Abstract:
A method, apparatus, and program products for designing, implementing, distributing and deploying computer programs. Such programs bind the symbolic representation of a biological or chemical process to a physical implementation in computer memory. A Knowledge model defines a model for representing biological or chemical entities, knowledge on these systems, and packaging facts and intelligence using Knowledge Oriented Programming (KOP). The resulting knowledge components are implemented as off the shelf object oriented programming languages and tools. A Logic Model interprets existing algorithms and computational tools according to KOP. It also provides tools for encoding inference about the system. The Discovery Model assembles the components of the Knowledge and Logic Model for execution in computer memory. The Graphical User Interface (GUI) provides a tool for designing and executing a discovery application according to KOP.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application claims priority to U.S. provisional application serial No. 60/352,729, filed Jan. 29, 2002, entitled BIOINFORMATICS KNOWLEDGE ORIENTED PROGRAMMING, which is hereby incorporated by reference. This application is a continuation-in-part of and claims priority to U.S. patent application Ser. No. 10/034,601, filed Dec. 26, 2001, entitled KNOWLEDGE ORIENTED PROGRAMMING, which is hereby incorporated by reference. 
     
    
     
       LIMITED COPYRIGHT WAIVER  
         [0002]    A portion of the disclosure of this patent document contains material to which the claim of copyright protection is made. The copyright owner has no objection to the facsimile reproduction by any person of the patent document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office file or records, but reserves all other rights whatsoever.  
         FIELD OF THE INVENTION  
         [0003]    The invention relates generally to computer systems, and more particularly to a systems and methods that use knowledge oriented programming to execute on a computer the logical process of discovery from biological and/or chemical data.  
         BACKGROUND  
         [0004]    Informatics for the Life Sciences is a science that provides information on the function of the human system through the use of methods, apparatus, and programs that extract information from genomics, proteonomics, and chemical data.  
           [0005]    The wealth of information arising from high-throughput genomics, proteonomics, and combinatorial chemistry presents a challenge to academia, pharmaceutical, and biotechnology companies. The discovery process requires complex data analysis to derive new knowledge and the application of algorithms to model biological systems.  
           [0006]    Current bioinformatics and computational biotechnology tools focus on developing and improving specific algorithms to develop a method for extracting information. Automated analysis of complex biological systems typically requires the integrated power of three distinct technologies: Relational Databases, Logic Computing, and Object Oriented Programming. These three methodologies, when used separately, may not always provide what users need. The computational power of relational databases queries is limited by the expressive power of query languages, such as Structure Query Language (SQL). SQL becomes rapidly ineffective when complex objects must be represented, correlated, and analyzed with powerful algorithms. Artificial Intelligence tools, such as Rule engines, deductive databases, and expert systems can represent and execute complex knowledge-based queries, but Life Sciences tools based on these technologies are typically specialized solutions that are not likely to be available as easy-to-use and economical commercial products. Object oriented programming is best suited to implement algorithms, interactive user interfaces, and visualization tools.  
           [0007]    What is needed is a common, easy-to-use automation framework by which disparate data can be correlated, transformed into knowledge, used in algorithmic computations, and shared among diverse groups of researchers.  
         SUMMARY  
         [0008]    In various embodiments, a method, system, apparatus, and signal-bearing medium are provided for designing, implementing, distributing, and deploying computer programs that consist of packaged knowledge components for applications in the life sciences written in object oriented programming languages and modeled according to knowledge oriented programming (KOP). A discovery model for application in the Life Sciences defines a model for representing facts, intelligence, and packaging facts and intelligence into readily usable knowledge components implemented in off-the-shelf object-oriented programming languages and tools. Components of the discovery process are provided that can be executed by a KOP kernel. A KOP runtime is provided to bind symbols and execute computer programs made of generic components designed according to the KOP environment. A user interface, accessible via the Internet or other media, is easily customizable by the user. 
       
    
    
     BRIEF DESCRIPTION OF THE FIGURES  
       [0009]    [0009]FIG. 1 depicts a block diagram of the encoding of the discovery process for life sciences applications, according to an embodiment of the invention.  
         [0010]    [0010]FIG. 2 depicts a block diagram of example encoding of entities into the Knowledge Model, according to an embodiment of the invention.  
         [0011]    [0011]FIG. 3 depicts a block diagram of an example of a biological component, a protein, modeled using Knowledge Oriented Programming, according to an embodiment of the invention.  
