Patent Publication Number: US-2005131649-A1

Title: Advanced databasing system for chemical, molecular and cellular biology

Description:
This application claims the benefit of U.S. Provisional Application No. 60/494,364 filed Aug.  12 ,  2003  which is herein incorporated by reference. 
    
    
     FIELD OF THE INVENTION  
      This invention relates to the field of biomedical information management and research. More specifically, the invention relates to a system and method for extracting public and private chemical, biological and/or molecular research data, integrating the extracted information with entries in a relational database, and providing utilities for analyzing the stored data and information.  
     BACKGROUND INFORMATION  
      Generally, lifescience researchers need an information management system that allows its users to easily comprehend the extremely complex and vast amounts of data associated with chemical, biological, and/or molecular research. There has not been a comprehensive research system and method including 1) relational database schema and tables, 2) standardized ontologies and vocabularies, 3) scientific applications, and 4) user friendly data annotation services. Previous attempts at similar systems gave rise to individual modules and do not provide the full range of capabilities and functionality of the present invention. For example, past attempts to annotate data in a database often required a human curator to manually input data as free text “comments.” The data appended with stored data entries in such systems is collected and saved in non-standardized data formats, impeding interaction with other data processing systems.  
      Previous attempts at research information management systems have developed in narrow applications. One such system references sequence data related to proteins, genes and gene loci. Generally, such sequence data related to proteins, genes and gene loci are archived in publicly available databases. Such systems may append a sequence citation to a data entry. Such systems simply append source reference citations as internet hyperlinks and do not require a literature source reference citation. Other systems allow the capture of data regarding a single type of molecular data or protein functions, but do not include the source references for the data. There is a system that defines a hierarchical structure for annotating protein functions. However, the system does not integrate information about tissue specificity, cellular processes, sub-cellular localization, disease associations, mutations, modifications, molecular genetics, molecular complexes, compound registries, interaction networks, and gene linkages, as does this invention.  
      Previous attempts of displaying processed data include a system that displays processed data related to interactions associated with a specific yeast protein. Another system displays analyzed data related to simple interactions for a virus in a yes/no format. However, neither system interacts well with a relational database. Yet another system for analyzing molecular interactions displays signal transduction interaction networks as either text-based cascades or flatly drawn maps. The system does not draw molecular networks dynamically, and furthermore the system does not readily interact with the database used to store the displayed data.  
      A few other commercial applications have been created for viewing protein interaction maps, but such applications do not address biochemical intermediates, or drug compounds. These applications do not provide additional information related to the actual interaction, such as the type of interaction (Binding, covalent modification, etc . . . ), the interaction logic (activates, inhibits), the effects (cleavage, phosphorylation), or the downstream ramifications to the cellular process (cellular growth, cell division). Generally, previous attempts at analyzing and displaying interactions simply show data content and do not facilitate data processing, analysis or new data entry.  
      Generally, the prior process involving an individual user manually appending non-standardized data to data entries in a molecular life science database has not been a scalable, extensible, or efficient method for collecting, analyzing, or archiving data related to chemical, biological, and/or molecular data entries. Further, such practices seriously impede a user attempting to research aspects of complex interactions between data entries.  
     SUMMARY OF THE INVENTION  
      The invention provides a comprehensive method and system allowing a researcher to break down the often complex and overwhelming amount of data related research findings into manageable easy-to-understand visual representations. Generally, the system focuses on two facets of scientific research: data annotation and data analysis. The annotation module uses ontology browsers, pull down menus filled with standard search terms, and reference managers, which populate the information management system with relevant data. The analysis module employs advanced search algorithms, network builders, and tools to examine data already present in the system. Unencumbered access to the interactions of chemical, biological, and/or molecular data is critical for advances to occur in related scientific research. Without a central system for organizing, entering, and analyzing data, experiments may be repeated, performed without knowledge of prior findings and inappropriately prioritized. The present invention creates a method, system and apparatus for resolving the shortcomings of the systems discussed above. Hereafter, the system may be referred to as Cognia Molecular™ or CM™.  
      Other and further aspects of the invention will become apparent from the following detailed description with reference to the accompanying drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      FIG  1 A. is an exemplary overview of a three-tier architecture system associated with the Cognia Molecular™ system.  
       FIG. 1B  is an exemplary overview of the Cognia Molecular™ system  
       FIG. 2  is an exemplary screen from Cognia Molecular™ system&#39;s logon entry screen.  
       FIG. 3  is an exemplary screen of an embodiment of an annotation module and a preliminary search page.  
       FIG. 4  is an exemplary screen of a universal ontology hierarchy browser  
       FIG. 5  is an exemplary screen of search results associated with an ontology browser&#39;s search engine.  
       FIG. 6  is an exemplary screen associated with the process of adding attribute terms to the annotation in the ontology browser.  
       FIG. 7  is an exemplary screen of a reference manager entry point.  
       FIG. 8  is an exemplary screen of the launched reference annotation module.  
       FIG. 9  illustrates the exemplary results of a search based on PubMed identification numbers.  
       FIG. 10  is an exemplary screen shot associated with the referencing module saved results.  
       FIG. 11  is an exemplary generic reference addition to the database.  
       FIG. 12  is an exemplary screen shot of a network builder entry point.  
