Carazo, JM

Chagoyen, M

de AlacónP A, F

Engel, A

Fita, I

Henn, C

J B, K

J J, R-T

Machtynger, J

McNeil, P

P, B

R, H

S, P

Shotton, DM

Stelzer, EHK

English

UCL Discovery

  1999 Oxford University Press 280–283 Nucleic Acids Research, 1999, Vol. 27, No. 1Organising multi-dimensional biological imageinformation: The BioImage DatabaseJ. M. Carazo*, E. H. K. Stelzer1, A. Engel2, I. Fita3, C. Henn4, J. Machtynger5, P. McNeil6,D. M. Shotton7, M. Chagoyen, P. A. de Alarcón, R. Fritsch1, J. B. Heymann2, S. Kalko,J. J. Pittet4, P. Rodriguez-Tomé6 and T. Boudier7Centro Nacional de Biotecnología-CSIC, Campus Univ. Autónoma, E-28049 Madrid, Spain, 1European MolecularBiology Laboratory (EMBL), Postfach 102209, D-69012 Heidelberg, Germany, 2M. E. Müller Institute forMicroscopic Structural Biology, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel,Switzerland, 3Centro de Investigación y Desarrollo-CSIC, Jordi Girona Salgado 18–26, E-08034 Barcelona,Spain, 4Advanced Technology Center Silicon Graphics Inc. Chemin des Rochettes 2, CH-2016 Cortaillod,Switzerland, 5Informix Software Ltd., 6 New Square, Bedfont Lakes, Feltham TW14 8HA, UK, 6The EuropeanBioInformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK and 7Departmentof Zoology, Univeristy of Oxford, South Parks Road, Oxford OX1 3PS, UKReceived September 8, 1998; Revised and Accepted October 21, 1998ABSTRACTNowadays it is possible to unravel complex informa-tion at all levels of cellular organization by obtainingmulti-dimensional image information. At the macromo-lecular level, three-dimensional (3D) electron micro-scopy, together with other techniques, is able to reachresolutions at the nanometer or subnanometer level.The information is delivered in the form of 3D volumescontaining samples of a given function, for example,the electron density distribution within a given macro-molecule. The same situation happens at the cellularlevel with the new forms of light microscopy, particu-larly confocal microscopy, all of which produce bio-logical 3D volume information. Furthermore, it ispossible to record sequences of images over time(videos), as well as sequences of volumes, bringingkey information on the dynamics of living biologicalsystems. It is in this context that work on BioImagestarted two years ago, and that its first version is nowpresented here. In essence, BioImage is a databasespecifically designed to contain multi-dimensionalimages, perform queries and interactively work withthe resulting multi-dimensional information on theWorld Wide Web, as well as accomplish the requiredcross-database links. Two sister home pages ofBioImage can be accessed at http://www.bioimage.organd http://www-embl.bioimage.orgINTRODUCTIONIt is often said that an image is worth a thousand words. However,implicit in this statement is the capability to access the specificimage portraying the situation we are interested in studying, aswell as a precise understanding of the informational content ofthis image. The BioImage Database Project is designed to makethis process of accessing, retrieval and understanding imageinformation of multi-dimensional biological specimens an easyand user friendly task for the scientific community at large.On technological grounds, nowadays a broad range of ap-proaches, chiefly the diverse forms of microscope techniques, canproduce either images, volumes, or time series of images andvolumes that help unravel key biological processes ranging frommacromolecular structure to subcellular and cellular structure andorganisation. Collectively, we will refer to these different types ofimages, volumes and time series as ‘multi-dimensional images’.In spite of its importance in biology, the situation has been thatsuch multi-dimensional data were not organised in any database.In fact, there has been no way either to query specifically formulti-dimensional images or to automatically retrieve any suchimages. This clearly unsatisfactory situation led to the start ofseveral exploratory projects from 1993 to 1996, which helpeddefine the general need within the scientific community for adatabase for such multi-dimensional images. A proof-of-conceptprototype was developed and was described by Marabini et al.