         [0012]    [0012]FIG. 4 depicts a block diagram of an example of components of the Logic Model, according to an embodiment of the invention.  
         [0013]    [0013]FIG. 5 depicts a block diagram of an example of how an algorithm is used in the Logic Model, according to an embodiment of the invention.  
         [0014]    [0014]FIG. 6 depicts a block diagram of an example of a Discovery Model, according to an embodiment of the invention.  
         [0015]    [0015]FIG. 7 depicts an example of Graphical User Interface for the discovery application that uses a KOP environment, according to an embodiment of the invention.  
         [0016]    [0016]FIG. 8 depicts a block diagram of an example system for implementing an embodiment of the invention. 
     
    
     DETAILED DESCRIPTION  
       [0017]    [0017]FIG. 1 depicts a schematic diagram illustrating the interaction between data and software, including GUI  150  and runtime  140  according to an embodiment of the invention. The computer memory representation illustrated in block  130  is better understood by first describing blocks  110  and  120 . The Physical World  110  comprises the biological/chemical system  111  under consideration and the set of entities that describe this system. Examples of such entities are genes, proteins and chemicals, although in other embodiments any appropriate entities may be used.  
         [0018]    Current Biological Knowledge  112  comprises the set of findings about a particular biological or chemical system. Such findings may be obtained through experimentation or computation of the biological or chemical variables. Examples of such finding are the discovery of a protein function, the mapping of a metabolic pathway, or relation between protein families. Current Biological/Chemical Knowledge  112  represents the state of knowledge for a biological or chemical system at a given time.  
         [0019]    New Knowledge  113  comprises the discovery of new relations among biological or chemical entities. The new discoveries may validate or refute current hypothesis on the system. New knowledge  113  can be obtained through various means, such as statistical analysis, logical analysis, and computations.  
         [0020]    Logic Representation  120  is a human interpretation of the Physical World  110 . Entities of the biological or chemical system  111  are in various embodiments stored in databases, text files, and may be recorded in a variety of paper or electronic media, although in other embodiments any type of storage may be used. Hypotheses on the System  122  and assessment of current knowledge  123  are formulated based on processes chosen to analyze the data in the formal representation  121 . In various embodiments, such processes can be computational algorithms, statistical analyses, or inference tools, although any appropriate processes may be used. In various embodiments, processes can be expressed in computer programs, notebook notes, or speech, in other embodiments any appropriate expression may be used. Representation in Computer Memory  130  is the capture of the Logic Representation  120  of the Physical World  110  using a Knowledge Oriented Programming (KOP) formalism. Knowledge Oriented Programming comprises an environment that transforms data into knowledge and utilizes it in the discovery process. In some embodiments, the KOP environment is a computing environment that integrates object-oriented programming, first order logic, and relations of complex objects. The KOP environment provides mechanisms that support the design, implementation, distribution, and deployment of computer programs that are comprised of packaged knowledge components written in object oriented programming languages. The KOP environment used in some embodiments of the invention is described in U.S. patent application Ser. No. 10/034,601, filed Dec. 26, 2001, entitled KNOWLEDGE ORIENTED PROGRAMMING, which is hereby incorporated by reference herein for all purposes.  
         [0021]    The Knowledge Model  131  comprises a set of one or more components for declaring and storing the variables of the Biological or Chemical system  111 . The components may include one or more methods that may involve accessing databases, text files, or other types of recorded material to populate the component of the Knowledge Model  131 . The Logic Model  132  comprises a method for accessing existing algorithms and statistical tools (i.e. computational tools). The Logic Model  132  provides the language for interpreting the existing computational tools according to Knowledge Oriented Programming. The Logic Model  132  further provides a method for storing inference data, such as rules and constraints, which in some embodiments are expressed according to a KOP formalism. The Knowledge Model  131  and Logic Model  132  are assembled for execution by the Discovery Model  133 . The Discovery Model  133  executes the discovery logic in computer memory by using the KOP runtime. In some embodiments, code representing models  131 ,  132  and  133  is generated in the following fashion. The user provides the logical declaration of an entity (for example, the entity Protein) through a Graphical User Interface (GUI)  150  and/or an application descriptor language that may be part of the GUI  150  or separately provided. In some embodiments, such GUI will have a text editor for declaring the properties of the entity (for example, a user may define a Protein as an entity with properties such as sequence, structure, etc.). In further alternative embodiments, the GUI  150  includes graphical elements such as menus, buttons, and icons that may be used to declare property elements. The user declaration is then automatically converted into one or more components that may be stored and executed in computer memory using the KOP runtime  140  without additional intervention from the user.  