       FIG. 13  is an exemplary illustration created by a molecular interaction builder.  
       FIG. 14  is an exemplary screen shot that illustrates functionality associated with molecular interaction builder.  
       FIG. 15  illustrates an exemplary filter apparatus for eliminating extraneous interactions in a drawn network.  
       FIG. 16  is an exemplary screen shot of an advanced search screen.  
       FIG. 17  is an exemplary screen shot of an advanced search screen implementing a Boolean recombined search.  
       FIG. 18  is an exemplary screen shot of a user-specific saved advanced search.  
       FIG. 19  is an exemplary screen shot displaying results obtained during an advanced search.  
       FIG. 20  is an exemplary screen shot of an output table corresponding to a data entry from the Cognia Molecular™ database system.  
       FIG. 21  is an exemplary screen shot of a representative user interface associated with an interaction loader.  
       FIG. 22  is an exemplary screen shot of a user interface for curation menus associated with the Cognia Molecular™ database system.  
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      In the following description of the various embodiments of the invention, reference is made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration various embodiments in which the invention may be practiced. It is to be understood that other advancing embodiments may be utilized, and structural and functional modifications may be made, without departing from the scope of the present invention.  
      Overview  
      This invention provides a comprehensive method and system for storing, searching, and analyzing the vast amount of knowledge present in published and private scientific literature. Without databases that aggregate and reference facts about cellular and molecular biology, research efforts in drug discovery and basic research are significantly hampered by tangled or unconnected data and research information.  
      The system is a unified solution of an organized IT system used for pharmaceutical research. As such, it is not simply a database per se, nor is it simply a body of database content. Rather, it is a method and system for capturing, downloading, annotating, analyzing, and sharing data about the molecular sciences. Cognia Molecular™ is an integrated platform for data entry, sharing, and analysis based on researching component modules in coordination with a relational database, its tables, the user interface, accepted ontologies, and visualization tools. The system is an expansive tool enabling researchers to centralize and analyze complex data associated with interactions between chemical, biological, and/or molecular data entries, among other things.  
      Described herein are various aspects of the Cognia Molecular™ research information management system. One such aspect of the present invention is a network builder that constructs interaction networks between molecules in the context of other cellular proteins. The molecular interaction networking tool, when coupled with an underlying relational database, forms a graphical output of any tabulation or collection of interaction data regarding biomolecules. The network builder module implements a database driven, force directed node-edge display format for displaying database interaction content. One of the advantages of the Cognia Molecular™ network builder involves coupling the system to an underlying robust relational database. Scientific research functionality is bolstered by features of the Cognia Molecular™ system. For example, a user may create interaction maps that are multi-layered that allow a user to easily access the underlying data used to create the representative molecular interaction.  
      Another aspect of the present invention involves an advanced search capability of the Cognia Molecular™ system, which allows for the detailed search and retrieval of biomolecular information. Users of the Cognia Molecular™ system can search and retrieve information regarding biomolecules and bioactive compounds form a variety of resources. The advanced search capability described herein can locate proteins based a wide range of search terms including, but not limited to: their molecular weight, sequence length, structural motifs, sequence domains, names, synonyms, tissue specificity, cell cycle expression, and presence during development and differentiation. By way of example only, a synonym may be a secondary database identifier such as “UCHBL1”, or a name referring to the identical molecule as reported in the literature such as “UCH-Low mass number 1.” 
      The characteristics provide useful tags whereby the vast amount of biomedical information present in databases can be queried. Recombination of searches in a Boolean fashion allows the searches to be even more useful, as several characteristics of proteins can be recombined into a single set of search terms, enabling a user to create an extremely focused search. This leads to eliminating extraneous search results and providing more detailed searches, more relevant results, and greater speed of use and utility for the users. Previous databases and systems were not able to perform these searches because they either did not capture such types of information or were unable to create detailed searches based on these molecular characteristics.  
      Described herein are the features of the various modules of the Cognia Molecular™ databasing system, such as annotation modules, reference managers, advanced search algorithms, ontology browsers, molecular network builders, applets, and text processing scripts. The three-level architecture system illustrated in  FIG. 1A , includes a user&#39;s web application node  100 , running the front end graphical user interface, implementing the annotation module of the CM™ system, as well as the other modules described in detail below. It is to be understood that depending on the actual implementation, the various modules may be situated on different hosts. The user node communicates with a middle-tier web server  110 , acting as the intermediary between the back end relational database  120 , the user node  100 , and the internet (not shown).  
       FIG. 1A  illustrates the server side functionality for an embodiment of the invention. It is to be understood that the various operational modules, database modules and hardware elements may be supplemented to achieve additional functionality and that the embodiment illustrated herein is non-limiting.  
      FIG  1 B is an exemplary diagram illustrating system elements associated with an embodiment of Cognia Molecular™ (CM™). Cognia Molecular™  101  may be connected to and/or communicate with entities such as, but not limited to: one or more user nodes  112  connected through a communications network and/or the internet  113 . Depending on the actual implementation, the system may even be connected to and/or communicate with a cryptographic processor device  128 .  