(1). Subsequently, the design and implementation of the Bio-Image database of multi-dimensional microscopic images ofbiological specimens has been the work of a multi-nationalconsortium of research laboratories together with technicalindustrial partners. Its first implementation was released inSeptember 1998, in the 14th International Congress on ElectronMicroscopy, held in Cancun, Mexico. Further information aboutthe BioImage database can be found in the two sister home pagesof the project at www.bioimage.org and www-embl.bioimage.org.An open discussion forum for BioImage has just been set up*To whom correspondence should be addressed. Tel: +34 91 585 45 43; Fax: +34 91 585 45 06; Email: carazo@cnb.uam.es281Nucleic Acids Research, 1994, Vol. 22, No. 1 Nucleic Acids Research, 1999, Vol. 27, No. 1 281Figure 1. Example of a BioImage entry (only the multi-dimensionalimage—and not their accompanying metadata—is shown): Volume of thehelicase DnaB of E.coli obtained by cryo-electron microscopy and imageprocessing at 3.2 nm resolution. The volume is presented as a series of 2Dsections parallel to the electron microscopy grid from ref. 4. ( Current BiologyLimited, reproduced with permission).through an Email distribution list at the address bioimage@listserv.cnb.uam.es.INFORMATION CONTENT OF BIOIMAGEFocusing on multi-dimensional digital images, we can definethem as samples of a given magnitude over either a 2D, 3D or 4Dmatrix of elements generically refereed to as ‘pixels’. Theinformation contained in these images relies upon both the pixelvalues as well as the spatial and temporal relationships betweenthem.An example of the type of volume information we refer to ispresented in Figure 1, where we reproduce 2D sections parallelto the specimen support grid corresponding to the 3D structure atpH 7.8 of the helicase DnaB from Escherichia coli, as obtainedby cryo electron microscopy and 3D image processing techniquesat 3.2 nm resolution (2). It is clear that, in spite of the fact that weknow the precise amino acid sequence of the protein and itsquaternary architecture as a homohexamer, we do not havesufficient resolution to interpret this volume in terms of itsbiochemical constituents and obtain, for instance, the C-acoordinates of the protein backbone. Therefore, the volume itselfis the particular piece of experimental information we have towork with.Having defined the informational core of BioImage as themulti-dimensional images it contains, it is also clear that asubstantial amount of textual information must accompany theseimages in order for them to be understood within their correctbiological and instrumentation context. Thus, each multi-dimensional image is accompanied by metadata specifying thebiological organism being studied, together with experimentaldetails about the sample preparation, the instrumentation setupand the image processing steps. A schema depicting in generalterms the relation between the multi-dimensional images andtheir associated metadata is shown in Figure 2.The image data stored in BioImage certainly have manyinterrelations with other pieces of biological information whichare normally organised in other databases. Therefore, links withthese other databases are also included. In general, bibliographicand taxonomic information is vital for all entries. In particular,links to PDB and Swiss-Prot (3,4) are essential for entries on thestructure of macromolecules while, for example, links to tissuecollections and whole organisms databases are key in many cellbiology studies.INTERNAL ORGANISATION OF THE DATABASEThe organisation of BioImage has been an international effortaimed at developing this ‘missing’ database of key biologicalinformation of a complex data type: multi-dimensional images.In this way the consortium developing BioImage represents ablend of scientific knowledge in different biological areas, plustechnical expertise in the fields of information technology and ofthe visualisation and manipulation of multi-dimensional data.Figure 2. Schema of the information content of BioImage. The core of the database is formed by the multi-dimensional images organised in ‘Studies’. Each studymay have several datasets, each of them being a multi-dimensional image. Describing each dataset there is textual information (metadata) about the specimen beingstudied, as well as the experimental conditions in which the study was carried out. Nucleic Acids Research, 1999, Vol. 27, No. 1 282Figure 3. Schema of the internal organisation of BioImage. There are sevenpartners in the project, two of them providing the data servers. Around thepartners there is a network of ‘Test Users’ (these Test Users are or have been thelaboratories of Drs J. Bereiter-Hahn, A. Brisson, S. Fuller, H. Gross, R. Hegerl,M. J. Miles, P. Shaw, H. J. Tanke, J. M. Valpuesta, S. Vilaro and R. Wade).The image information in BioImage is quite homogeneousfrom the viewpoint of data types. However, it clearly addressesseveral distinct levels of biological organisation, ranging fromstructural biology of macromolecules to lower resolution 3Dimages and videos often found in cell biological studies. Topermit access to all types of multi-dimensional image informationin a homogeneous way, while paying attention to the specificneeds of the different levels of cellular organisation underconsideration, BioImage has been set up using two databaseservers specialising in two broad areas of biological interest:structural biology of macromolecules and cell biology. A diagramof the internal BioImage organisation