         [0022]    [0022]FIG. 2 depicts a block diagram of the encoding of the entities of the Biological/Chemical System  111  into the Knowledge Model  131 . For example, a protein  202  is represented by a Protein type  204 . This type may be encoded using an object oriented language. At the Meta Model level, the Protein type  204  is identified as type Thing  206 , which is an element of Knowledge Oriented Programming environment. An identification number (ID #) used to identify biological or chemical entities in databases may be specified using the Key type  208  of a KOP environment. Relationships among biological or chemical entities may be represented at the Meta Model level by the Relation type  210 , which may be an element defined by the KOP environment. Such Relation types are then implemented using an object oriented language. Examples of a relationship are association by similarity  214  (such as structure similarity or sequence similarity), association by function  214  (for example proteins that belong to the same metabolic pathway), or by chemical characteristics  216  (for example classes of chemical compounds).  
         [0023]    [0023]FIG. 3 depicts an example of how biological and chemical entities are transformed into computer code using a KOP runtime. Within Knowledge Model  131 , a user describes a biological or chemical entity through a GUI  150 . Block  302  shows a typical database record for a protein. A protein has properties including a sequence, organism of origin, physiological function, etc. (outlined in bold characters in block  302 ). The user may use the GUI to specify such properties by inputting records such as “protein_id”, “date”, “name”, etc. By using the KOP-run time  140 , such records are converted into KOP types and then into computer code. The entity Protein is now of type Thing and it is implemented as a class (“public class Protein extends Thing”  206 ). The class Protein extends the class Thing, which, in turn, is the implementation of the type Thing of the KOP environment. The “protein_id” is associated with Key  208  and it is obtained using a getKey method. Additional properties may be defined using additional methods provided within the KOP runtime environment. For example, “getSequence” returns the sequence of the protein. Following generation of Protein as a Thing, components that extend Fact and Relation defined by the KOP environment are also generated. The example shows an implementation using Java, but the process is applicable to other object oriented languages as well. For example, the C++ language could be used. Computer code  304  is generated automatically without user intervention. Properties may be added, or deleted as needed, and the code may be regenerated to reflect the modifications to the various models.  
         [0024]    [0024]FIG. 4 depicts a block diagram of the encoding of the Logic Model  132 . Computational operations among biological or chemical entities are usually carried out using computational chemistry tools, bioinformatics tools (such as algorithms for sequence comparison or pattern search), and inference tools. Such inference tools may be external or internal algorithms or may be logical statements expressed by the user of the system using GUI  150 . Examples are computational chemistry software  402 , bioinformatics algorithms  404 , and validation and inference tools  406 . Such components are represented in the Logic Model  132  by using the Relation Function  408  elements of the Meta model and described using the KOP environment. Wrappers  410 ,  412 , and  414  translate the input and output of the algorithms into components defined and understood by the KOP environment. Wrappers  410 ,  412 , and  414  comprise computer code written using an object oriented language. In an embodiment, a wrapper is a small program that translates the input and output from an existing program into elements of the KOP environment. Inputs and outputs to and from the wrapper can be defined using the GUI  150 , while the user may supply the algorithm executed by the wrapper. Execution of the Relation Function is controlled by a Event/Event Handler pair of the Meta Model.  
         [0025]    [0025]FIG. 5 depicts an example of a component of the Logic Model  132 . In this example, the Logic Model  132  comprises an algorithm to compute sequence similarity between a list of proteins and a chosen protein. In this example, the BLAST (Basic Local Analysis Search Tool) algorithm  512  is used and a wrapper  514  is written to communicate with the components of the Knowledge Model  131 . The BLAST algorithm is further described in Altschul S F, Gish W, Miller W, Myers E W, Lipman D J. BLAST Basic local alignment search tool. J Mol Biol. 215:403-410 (1990). The user, using the GUI  150 , specifies the required inputs and outputs to BLAST. In this particular example, two inputs are required, the test protein and a protein database. These elements are described in the Knowledge Model by the type Protein  204 . The output of the calculation will be a new relation that reports the degree of similarity of the test protein. The results are stored in a new entity, also designed according to the procedure in FIGS. 2 and 3. “KOP-BLAST” comprises generated computer code  516  which extends the Relation Function component of the KOP environment  140  and is handled at execution through an Event/EventHandler pair of the Meta Model. KOP-BLAST accepts elements of the Knowledge Model  131  and makes use of a wrapper  514 . The class may be generated automatically, without user intervention.  