      The Cognia Molecular™ system  101  may comprise a clock  130 , central processing unit (CPU)  103 , a read only memory (ROM  106 ), a random access memory (RAM  105 ), and/or an interface bus  107 , and conventionally, although not necessarily, are all interconnected and/or communicating through a system bus  104 . The system clock typically has a crystal oscillator and provides a base signal. The clock is typically coupled to the system bus and various means that will increase or decrease the base operating frequency for other components interconnected in the computer systemization. The clock and various components in a computer systemization drive signals embodying information throughout the system. Such transmission and reception of signals embodying information throughout a computer systemization may be commonly referred to as communications. These communicative signals may further be transmitted, received, and the cause of return and/or reply signal communications beyond the instant computer systemization to: communications networks, input devices, other computer systemizations, peripheral devices, and/or the like. Optionally, a cryptographic processor  126  may similarly be connected to the system bus. Of course, any of the above components may be connected directly to one another, connected to the CPU, and/or organized in numerous variations employed as exemplified by various computer systems.  
      The CPU  103  comprises at least one high-speed data processor adequate to execute program modules for executing user and/or system-generated requests. The CPU  103  may be a microprocessor such as the Intel Pentium Processor and/or the like. The CPU  103  interacts with memory through signal passing through conductive conduits to execute stored program code according to conventional data processing techniques. Such signal passing facilitates communication within the Cognia Molecular™ and beyond through various interfaces.  
      Interface Adapters  
      Interface bus(es)  107  may accept, connect, and/or communicate to a number of interface adapters, conventionally although not necessarily in the form of adapter cards, such as but not limited to: input output interfaces (I/O)  108 , storage interfaces  109 , network interfaces  110 , and/or the like. Optionally, cryptographic processor interfaces  127  similarly may be connected to the interface bus. The interface bus provides for the communications of interface adapters with one another as well as with other components of the computer systemization. Interface adapters are adapted for a compatible interface bus. Interface adapters conventionally connect to the interface bus via a slot architecture. Conventional slot architectures may be employed, such as, but not limited to: Accelerated Graphics Port (AGP), Card Bus, (Extended) Industry Standard Architecture ((E)ISA), Micro Channel Architecture (MCA), NuBus, Peripheral Component Interconnect (PCI), Personal Computer Memory Card International Association (PCMCIA), and/or the like.  
      Storage interfaces  109  may accept, communicate, and/or connect to a number of storage devices such as, but not limited to: storage devices comprising system modules/databases  114 , removable disc devices, and/or the like. Storage interfaces may employ connection protocols such as, but not limited to: (Ultra) Advanced Technology Attachment (Packet Interface) ((Ultra) ATA(PI)), (Enhanced) Integrated Drive Electronics ((E)IDE), Institute of Electrical and Electronics Engineers (IEEE)  1394 , fiber channel, Small Computer Systems Interface (SCSI), Universal Serial Bus (USB), and/or the like.  
      Network interfaces  110  may accept, communicate, and/or connect Cognia Molecular™ with a communications network/the internet  113  and in turn, with user node(s)  112 . Network interfaces may employ connection protocols such as, but not limited to: direct connect, Ethernet (thick, thin, twisted pair 10/100/1000 Base T, and/or the like), Token Ring, wireless connection such as IEEE 802.11 a/b/g, Bluetooth, and/or the like. A communications network may be any one and/or the combination of the following: a direct interconnection; the Internet; a Local Area Network (LAN); Storage Area Network (SAN), Metropolitan Area Network (MAN); an Operating Missions as Nodes on the Internet (OMNI); a secured custom connection; a Wide Area Network (WAN); a wireless network (e.g., employing protocols such as, but not limited to a Wireless Application Protocol (WAP), I-mode, and/or the like); and/or the like. A network interface may be regarded as a specialized form of an input output interface.  
      Input Output interfaces (I/O)  108  may accept, communicate, and/or connect to cryptographic processor devices  128 , alternate system input device (not shown) and/or the like. I/O may employ connection protocols such as, but not limited to: Apple Desktop Bus (ADB); Apple Desktop Connector (ADC); audio: analog, digital, monaural, RCA, stereo, and/or the like; IEEE 1394; infrared; joystick; keyboard; midi; optical; PC AT; PS/2; parallel; radio; serial; USB; video interface: BNC, composite, digital, RCA, S-Video, VGA, and/or the like; wireless; and/or the like. A common output device is a video display, which typically comprises a CRT or LCD based monitor with an interface (e.g., VGA circuitry and cable) that accepts signals from a video interface. The video interface composites information generated by a computer systemization and generates video signals based on the composited information. Typically, the video interface provides the composited video information through a video connection interface that accepts a video display interface (e.g., a VGA connector accepting a VGA display cable).  
      User node device(s)  112  may be connected and/or communicate with or to I/O Interface  108  and/or with or to other facilities of the like such as network interfaces  110 , storage interfaces  109 , and/or the like. A user node device  112  may be connected with a range of peripheral devices configured to interact with a user. Such peripherals may include cameras, dongles (for copy protection, ensuring secure transactions as a digital signature, and/or the like), external processors (for added functionality), goggles, microphones, microscopes, anatomical or cellular imaging systems, monitors, network interfaces, printers, scanners, storage devices, visors, and/or the like.  