is shown in Figure 3. Thetwo database servers have the same data model, as well ascommon interfaces for query and visualisation. However, theactual multi-dimensional image data are kept only on the databaseserver to which they have been submitted. Also, the submissioninterfaces and the curation processes of the two servers are moreoriented towards a given community or other.The data server at Madrid specializes in structural biology ofmacromolecules, while the one at the EMBL-Heidelbergaddresses the cell biology field. The laboratories at Madrid,Barcelona and Basel provide scientific expertise in macro-molecular structure, while those at the EMBL and Oxford arerecognised in cell biology. The European BioInformatics Instituteat Cambridge provides their applied expertise in runningsequence and structure databases. Silicon Graphics is an indus-trial partner of the project, providing key technology formulti-dimensional image display and manipulation. The secondindustrial partner, Informix, provides the needed experience ininformation technology in the emerging area of large distributeddatabases of complex data types.Another key feature that is proving most valuable in thedevelopment of BioImage is the organisation of a network ofresearch laboratories around the project chosen in such a way tocover a wide spectrum of potential users of the database. They arereferred to as ‘Test Users’. Their input helps the BioImagedevelopers to remain close to the needs of the scientificFigure 4. Data manipulation tools to interactively study multi-dimensional dataover the Web. (a) Interface for volume visualisation. (b) Interface for automaticisosurface generation by thresholding. (c) Example of the volume annotationcapabilities under development.community for which this database is being developed, as well asto increase the visibility of the project in that moment in which weinitiate an outreach program and involve the wider scientificcommunity in the use of BioImage (this Test Users network is alsoshown in Figure 3).ELECTRONIC ACCESS TO BIOIMAGEFrom the very beginning, BioImage has been designed as anelectronically accessible database, with all its interfaces devel-oped for Web-based usage. This design starting point followsmodern technological trends. However, due to the complexnature of the multi-dimensional images, this approach hasdemanded some special new technical developments that will bediscussed in the next section.During the development stage of the database, access will begranted upon request. Refer to the BioImage Web Sites for furtherdetails.MULTI-DIMENSIONAL IMAGE VISUALIZATION ANDMANIPULATION OVER THE INTERNETThe core of BioImage has been defined as multi-dimensionalimages. It then follows that the tasks of visualising andmanipulating such complex information over the Web have to beaddressed from the onset. To start with, it is a fact that there existsno common image format across the range of techniquesembraced by BioImage. Therefore, one of the first tasks was toextend basic I/O system libraries in such a way that they wouldbe able to handle the different formats in common usage in the283Nucleic Acids Research, 1994, Vol. 22, No. 1 Nucleic Acids Research, 1999, Vol. 27, No. 1 283different research fields. This goal has been accomplished byextending the Image Format Library (IFL) of Silicon Graphics insuch a way that new formats such as the so-called MRC, CCP4,Spider and Imagic formats are now recognised, in addition to theindustry standards already recognised by the original IFL. Thisshared-object approach has the distinct advantage that allapplications using IFL can now handle the different formats in amanner transparent to the application programmer, and thatfurther new formats can be added to the basic IFL as needed.The next task was then the development of specific Web browserplug-ins that allowed the manipulation of multi-dimensional imageswithin the Web. Volume information that matches a given (textual)query can now be interactively studied within a VRML environmentin such a way that volume rendering as well as isosurfaces derivationand surface rendering can be performed interactively. Tools are indevelopment to allow the data submitter to ‘annotate’ the input datain such a way that specific biological information, such as pointsymmetries, specific contact surfaces and so on, can be incorporatedat the time of data submission (Fig. 4).Interesting volumes can then be retrieved from the servers andbe used for the specific purpose of the user who has performed thequery to BioImage. This software, developed within the BioImageconsortium, may be accessed via the home page of the project.More complex queries, in which the actual structural content of thevolumes can be addressed, in addition to their accompanyingtextual information, are starting to be implemented.PRESENT SITUATION AND PLANS FOR