         [0026]    [0026]FIG. 6 depicts a block diagram of the design and execution of a discovery application using the Discovery Model  133 . By using the GUI  150 , a user selects the components  602  needed to execute the application. A discovery process may have any number of components, both in the Knowledge Model  131  and in the Logic Model  132 . Components of the Knowledge Model are generated as described in FIG. 2. Various Logical Algorithms, generated as described in FIG. 5, can be cascaded as needed. The user designs the entire applications by specifying how different components are linked to each other. After assembly using the GUI  150 , an Application  604  is executed in computer memory by the KOP runtime  140 . The Discovery Model  133  makes use of Kernel, Application and Session of the Meta Model. Output Data  606  resulting from the execution of the application will be stored in entities described according to the Knowledge Model  131 .  
         [0027]    [0027]FIG. 7 is a block diagram of a screen image  700  of graphical user interface (GUI)  150  according to an embodiment of the invention that depicts how biological and chemical knowledge components, modeled according to a KOP environment are assembled and used by the user. The GUI  150  may be used to access, store, retrieve, design and to share the components of the Discovery Model  133 . In some embodiments, the GUI  150  provides folders for the Knowledge Model  131 , the Logic Model  132 , and the Discovery Model  133 . In some embodiments, a user first designs the components of the Knowledge Model  131  and the Logic Model  132 . These are then accessed through a pull-down menu and imported into the Discovery Model  133  upon request.  
         [0028]    In the example, the requested Knowledge Model  131  components are entities describing a Protein, its Structure, a Homology Relation and the chemicals to be tested (labeled Chemical in screen image  700 ). Logic Model  132  components are the functions and algorithms that may be used to carry out this test. In this example, algorithms such as DOCK, and MODELER may be called, as well as rules set up by the user (Rule #1 etc). The DOCK algorithm is further described in Meng, E. C., Shoichet, B. K., and Kuntz I. D. DOCK Automated docking with grid-based energy evaluation.  J. Comp. Chem  13:505-524 (1992). The MODELER algorithm is further described in Fiser A, Sali A. MODELLER: generation and refinement of homology models. In: Methods in Enzymology. Ed: Carter, C. W. and Sweet, R. M. Academic Press, San Diego, Calif., 2001.  
         [0029]    The components may then be presented on the Knowledge Model  131  using a drag and drop procedure. In the example, the Structure of a Protein (indicated here as ORL1) is obtained through a modeling procedure that involves finding a Homology relation with a known protein (rhodopsin) and then applying a modeling algorithm (KOP-Modeler). The modeled protein is then used in docking simulations (by invoking KOP-DOCK) and applying rules to screen the compounds. The end result is a list of chemical leads, e.g., a drug target, for the protein ORL1. In some embodiments, the arrows  702  represent a set of Event/Event Handler pairs that organize the logical flow of the application and execute it by binding it to the KOP-Kernel. The design flow is completely customizable, as the user may assemble the application as needed.  
         [0030]    [0030]FIG. 8 depicts a block diagram of an example system  800  for implementing an embodiment of the invention. The system  800  includes a computer  801  connected to a server  802  via a network  805 . Although one computer  801 , one server  802 , and one network  805  are shown, in other embodiments any number or combinations of them are present.  
         [0031]    The computer  801  includes a processor  830 , a storage device  835 , an input device  840 , and an output device  845 , all connected directly or indirectly via a bus  850 .  
         [0032]    The processor  830  represents a central processing unit of any type of architecture, such as a CISC (Complex Instruction Set Computing), RISC (Reduced Instruction Set Computing), VLIW (Very Long Instruction Word), or hybrid architecture, although any appropriate processor may be used. The processor  830  executes instructions and includes that portion of the computer  801  that controls the operation of the entire computer. Although not depicted in FIG. 8, the processor  830  typically includes a control unit that organizes data and program storage in memory and transfers data and other information between the various parts of the computer  801 . The processor  830  receives input data from the network  805  and the input device  840 , reads and stores code and data in the storage device  835 , and presents data to the network  805  and/or the output device  845 .  