      Cryptographic units such as, but not limited to, microcontrollers, processors  126 , interfaces  127 , and/or devices  128  may be attached, and/or communicate with Cognia Molecular™. A MC68HC16 microcontroller, commonly manufactured by Motorola Inc., may be used for and/or within cryptographic units. Equivalent microcontrollers and/or processors may also be used. The MC68HC16 microcontroller utilizes a 16-bit multiply-and-accumulate instruction in the 16 MHz configuration and requires less than one second to perform a 512-bit RSA private key operation. Cryptographic units support the authentication of communications from interacting agents, as well as allowing for anonymous transactions. Cryptographic units may also be configured as part of CPU. Other commercially available specialized cryptographic processors include VLSI Technology&#39;s 33 MHz 6868, Mykotronx 24 MHz MYK-82A, or Semaphore Communications&#39; 40 MHz Roadrunner 284.  
      Memory  
      A storage device for storing the system modules/databases  114  may be any conventional computer system storage. Storage devices may be a fixed hard disk drive, and/or other devices of the like. However, it is to be understood that Cognia Molecular™ may employ various forms of memory  129  and that the various modules comprising the system are not limited to residing in the same memory. In a typical configuration, memory  129  will include ROM, RAM, and a storage device  114 . Generally, any mechanization and/or embodiment allowing a processor to affect the storage and/or retrieval of information is regarded as memory  129 . Thus, a computer systemization generally requires and makes use of memory. However, memory is a fungible technology and resource, thus, any number of memory embodiments may be employed in lieu of or in concert with one another.  
      Module Collection  
      The storage device  114  may contain a collection of program and/or database modules and/or data such as, but not limited to: an annotation module  115 ; ontology module  116 ; a reference manager module  117 ; a network builder module  118 ; an advanced search module  119 ; data import module  120 ; a curator administration module  121 ; and Cognia Molecular™ databases  122 . These modules may be stored and accessed from the storage devices and/or from storage devices accessible through an interface bus. Although non-conventional software modules such as those in the module collection, typically and are stored in a local storage device  114 , they may also be loaded and/or stored in memory such as: peripheral devices, RAM, remote storage facilities through a communications network, ROM, various forms of memory, and/or the like. The functionality associated with the Cognia Molecular™ modules and databases will be described in greater detail below.  
      The Cognia Molecular™ database  122  may be embodied in a database that is stored program code and executed by the CPU. The stored program code portion configures the CPU to process the data stored in the database. The databases may be conventional, fault tolerant, relational, scalable, extensible and secure databases. Relational databases are an extension of a flat file, and are collections of such. Specifically, relational databases such as used by this invention consist of a series of related tables. The tables are interconnected via a key field and/or table constraints. Use of the key field allows the joining or combination of the tables by indexing against the key field; i.e., the key fields act as dimensional pivot points for combining or selecting information from various tables. Relationships generally identify links maintained between tables by matching primary or logical keys. Primary or logical keys represent fields that uniquely identify the rows of a table in a relational database. More precisely, they may uniquely identify rows of a table on the “one” side of a one-to-many relationship, or one-to-one relationship. Because of the breadth of knowledge able to be imported into the present embodiment, this invention heavily utilizes a flexible, non-redundant key system for its unique and powerful abilities.  
      Alternatively, the Cognia Molecular™ databases may be implemented using various standard data-structures, such as an array, hash, (linked) list, struct, table, and/or the like. Such data-structures may be stored in memory and/or in (structured) files. If the Cognia Molecular™ databases are implemented as data-structures, the use of the Cognia Molecular™ databases may be integrated into another module such a data management module. Databases may be consolidated and/or distributed in countless variations through standard data processing techniques. Portions of databases, e.g., tables, may be exported and/or imported and thus decentralized and/or integrated.  
      In an alternative embodiment, such tables are capable of being decentralized into their own databases and their respective database controllers (i.e., individual database controllers for each table). Of course, employing standard data processing techniques, one may further distribute the databases over several computer systemizations and/or storage devices. Similarly, configurations of the decentralized database controllers may be varied by consolidating and/or distributing various database modules.  
      Cognia Molecular™ databases may communicate to and/or with other modules in a module collection, including themselves, and/or facilities of the like. The databases may contain, retain, and provide information regarding other user nodes and data.  
      Finally, it is to be understood that the logical and/or topological structure of any combination of the module collection and/or the present invention as described in the figures and throughout are not limited to a fixed execution order and/or arrangement, but rather, any disclosed order is exemplary and all functional equivalents, regardless of order, are contemplated by the disclosure. Furthermore, it is to be understood that such structures are not limited to serial execution, but rather, any number of threads, processes, services, servers, and/or the like that may execute asynchronously, simultaneously, synchronously, and/or the like are contemplated by the disclosure.  
       FIG. 2  illustrates an exemplary user entry screen implemented on the user node  100 . Depending on the actual implementation, a user may be requested to provide a username  205  and a password  210 . In the embodiment shown in  FIG. 2 , the user is required to provide a specific project  215 . The system may provide limited access to certain users based on either the type of project entered or on the specific project  215 .  
      In one embodiment of the present invention, the software modules of the system implemented to accomplish the functionality described herein were created using HTML, dynamic HTML, XML, C, Java 2, SQL, PL/SQL, Perl, Javascript, Ruby, Python, visual basic, and Java Server Pages (JSP) software code. However, it is to be understood that the modules may be created by using any of a range of computer programming languages, and/or scripting languages. Further, it is to be understood that the software modules and the corresponding hardware for implementing the invention vary based on actual the application. In one embodiment, the software modules are implemented on a computer system with a 32 or 64-bit operating system, a web browser such as Microsoft Internet Explorer 5 or later, and a database such as a three-tiered Oracle relational database architecture that is J2EE compliant and web-capable. Although alternative embodiments may be implemented, this embodiment also includes either a local installation of, or a network connection connected to, a databasing system.  
