic fluxes.
- This stoichiometric relationship can also be viewed as a connectivity relationship that connects the intermediates through the fluxes that they are involved in.
- the stoichiometric relationship can be used in identifying the properties of a network of metabolic reactions. These properties include, the identification of conserved quantities, and pathways of fundamental importance in the connectivity of a network.
- rf is the rate of formation of the cell dt species, x bin and rf , is the rate of death of the cell species.
- rf is the rate of formation of the cell dt species, x ester and rf , is the rate of death of the cell species.
- Each rate is a complex function of metabolites and cells, i.e.,
- m * represents external metabolite concentrations
- m,' internal metabolite concentrations
- the models generated by the system may be further transformed into textual or graphical representations by use of graphical user interface 23.
- the models may also be analyzed using techniques from nonlinear systems theory.
- public domain tools such as AUTO and XPP, accessible from the Internet can be used to perform analyses of the parameter dependence and asymptotic behaviors of biological models. This permits the calculation of qualitative behaviors of complex models as key model parameters are changed.
- Graphical user interface 23 provides a user with input to and output from information in the system. More specifically, graphical user interface 23 may be used to (1) draw genetic and biochemical pathway diagrams, and to enter functions specifying rate constants in these reaction pathways, for storage in database 11 or for symbolic and computational modeling; (2) interconnect EDS, BDS, and PDS data structures in order to compose hierarchical models of biological systems; (3) construct and manipulate biophysical and structural models; (4) display and interact with previously developed genetic, biochemical, biophysical, and structural models; and (5) control formulation and solution of computational and symbolic models, and to view simulation output.
- Graphical user interface 23 can be customized for a particular application. Typically, interface elements such as video monitors, touchscreens, keyboards, a mouse, printers and the like may be used.
- a model may be created to study any type of subcellular, cellular, tissue or organ information as, for example, the function of a gene, a specific biological process, the behavior of a target protein in the presence of a particular drug, or system functions in response to certain therapies.
- the user will select the information from the database that will serve as the building blocks for developing the model. For example, a user may wish to predict the quantity of certain intermediates in the pyruvate dehydrogenate reaction in a specific cell type both in health and disease.
- a model would be generated based upon the structural elements of the cell together with the biochemical and biophysical processes and their associated interconnection topologies. These models can be displayed on the display monitor.
- each icon represents some binary or pathway data structure, such as a biochemical or biophysical mechanism previously defined and stored in the system.
- the user would interact with this graphical display by use of a mouse.
- the user can add these components to the structural model by selecting icons and dragging them to the point of insertion in the model.
- the user may view information regarding the biochemical/ biophysical mechanism inserted into the model by clicking on the representation of that mechanism. For example, clicking on the icon for the pyruvate dehydrogenase reaction will trigger a display of the pathway illustrated in FIG. 2 on the display monitor.
- the user can then query the system for information associated with the intermediates of these reactions.
- pyruvate dehydrogenase Clicking on, for example, pyruvate dehydrogenase will initiate a pop-up display of all of the attributes describing pyruvate dehydrogenase that may be examined. The user will select from one of these attributes.
- the linked attribute list will cause the system to initiate a query and display of information to the appropriate database, for example, a display of the gene sequence of pyruvate dehydrogenase. All of the elements of the attribute list associated with pyruvate dehydrogenase could be displayed in this manner.
- the simple act of clicking on pyruvate dehydrogenase retrieves for the user all information on pyruvate dehydrogenase stored in the system and makes it available to facilitate modeling.
- This configuration permits a user to interact with graphical user interface 23 to retrieve any of the information associated with or generated by the system. In this way, the user is presented with a complete representation of specific biological processes.
- the user can invoke an equation generation engine to generate a symbolic set of coupled differential equations defining the model.
- equations could be saved as part of a documentation of the model and/or they may be input into translators that would map them into computer instructions in the desired programming language.
- This source code can then be linked with a computational engine to produce executable code for modeling the cell.
- this executable code may be stored in the system for future use.
- the user may wish to model intracellular protein in trafficking which occurs following ligand:receptor interactions which occur in signaling processes that allow molecules to move from the plasma membrane, or the cytosol, to the nucleus.
- the T-cell receptor binds a ligand (MHC and antigen) to initiate a signaling cascade that progresses through the cytosol and culminates in both new protein synthesis and in active inhibition of gene activity.
- a ligand MHC and antigen
- Creation of a single-cell model in accordance with the present invention will allow a user to follow protein signaling events, and in this way, define possible gene(s) and gene modulation activity of the protein in question.
- the intracellular representation of molecules (and their functional moieties) are in some cases unique to one ceil type (i.e., the expression of the CD4 molecule is restricted to CD4 T-cells), this is not true for many intracellular molecules. Accordingly, the results of a single intracellular model may apply to a number of other cells in an organism. Thus, the protein signaling system described above may have broader implications in cellular signaling in other cells of the organism. For instance, a CD4 T-cell secretes IL-4, 11-5 which are cytokines that affect the performance of the B-cell, which is another component of the immune organ system. The T-cell also has specific molecules, e.g.