         [0033]    Although the computer  801  is shown to contain only a single processor  830  and a single bus  850 , the present invention applies equally to computers that may have multiple processors and to computers that may have multiple buses with some or all performing different functions in different ways.  
         [0034]    The storage device  835  represents one or more mechanisms for storing data. For example, the storage device  835  may include read only memory (ROM), random access memory (RAM), magnetic disk storage media, optical storage media, flash memory devices, and/or other machine-readable media. In other embodiments, any appropriate type of storage device may be used. Although only one storage device  835  is shown, multiple storage devices and multiple types of storage devices may be present. Further, although the computer  801  is drawn to contain the storage device  835 , it may be distributed across other electronic devices.  
         [0035]    The storage device  835  includes the Logic Representation  130 , which includes Knowledge Model  131 , the Logic Model  132 , and the Discovery Model  133 , all of which include data and/or instructions capable of being executed on the processor  830  to carry out the functions of the present invention, as previously described above with reference to FIGS.  1 - 7 . In another embodiment, some or all of the functions of the present invention are carried out via hardware. Of course, the storage device  835  may also contain additional software and data (not shown), which is not necessary to understanding the invention.  
         [0036]    Although the Knowledge Model  131 , the Logic Model  132 , and the Discovery Model  133  are shown to be within the storage device  835  in the computer  801 , in another embodiment they may be distributed across other systems, e.g., on the server  802  and accessed remotely.  
         [0037]    The bus  850  may represent one or more busses, e.g., PCI, ISA (Industry Standard Architecture), X-Bus, EISA (Extended Industry Standard Architecture), or any other appropriate bus and/or bridge (also called a bus controller).  
         [0038]    The computer  801  may be implemented using any suitable hardware and/or software, such as a personal computer or other electronic computing device. Portable computers, laptop or notebook computers, PDAs (Personal Digital Assistants), pocket computers, telephones, and mainframe computers are examples of other possible configurations of the computer  801 . The hardware and software depicted in FIG. 8 may vary for specific applications and may include more or fewer elements than those depicted. For example, other peripheral devices such as audio adapters, or chip programming devices, such as EPROM (Erasable Programmable Read-Only Memory) programming devices may be used in addition to or in place of the hardware already depicted.  
         [0039]    The server  802  may include components analogous to some or all of the components already described for the computer  801 . In another embodiment, the server is not present.  
         [0040]    The network  805  may be any type of network or combination of networks suitable for communicating between the computer  801  and the server  802 . In another embodiment, the network  805  is not present.  
         [0041]    As was described in detail above, aspects of an embodiment pertain to specific apparatus and method elements implementable on a computer or other electronic device. In another embodiment, the invention may be implemented as a program product for use with an electronic device. The programs defining the functions of this embodiment may be delivered to a computer via a variety of signal-bearing media, which include, but are not limited to:  
         [0042]    (1) information permanently stored on a non-rewriteable storage medium, e.g., a read-only memory device attached to or within an electronic device, such as a CD-ROM readable by a CD-ROM drive;  
         [0043]    (2) alterable information stored on a rewriteable storage medium, e.g., a hard disk drive or diskette; or  
         [0044]    (3) information conveyed to a computer by a communications medium, such as through a computer or a telephone network, including wireless communications.  
         [0045]    Such signal-bearing media, when carrying machine-readable instructions that direct the functions of the present invention, represent embodiments of the present invention.  
         [0046]    Various embodiments of the present invention provide a method for extracting knowledge from biological and chemical data using a KOP environment. The KOP framework helps users rapidly process large biological and/or chemical data into knowledge. Application of a KOP environment to the biological and chemical sciences may meet the needs for facilitating and speeding discovery processes, such as drug design, although it may be used in any appropriate discovery process. Implementation of the method into software tools result in a system that can be customized by the end user, typically without the need of additional skills. The discovery process can be saved as a text file and easily shared among researchers. Security may be provided for defining ownership and access privileges. Some embodiments of the invention provide a system that can be accessed through a Web-accessible browser or that be started remotely (such as WebStart). Other embodiments are used on a stand-alone computer.