      Annotation Module  
      Data entry into the system is achieved by the use of a module including annotation pages. One possible embodiment of such annotation pages involves HTML/Java based software utilities for capturing data, information, and/or characteristics related to a specific research source. A user may select a chemical, biological, or molecular data entry from a wide range of public and private biomedical data resources. The Cognia Molecular™ system includes modular components, which together define a databasing system used in basic research and industrial drug discovery, in an effort to capture, process, and analyze the large amount of knowledge present in published and private scientific resources.  
      In an embodiment of the present invention implementing web browser technology, the annotation module uses over 2000 pre-defined terms to describe the biology and chemistry of applied pharmaceutical and biotech research, as well as basic scientific research. Software scripts streamline the process of data entry, and various technologies facilitate standardizing the data entry, assure quality control of the data, and increase the accuracy of the input.  
       FIG. 3  illustrates an exemplary screen shot of an embodiment of an annotation module and a preliminary search page  300 . A user may enter an entry name (selected entry)  310  that is the focus of an annotation. An initial search is conducted to verify that the selected entry  310  is not already part of the database. In order to further refine the initial search, a user may select a particular species containing the molecule in pull-down menu  320 .  
      The Cognia Molecular™ annotation module allows for the entry of biological and chemical data, as well as the association of the entered data with a database entry. As illustrated in a universal hierarchy browser in  FIG. 4 , a molecular function term  405  has been annotated. Alternately, a user could annotate aspects of a data entry&#39;s biological process  410 , and/or cellular component  415 . In this embodiment, the universal browser allows a user to associate at least three attributes  420  with a selected data entry. In the illustrated embodiment, the annotation module is used with the GeneOntology (“GO”) consortium codebase of terms. In one embodiment of the invention, the database system can be used to annotate over 100 different molecular attributes, from proprietary and open-source origins.  
      Another component module of the Cognia Molecular™ system involves an ontology browser for finding, selecting, and adding terms from inside an ontological system. These terms, in turn, are then used as entry attributes, or flags associated with data entries inside the system and its content.  
      Ontology Browser and Annotation Utility  
      Ontologies are standardized vernacular relationships, organized in a rule-based, hierarchical way, whereby terms are defined by a scientific community as a group of relevant semantic descriptors. Without an accepted ontological system, databases can be made. However, they are extremely difficult to integrate with other information systems or data from other sources without some type of standardization. Cognia Molecular™ implements ontologies created from references such as, the Gene Ontology (GO) Consortium and the National Library of Medicine&#39;s Medical Subject Headings (MeSH) list. These world standards are the result of consortia of scientists deciding on precise definitions of terms for descriptive cellular, molecular, and physiological biology.  
      The ontology browser exists as a utility inside the data capture system and is used by a human annotator to add detail to a data entry. Ontologies described herein provide standardized descriptive terms related to aspects of chemical, biological, molecular research such as, but not limited to: protein function, cellular process, sub-cellular location, phylogenetic taxonomy, and disease association. The ontology browser allows the controlled incorporation and association of one or more terms with a database entry. These terms allow the tagging of information and thus, allow the use of searches to retrieve that information through user-defined searches. This invention facilitates the attachment of standard terms to data being entered into a relational database for data entries corresponding to proteins, genes, compounds, complexes and interactions between data entries.  
      The ontology browser may be used to append reference citations to facts or alternately assertions annotated by human curators to be associated with data entries in the database. Without such references, the database utility and veracity is severely impaired, because researchers require data to be supplied by a credible reference before it can be relied on. The browser polls websites, archives and other scientific resources containing reference material presented in a standard format. To enter data into the database so that other data systems may use the data, the system implements controlled standardized vocabularies from such entities as the GeneOntology consortium, or the Medical Subject Headings list, or other standardized vocabularies. These terms allow the vernacular of biology to be related and controlled in ways that other databases are able to process. Other ontology-related library systems used by Cognia Molecular™ include, but are not limited to, pFAM (protein family) terms, cell type lists from the Cell Line Database and American Type Culture Collection, CDDB, UMLS, SMIRK, SMILES, CD-SMART, SBML, CellML, and open source compound nomenclature from the National Cancer Institute and Daylight technologies. In certain instances, the system implements customized terms, for example, to describe names of research experiments used to demonstrate an empirical fact to be annotated within the system. Depending on the actual embodiment, these term libraries and ontological systems may be configured and accessed by a user in pull down menus (Java based combo boxes or scroll boxes). Alternately, such terms may be embedded in navigation browsers.  
       FIG. 5  illustrates an exemplary screen shot of search results associated with an ontology browser&#39;s search engine for an embodiment of the present invention. The figure illustrates the current search term  500 , as well as search results from previous searches  505  in tabular format. Potential annotation terms are selected by the use of radio buttons  510  embedded in the ontological search browser for entering biological terms into a database. An indefinite number of terms may be appended to a selected database entry. Browser button  515  allows a user to save a term by “adding” it to the list.  