DATAPOPULATIONThe first implementation of BioImage has just been released. Thedatabase is implemented using the Informix Universal Serverrunning on Silicon Graphics servers at Madrid and Heildelberg.The query and visualisation interfaces have been developed usingthe Informix Web Datablade. To enhance the visualisationinterface, the image handling tools developed by Silicon Graphicsand described above have been incorporated. The Web-basedsubmission interface has gone through several cycles of refine-ments with the help of the Test Users.During the initial development process, the number of multi-dimensional images stored in the database has intentionally beenkept small. The logical steps for data population have involvedfirst the data supplied by the partner laboratories, then that of theTest Users (in order to test the complete implementation), andfinally the opening of the database to a wider participation whichwe now invite.BioImage is now interested in collecting high quality multi-dimensional microscopic images of biological specimens, andtheir associated metadata. Thus, all producers of these types ofdata are encouraged to contact either Madrid (for structural dataon macromolecules acquired by electron microscopy or scanningprobe microscopy) or Heidelberg (for multi-dimensional cellbiological images, particularly those obtained by all kinds of lightmicroscopy). At the same time, and in order to assure a fastpopulation in a number of key fields, three areas of specialattention have been defined in which active data collectionschema are being followed. They are viral structures (coordinatedby Stephen Fuller and with I. Fita as contact point:ifrcri@cid.csic.es), membrane proteins (coordinated by AndreasEngel and with B. Heyman as contact point: heymann@ubaclu.unibas.ch), and the cytoskeleton (coordinated by ErnstStelzer and with E. Lindek as contact point: bioimage@embl-heidelberg.de). As a rule, multi-dimensional image data beingsubmitted to BioImage should be supported by a peer-reviewedpaper describing the work, which is then taken as the ‘scientificvalidity check’. In future, we hope to move to a situation in whichsubmission of such image data to BioImage will automaticallyaccompany publication of scientific papers, as is presently thenorm for protein and nucleic acid sequences and macromolecularcoordinates to their respective databases.The final goal of BioImage is to help to make available suchmulti-dimensional image information to the scientific communityrapidly and in a user-friendly manner. However, it is acknowl-edged that the scientific community may develop specificpolicies about confidentiality of data, as it is the case for othertypes of information. Therefore BioImage incorporates thecapability to set embargos upon the publication of specificsubmissions.CONCLUSIONSBioImage is already a reality. Multi-dimensional images can nowbe organised and accessible in this new database. So far, most ofthe effort of the BioImage consortium has gone into the designand implementation of the database, leading to the presentprototype. The database is now open to the interested scientificcommunity, and its general data population on a wider scale hasalready started. Information about BioImage can be found at thetwo sister home pages at http://www.bioimage.org (Madrid) andhttp://www-embl.bioimage.org (Heidelberg). A discussionforum has been established at bioimage@listserv.cnb.uam.es, inwhich all comments and opinions about BioImage are mostwelcomed.ACKNOWLEDGEMENTSThe European Union through grant PL960472 has mainlyfinanced work on this project. Special actions or extensions arebeing made possible in some partners laboratories by corenational funding (J.M.C. acknowledges grants BI097-1485-CEand BIO98-0761). Initial support from the European MolecularBiology Network, as well as the many vivid discussions andproof-of-concept work in the field of macromolecular structureperformed in collaboration with Dr Joachim Frank (Albany, US)is acknowledged by J.M.C. J.M.C. and J.F. would also thank theparticipants of the 1993, 1995 and 1997 Gordon Conferences inThree-dimensional Electron Microscopy for their support andideas during all these years.REFERENCES1 Marabini,R., Vaquerizo,C., Fernandez,J.J., Carazo,J.M., Engel,A., Frank,J.(1996) J. Struct. Biol., 116, 161–167.2 San Martin,C., Radermacher,M., Wolpensinger,B., Engel,A., Miles,C.S.,Dixon,N.E., Carazo,J.M. (1998) Structure, 6, 501–509.3 Bernstein,F.C., Koetzle,T.F., Williams,G.J.B., Meyer,E.F., Brice,M.D.,Rodgers,J.R., Kennard,O., Shimanouchi,T. and Tasumi,M. (1977) J. Mol.Biol., 112, 535–542.4 Bairoch,A. and Apweiler,R. (1998) Nucleic Acids Res., 26, 38–42.

Organising multi-dimensional biological image imformation: The BioImage Database

Organising multi-dimensional biological image imformation: The BioImage Database

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