- CD40 ligand which binds to a CD-40 receptor on a macrophage.
- the cell models can therefore be combined by linking the BRNs in the T-cell that form IL-4 to the BRNs that IL-4 affects in the B-cells, and by the BRNs that form CD40 ligand to the BRNs affected by the CD40 ligand-receptor compex in the macrophage.
- organ model is built from several cell models that are built from several BRNs, a single step or a number of single steps can be removed or changed in the model to mimic the effect of a drug. So one or a few steps in synthesis of IL-4 in the T-cell can be targeted in the model simulator and its characteristics can be changed.
- the overall results on the organ function can be measured by tracking the effect of these changes on the function of all the cells and tissue types and the overall organ function. Specifically, the effect on the B-cell function and the effect on macrophage function can be tracked.
- the ability to respond to an infection can also be tracked, which is a feature of organ function.
- the changes to 11-4 production can be changed to look at the organ function change.
- a patient's characteristics can be input into the model and then measured against a normal person's model, to obtain the specific abnormalities at the cell level for that patient.
- the models generated in accordance with the present invention are validated against information gleaned from clinical data, expert opinion, or a combination thereof. Where disagreement between the model and known data exist, the model is corrected iteratively until a correlation is found. After the model is created, the system compares the solution of equations to experimental data, measuring goodness-of-fit of the model.
- a user can interactively adjust any of the attributes associated with the model to create a new hierarchical description which approximates user selected properties of the experimental data.
- a system identification engine can be invoked to adjust the parameters of the equations defining the model to create a new system of equations, the solution of which approximates user selected properties of the experimental data.
- the system identification engine includes routines for optimally updating the parameters of a model, taking into account measurement and model uncertainty.
- Example algorithms include Kalman Filters and batch least-square filters.
- the system identification engine can also include algorithms for estimating the quality of the fit of the model to the experimental data. Complete systems for doing system identification are available as add-on packages to Matlab (Mathworks, Nattick, MA), and integrated in the Scilab data analysis system (INRIA, France). Linking Models
- a number of different biochemical or biophysical mechanisms may be inserted into a single structural model.
- several models would be merged into a single model by an interface which would effectuate the flow of information between the respective models.
- the outputs or intermediates in a biochemical reaction network describing a PDS s ⁇ ch as described in FIG. 2 may act directly or indirectly to modulate the function of another process such as the BDS representing an ion channel model of FIG. 5.
- a specific case may be the output variable of adenosine triphosphate (ATP) of glycolytic biochemical reaction networks and its modulating action of ATP- sensitive membrane potassium channels.
- ATP adenosine triphosphate
- Single cell models may be integrated with organ models.
- intracellular models of cell states for normal and diseased states can be generated in order to allow cell types, and mediators of cellular function to be modulated and analyzed in a specific disease state. Such information can be used to identify specific points of disease progression best suited for therapeutic intervention.
- an immune cell/organ integrated model is network regulation dynamics, some of which are universal (i.e., mass-balance and metabolism) and some of which are unique to the immune system (i.e., differentiation).
- Single cell models that could be generated in this instance include macrophages, dendritic cells, naive T-cells (CD4, CD8), effect on and memory T-cells, B-cells, plasma cells, mast cells and basophils. These models could be integrated into an organ model in order to provide a more complex representation of a biological system.
- a model for therapeutic intervention of rheumatoid arthritis could be developed based on animal models of arthritis induced with antigens or infectious agents.
- disease severity correlates with a dominant Thl -type cell response characterized by a higher ratio of IFN- ⁇ to IL-4.
- Th2 cytokine therapy e.g., infusion of IL-4
- Th2 cytokine therapy may suppress disease symptomatology.
- IL-1 , IL-6 and TNF- ⁇ are secreted in very high levels in arthritic joints and therapies directed to these mediators may be effective.
- an intracellular model of the TNF- « could be generated in health and in various states of disease progression.
- FIG. 1 1 illustrates the information obtained from these modulators that may be used in the creation of a model of Th.1 cell differentiation in rheumatoid arthritis.
- Output data from each simulation, as well as the underlying data, may be displayed on the graphical user interface.
- Output data may include gene data (i.e., recruitment, activator and expression), in expression data (i.e., activator and expression), protein modulation data (i.e., phosphorylation, glycosylation, association, etc..) cell turnover rates (i.e., recruitment, proliferation, differentiation, death), protein accumulation, calcium fluxes, cell trafficking rates, uniquely defined parameters of clinical relevance to track pathophysiology and the like.
- FIG. 13 provides an example of a descriptive report generated in response to a specific modeling query.
- a user can modify the data from each simulation as well as the underlying information which the data represents.
- the user may also customize the physical appearance of the graphics or textual appearance of the output data.
- the user can double-click on a compartment of the model, and would be presented with a list of variables used.