       FIG. 6  is an exemplary screen shot associated with the process of adding attribute terms to the annotation through the ontology browser. The figure illustrates the process of “adding” a term. Specifically, as illustrated “DEAD/H-box RNA helicase” binding term  605  has been added to the annotation shown in  FIG. 4  and saved in the database.  
      Terms in the ontologies may be selected from either public or private sources. Such terms are used in a data annotation system that can also be used to create biological databases. The browsers are embedded into a web application and are launched when the user imports data related to a biological process into the database. The ontological component of a relational databasing system is necessary to facilitate viable research due to the complexity associated with the chemical, biological, and molecular elements involved, and the need for standard ontologies that describe similar aspects of cellular and organismal processes. No other data capture system for biological databases implements embedded browsers to house links to readily available scientific resources on the internet and inside the firewall of a user&#39;s system, as in the Cognia Molecular™ system.  
      The ontology browser is a module-based utility for streamlining the capture of biological information as defined by ontological systems. Such systems are necessary for the controlled development of biological databases and provide a standard vernacular whereby such a database may become viable for scientific research resources. Ontologies are not for organizing human thinking and natural intelligence (NI) per se, but rather are highly complex, hierarchical, binary parent-child systems of treed relationships whereby detailed processes, such as cell biology, can be finely subdivided into component logic for automated processing and analysis by artificial intelligence (Al) systems.  
      The ontology browser is used as part of the Cognia Molecular™ system&#39;s user interface when a new ontological term is to be annotated for a database entry. The browser opens, allows a search of the ontologies offline or online and encourages a selection of the ontological term to be appended to the data entry. In an embodiment, the user is presented with the option to save the data. Closing the browser ends the ontological annotation session and the system may revert back to the data entry system. The on-demand browser-in-browser system of CM™ is web enabled, platform agnostic, and universal for all descriptive hierarchical ontologies.  
      One advantage of the ontological browser system with an annotation module, as opposed to a pull down (“flat”) menu system, is that the ontology browser may be implemented with dynamic upkeep of the ontology by an external agency. This enables the development of the ontological system consistent with the content of the database implementing a universal browser. Accordingly, the invention achieves a dynamic system. Moreover, it guarantees that the user-annotated terms are placed in the correct relational database structure to facilitate advanced Boolean searching capabilities within the system.  
      The ontology browser enables the use of any ontological system with a hierarchical system of organization. By finely atomizing the biology parameters needed to describe, discuss and research the cell biology and pharmacology of these systems, greater efficiency can be achieved with regard to research information management. An embodiment of the present invention relies on a relational database, platform-general software code proprietary novel semantic lexicons, and universal ontologies.  
      Reference Manager Annotation Utility  
      Many types of data processed in the Cognia Molecular™ system are associated with reference tags to indicate the resources that provide the information saved by the annotation pages. This ensures that the data is accurate and is extracted from a reliable source. Implementing reference tags enables a user to trace data inception. Thus, a reference manager has been implemented to import reference and citation data, such as PubMed information. This invention allows a Cognia Molecular™ user to annotate facts in database entries and to append source references to those annotations. Utilizing software scripts, the browser described can automatically extract critical details about those references. This reference manager can be used on any web accessible or intranet data source that is structured according to a standard protocol. The referencing system is web-enabled, platform agnostic, universal for all references and is implemented within the Cognia Molecular™ system.  
      Disclosed herein is one embodiment of such reference manager, implemented as a medical reference management system. An annotated database resource should reference facts it has aggregated into its corpus. As related to this embodiment, a web-based system is described enabling a method for extracting reference matter from public and proprietary resources. The system is capable of extracting data from regularly structured files from the internet or a local network, as well as enabling a method to enter custom data from unstructured sources, such as anecdotes, seminars, public speeches, journal abstracts, and personal communications. A significant use of the reference parsers described herein involve the use of the medical database “PubMed” and its vast array of articles describing biological and chemical research related to cellular and molecular biology. This utility requires the incorporation of the power of computing and software scripts in aiding the speed and accuracy of data entry in large databases, where a human annotator would have too much information to manually parse individual entries.  
       FIG. 7  illustrates the reference manager  700  utility. The embodiment illustrated is an example capable of interacting with the National Library of Medicine&#39;s PubMed database. When entering information about a molecule into the relational database, the user: 
          1) launches a new browser window with a button termed “Add/Modify References  710 .”    2) This in turn opens a window shown in  FIG. 8 , where a user adds a PubMed identification number to the box termed PubMed ID  810 ; and     3) searches for the reference details using a “Find and Add reference” button  820 .     4) The reference manager responds to the user request by searching the National Library of Medicine databases and acquires specific bibliographic information.     5) When the corresponding data has been retrieved, the user may save those changes to the entry by selecting the button, “save those changes”  825 .     6) When the user is done adding references, the user may press the “close window”  830  button and proceed to step 7.     7) The user is returned to the original screen wherein the new reference is seen and can be verified  910 , shown as in  FIG. 9 . It is to be understood that the verification  910  is not limited to the illustrated step. The system may verify the spelling of attributes within Cognia Molecular™ database, stored libraries, checking external database identification numbers against database tables with specific formats of identifiers. In the network builder module verification may include calculating molecular weights by summarily adding the grams per mole of the totality of amino acids and generating such a molecule specified by its attributes; calculating protein and gene sequences by summing the number of symbols in their length as defined by standard biopolymer nomenclature.        
      As illustrated in  FIG. 10 , the saved reference information  1010 , provides credibility to the data saved by the annotation module for the particular protein&#39;s annotation. It is to be understood that the Cognia Molecular™ system may interact with any other data source comprising structured or unstructured data.  
      Alternately,  FIG. 9  illustrates a “Generic Reference” button  920 . This aspect of the present invention allows a user to manually input reference information. Exemplary general reference data is shown in  FIG. 11 . A user may enter data including, but not limited to the author of a reference  1110 , title of a reference  1120 , the journal the reference was published in  1130 , miscellaneous details  1140 , and/or the date of the reference  1150 .  
      Network Builders  
       FIGS. 12-15  illustrate one component module of the Cognia Molecular™ system enabling a user to create graphical representations of the cell biology interactions in a network builder module from data stored within the database. To this end, the network builder module is an interaction-building Java application, which creates a molecular interaction diagram (a map), comprising symbols that correspond to a selected data entry&#39;s attributes. A network builder provides an easy-to-read graphical representation of interactions between data entries and their corresponding characteristics. Generally, the cellular and molecular interaction data and characteristics are too complex to be addressed by tables, since such interactions often have many features and attributes. The CM™ network builder is integrated with the database schema and in one embodiment of the invention refers to data from at least 140 specific data tables defining various attributes of the data entries.  
      The network builder module is a software utility in CM™ that can graphically map out molecular interactions of a cell biological or a chemical network as shown in  FIG. 13 . Exemplary graphical representations may include, but are not limited to views of protein interaction networks, cellular positions of potential and existing drug intervention, the display of potential protein drug targets, the regulation of these networks by the members involved.  
       FIGS. 12-15  also illustrate an example based on data entered into the CM™ system using the annotation module. It is to be understood that the network builder can interact with other relational databases with data stored in normalized or regularized structures, through minor changes to its software code. Also, it is to be understood that although, the illustrated example only shows proteins, the network builder can work with any type of entry in the CM™ system, including protein, gene, complex or compound entries.  
      The network builder provides a user-friendly interface for a user to interact with the graphical representations illustrated as symbols  1300  in  FIG. 13  corresponding to data entries. The graphical representation may be modified by a user to focus on specific interactions through the use of control panel buttons  1310  displayed along the top of the graphical representation. A user may resize the graphical representation to focus on the symbols representing data entries of interest with bar  1320 . Alternately, a user may delete symbols associated with non-relevant data entries to focus upon specific data entries. Entries are depicted as nodes  1330  and interactions as lines  1340 .  
      In an embodiment illustrated in  FIG. 14 , certain characteristics associated with a given symbol may be displayed in another display window  1410  or  1510  in  FIGS. 14 and 15 , respectively, when a user selects the corresponding symbol. Further, in one embodiment, the user may filter the displayed symbols based on characteristics of the data entries, their interactions, and/or attributes saved by the Cognia Molecular™ system.  
      Users may filter symbols in the directed graph, using any of the advanced search attributes discussed below. It is to be understood that the invention is not limited to the advanced search attributes described herein. Moreover, in addition to shading, network nodes may be screened, eliminated, expanded or withdrawn.  
      Advanced Search Algorithms  
      Another aspect of the Cognia Molecular™ system involves advanced software that searches the chemical, biological, and/or molecular information created using the functionalities described above. The advanced search module uses Boolean search operators and allows recombination of previously executed advanced searches. The module may be configured to store information based on the user identity. Search results may be combined, stored, deleted, reassessed and used in other searches. In one embodiment of the present invention, users of the search facility can access any of 2000 descriptive tags that describe information about the database “entries” by using a series of entry forms and standardized ontological menus. It is to be understood that database entries may include, but are not limited to proteins, genes, bioactive compounds, complexes of these molecules and the interactions between them. The module enables a user to conduct an extremely detailed search of molecules based on their individual properties and attributes. The advanced search algorithm is an extension of the use of ontologies, and implements an exhaustive list of descriptive terms. In an embodiment of the present invention, the advanced searching module implements a database schema that uses tables and relational structures, wherein inherent relationships and interactions between data entries are provided by the nature of descriptive biology.  
      When a user of said computer system wishes to retrieve a database entry using the advanced search functionality based on its attributes, the user: 
          1) opens Cognia Molecular™;     2) selects the search term from the first menu;     3) views a new set of terms which define the scope of only those search parameters as shown in  FIG. 16 ;     4) selects the search term and executes the query.        

      The “fields” or characteristics associated with a data entry that are searched are critical to value and efficacy of such a research tool. Generally, the search fields are based on attributes of the molecule entries present in Cognia Molecular™. It is to be understood that examples of search field parameters may be defined as, but are not limited to terms associated with an entry&#39;s cellular and/or biological characteristics.  FIGS. 16-18  illustrate various aspects of the advanced search module, including search parameter selection  1610  and further subterm specification for a search as shown by reference numeral  1720 . The system also includes both a listing of the last  10  executed searches  1710 , as shown in  FIG. 17  and a listing of saved searches  1810  shown in  FIG. 18 .  