- the user could select a variable and display that variable on a graph drawn in a separate window.
- the user could modify the underlying variable and generate a new model.
- the user could select "global" variables, that is, those state variables defined everywhere within a model and display the global variable using a color coding scheme over the entire model domain.
- the model can be used to store and search all existing biological information (i.e., genetic, biochemical, biophysical and anatomical) on a given biological process at the subcellular, cellular or multicellular level. As such, the model may be used to integrate knowledge across all biological systems.
- the model thus provides a means for collecting and synthesizing biological information into a format by which function within a biological system may be analyzed. For example, the function of a particular gene could be ascertained by invoking the model to determine the sequence of the gene of interest and identify homologous genes and BRN's in which the homologous gene participates. Based on the BRN'S, the dynamic behavior of the homologous genes could be modeled, providing quantitative insight into the possible functional role of the gene of interest.
- the model could provide not only homology searches based on linear sequence analysis, but also functional search capabilities based on the similarity of the BRN's in which a gene participates.
- model may be used in drug discovery, as for example, to analyze the behavior of molecular targets in the presence of a particular drug.
- Computational models of drug/gene action would be generated and incorporated into models of physiological function in accordance with the present invention. These multi-dimensional models could then be used to screen candidate compounds.
- Computer System may be implemented on any computer architecture in any configuration such as multi-tiered or clustered services or a client-server paradigm.
- the type of computer system will depend on the complexity of the model(s) and the choice of an appropriate system is readily available to a skilled artisan.
- the components of such a computer system would include a central processing unit, RAM, ROM, I/O Adapter, data storage space, a graphical user interface having a keyboard, mouse and speakers attached thereto as well as an operating system and software capable of providing Internet connectivity.
- CellML This is an example of a "CellML” description of the basic FitzHugh-Nagumo model generated in accordance with the present invention.
- CellML is a subset of XML that is used to describe a cell model or a series of cell models.
- This model is treated as an ion current.
- This model contains two differential equations:
- a ⁇ DRAW> tag is used by the program to describe how the object is represented visually in the cell model.
- ENVIRONMENT tag is used to define all of the components (chemical species, variables, etc.) within the scope of an element.— > ⁇ ENVIRONMENT>
- CONSTNNT tags are used to contain information about the value of parameters used in this model.
- VARIABLE tags are similar to CONSTNNT tags except that the values can change during the execution of the model.
- the values given here represent the initial value for the variable.
- lONCURRENT is use to contain the actual model.
- This example describes the CellML tags used by the present invention to represent a cell model.
- CellML uses MathML to model the actual equations that it references.
- the tags in CellML are designed to be hierarchical in nature; that is a given tag is generally used to describe the properties of its parent. For example, a ⁇ SIZE> tag can be used to indicate the size of a ⁇ CELLMODEL>.
- CellML tags are broken down into several distinct classes, based on their purpose:
- Basic Elements are tags that are used to describe a general property such as the name of an object or its size. These are the lowest level elements and can be used by several different kinds of tags.
- each CellML document will obey a set of grammar rules defined in the CellML Document Type Definition (DTD).
- DTD CellML Document Type Definition
- Example 4 One of the unique aspects of the present invention is the ability of the system to build models with hidden mathematics. This allows users to construct complex models of biological systems without in-depth knowledge of mathematical modeling.
- FIG. 15 represents a graphical model of the various reaction pathways present when T-cells activate.
- NFIL6 1.0
- a user could click on the ".” linking each of the model components and insert various kinetic parameters (accessible from the database) thereby altering the system of equations representing the model.
- the model incorporates qualitative simulators with quantitative methods.
- This model can be integrated into a system model, such as T-cell differentiation in rheumatoid arthritis illustrated in FIG. 10. This allows the user to simulate the heterogeneous time scales found in the system model via qualitative and quantitative analysis.
Abstract
Description
Claims
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EP01908645A EP1368774A2 (en) | 2000-02-07 | 2001-01-22 | System and method for modelling genetic, biochemical, biophysical and anatomical information |
CA002399272A CA2399272A1 (en) | 2000-02-07 | 2001-01-22 | System and method for modeling genetic, biochemical, biophysical and anatomical information: in silico cell |
JP2001556956A JP2004501415A (en) | 2000-02-07 | 2001-01-22 | Genes, biochemistry, biophysics, and anatomical information systems and methods: insilico cells |
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CN104737172A (en) * | 2012-07-05 | 2015-06-24 | 西门子公司 | System and methods for integrated and predictive analysis of molecular, imaging, and clinical data for patient-specific management of diseases |
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Also Published As
Publication number | Publication date |
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WO2001057775A3 (en) | 2003-10-02 |
EP1368774A2 (en) | 2003-12-10 |
WO2001057775A9 (en) | 2003-11-27 |
JP2004501415A (en) | 2004-01-15 |
AU3649001A (en) | 2001-08-14 |
CA2399272A1 (en) | 2001-08-09 |
IL151070A0 (en) | 2003-04-10 |
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