      In an exemplary listing of search subterms associated with the term “Cell Cycle”, a user may search within such characteristics including, but not limited to such specific Cell Cycle subdivisions  1720  as: 
          Constitutive, Cytokinesis, G0, G1, G1/S, G2, G2/M, Meiosis I-Cytokinesis I, Meiosis I-Metaphase, Meiosis I-Prometaphase, Meiosis I-Prophase, Meiosis I-Telophase, Meiosis II-Metaphase, Meiosis II-Prometaphase, Meiosis II-, Meiosis II-Telophase, Meiosis-Cytokinesis II, Meiosis-all, Mitosis-Anaphase, Mitosis-, Mitosis-Prophase, Mitosis-Telophase, Mitosis-all, S, Terminal. 
 
 Further exemplary advanced search terms  1610  may include, each with their own subterms: 
    Cell cycle stage, Cell type, Molecular weight, Developmental stage, Protein length, Taxonomic group, Cellular component, Tissue, Annotation Project, Molecular function, Chemical, Disease, Network, Pathway, pI, pKa, boiling point, melting point, domain, Biological Process.        

      Alternately, the search may be directed to a scientifically topical project in question such as “catabolism,” “test project,” or “molecular trafficking.” It is to be understood that the example discussed above illustrates simply representative terms and actual search terms may include a vast range of biological, chemical and/or molecular descriptive characteristics. The advanced searching module enables biologists to search based on.biological characteristics of a given cellular system. By finely atomizing the parameters needed to discuss and research the cell biology and pharmacology of these systems, better research information management can be achieved.  
       FIG. 19  illustrates an exemplary screen shot displaying results obtained from an advanced search.  FIG. 20  illustrates an exemplary output table that corresponds to a data entry created using the components of the Cognia Molecular™ database system described above. More specifically,  FIG. 20  illustrates domains of proteins  2010 , their post-translational modifications  2020 , their mutations  2030 , proteins similar in sequence  2040  and the interactions of the molecule  2050 .  
      Structural Search Tools  
      The advanced searching module described above provides a broader search capability by incorporating other types of search algorithms. This results in a more robust search and retrieval of protein, nucleic acid and chemical structures. Through archiving based on features of chemicals, such as, but not limited to, functional groups, chemical moieties, and/or synthetic pathways, the Cognia Molecular™ system is able to retrieve entries including ketones, aldehydes, sulfydryls, alcohols, pyrolles, and other types of chemical groups or species.  
      Portions of chemical compounds may be searched by using text-based or SMILES-based searches for substructural components. Each element defined above may be specified in such a manner.  
      Batch Data Importers  
      The utility of Cognia Molecular™ is further enhanced by the ability of a user to incorporate a vast range of a user&#39;s existing in-house data into the system. The CM™ system is configurable to process and incorporate such pre-existing research data with data processing algorithms and become integrated with other data entries included in the Cognia Molecular™ system database.  
      Accordingly, a batch data importer module converts such batch data via high throughput methods for incorporation into the Cognia Molecular™ system. The batch data importer module may parse and incorporate user selected tables of information, wherein a user may specify table attributes for import and conversion. By way of example only, the batch data importer may incorporate a pre-existing user-developed list of proteins that interact with each other into a Cognia Molecular™ database, by specifying the translation protocol from the current data format to a Cognia Molecular™ system format. Specifically, in an embodiment of the invention, protein A becomes “component A” which “interacts with” protein B, or “component B”.  FIG. 21  shows a representative user interface for the interaction loader  2100 . Users may search their local node for a tabular file  2110  and load it into the system  2120 .  
      Cognia Molecular™ can incorporate data formats including, but not limited to excel-type spreadsheets, delimited text files, comma separated files, and other standardized data formats such as marked up text (XML, HTML, dHTML, SBML, CellML) and other relational database sources. Such data is imported into the relational structure of the database automatically, using a simple loader interface  2100  as shown in  FIG. 21 . The interface includes a browser  2110  for the user generated files and an “upload” button  2120 . The batch loader relies only on a regular structure of the data to be incorporated. Through use of the batch loader, the user can specify the target and destination database tables and import the batch data directly into the relational database tables of the invention. The import module thus removes human error and facilitates a more efficient data import. Specific batch loaders may also include those used expressly for the import of dichotomous/binary interaction data. Such data is simpler and does not necessarily need to be elaborated upon.  
      Administrator Control Applications.  
      A further aspect of the present invention involves administrator control (Admin functions) for the implementing the annotation system. Using the Administration functions present in a navigation bar, it is possible for a system administrator, “superuser,” to define accessibility and content features associated with the system. It is to be understood that such features may include, but are not limited to limited functionality privileges, user start and stop dates, and search menu content. Additionally, the admin panel allows the superuser to define paralogs, orthologs, access privileges, passwords, usemames, restricted access based on IP address and other system access parameters, without necessarily having to access the relational tables using a browser or schema manager. One exemplary manager for curation menus is shown in  FIG. 22 . Users may select the database table  2210 , add descriptions  2220 , and control the appearance in the parent table  2230 .  
      The many features and advantages of the present invention are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the invention which fall within the true spirit and scope of the invention. Furthermore, since the embodiments described above are exemplary, numerous modifications and variations will readily occur to those skilled in the art, and the invention should not be limited to the exact construction and operation illustrated and described herein.