Genre: Information/Explanation

raditionally , biology research begins with a hypothesis . A biologist then collects experimental data and analyzes them to support or disprove the hypothesis . However , information technology is changing this sequence of events . Today , large-scale exploratory experiments are gathering as much data as possible ; for example , the Human Genome Project is enumerating the three billion amino acids in the human genetic blueprint . So now when a biologist forms a hypothesis , the data may already be in such a collection , just a computer search away . An NPACI alpha project led by Russ Altman of Stanford University is developing new tools and techniques to extract insights from growing biology data collections . Alongside these collections , a new discipline has emerged , called bioinformatics . Bioinformatics researchers develop and apply computing tools to extract the secrets of the life and death of organisms from the genetic blueprints and molecular structures stored in digital collections . However , while large-scale activities are amassing vast quantities of data , the techniques for routinely analyzing these collections have not kept pace . " Because of activities like the Human Genome Project , exploratory data collection has come to be seen as more cost effective , " said Altman , associate professor of medicine in the section on Medical Informatics at Stanford University Medical Center and leader of NPACI's Molecular Science thrust area . " The collectors do not necessarily know why they are collecting . They figure that out later . This project will develop the infrastructure that will allow biologists to answer questions using these data collections . " For example , a biologist might hypothesize that a protein with certain features--such as a particular sequence or structure--must exist to carry out some task in a cell . A time-consuming approach is to devise an experimental technique to search for the hypothesized protein . However , with bioinformatics techniques , the biologist can scan a collection such as the Protein Data Bank ( PDB ) for proteins that meet the hypothesis criteria . LEGION-SCALE ANALYSIS The Bioinformatics Infrastructure alpha project is making a three-pronged assault on the problem : analysis , access , and movement of data . In the analysis component , participants are developing molecular scanning and comparison algorithms for various collections , and the Legion metasystem will recruit the computing resources required for large-scale analyses . " Legion's architecture and past work on other biological codes will allow us to make progress quickly , " said Andrew Grimshaw , the leader of the Legion effort and NPACI's Metasystems thrust area leader . " We already have a framework for similar database analyses , which can easily take advantage of Legion's built-in fault tolerance . " Altman's group , including Liping Wei , Allison Waugh , and Catherine Ying , have developed a scanning code that examines a PDB entry for active sites for which models exist , such as that for calcium . NPACI support has contributed to code improvements . Glenn Williams at Stanford is now working with the Legion team at the University of Virginia to modify the code to scan the entire PDB . " Our code takes a PDB entry and derives information about potential calcium binding sites , " Altman said . " Any similar code could be used , and we want to make tools like these more readily available . " The project also includes a molecular comparison algorithm for the PDB called combinatorial extension by Phil Bourne and Ilya Shindyalov at SDSC . An algorithm for phylogenetic analysis from David Hillis at the University of Texas and a genetic sequence comparison algorithm by David States at Washington University in St. Louis both run on sequence databases such as SWISS-PROT and GenBank . To run a scanning algorithm against every record in the PDB takes time proportional to the number of PDB entries . For example , Altman's code takes about 0.01 seconds per atom to scan a 3-D structure . With more than 10 million atoms in the PDB , the code takes days to scan the PDB on a workstation . All-versus-all comparisons , in contrast , take time proportional to the square of the number of entries . Last year , Bourne and Shindyalov used their combinatorial extension code , which finds similarities between structures , to compare more than 8,000 proteins in the PDB against every other protein . The effort consumed more than 24,000 processor hours on the Cray T3E at SDSC . On a workstation , the effort would have taken almost three years . Figure 1 . Growth of Biological Data The Bioinformatics Infrastructure alpha project is developing the tools and techniques for analyzing the the growing amount of biological data in databases . Left : The DNA base pairs stored in GenBank through August 1999 . Right : The structures stored and deposited in the Protein Data Bank through October 1999 . MIXED INFORMATION ACCESS In the data access component , participants from the Molecular Science and Data-Intensive Computing Environments ( DICE ) thrust areas are working to address the information access challenges of seamlessly accessing the information in different molecular data collections . When complete , the project will permit analyses to span not just one collection but several . " The information access challenge is to take these data collections and compare them on a high-performance system such as the Centurion cluster at the University of Virginia , " said Reagan Moore , associate director of SDSC and leader of the DICE thrust area . " To do that , we must have definitions of how the collections are organized , and we have to understand the structure of objects in the collection . " Operated by NPACI partners Rutgers University , SDSC , and the National Institute for Standards and Technology , the PDB is the premiere worldwide repository of 3-D protein structures , with 11,000 such structures today . Bourne leads the SDSC team . The Institute for Biomedical Computing at Washington University , directed by States , mirrors several protein and genetic databases . These databases include GenBank , which holds 3.4 billion bases in 4.6 million entries from 47,000 species , and SWISS-PROT , with 29 million amino acids in 80,000 entries ( Figure 1 ) . The collection that promises to seriously tax the data-handling infrastructure , however , is being created by Montgomery Pettitt , director of the Institute for Molecular Design at the University of Houston . Pettitt is creating a database of molecular dynamics trajectories , time-slice snapshots from molecular dynamics simulations . A one-microsecond simulation might , for example , produce a time slice every femtosecond--or one million database entries from a single simulation . This diverse set of collections will be integrated by applying technologies developed in the Mediation of Information using XML ( MIX ) project , led by Chaitan Baru at SDSC and Yannis Papakonstantinou , director of UC San Diego's Database Laboratory ( see enVision , July-September 1999 ) . The MIX software acts as a mediator between data sources with different structures , such as the collections in the alpha project . The MIX tools will use infrastructure-independent XML representations being developed by the collection maintainers to allow biologists to query , access , and analyze data from any or all of the collections from a single application or Web interface . STREAMLINED DATA MOVEMENT The data movement component joins the access and analysis components and is essential to the ultimate goal of the alpha project--large-scale analyses across more than one collection at a time . Initially , the Legion-enhanced codes will access data directly from the data collections , but the longer-term goal of moving data across the Grid is being addressed by efforts to integrate the SDSC Storage Resource Broker ( SRB ) , the cornerstone of NPACI's data-handling infrastructure , with the Legion architecture . " The only challenge for Legion will be the amount of data the codes will produce , " Grimshaw said . " We do n't have enough disk space , so we 'll need some way to manage the storage . " In addition , the code results could potentially exceed Legion's current 4-GB file size limit , and even when Legion allows larger files , the question of where to put the data remains . The SDSC SRB provides an interface to distributed , heterogeneous data resources . When requesting data through the SRB , applications and users need not know how or where a data collection is stored . With an interface between Legion and the SRB , an algorithm will be able to marshal both computing processors and data collections across the network . " Traditionally , data movement is handled by copying files via FTP to local disk or into memory , " Moore said . " We need an architecture to stream the data from collections to an application on an as-needed basis . That 's where the SRB fits in . " The DICE activities in this project build not only on NPACI activities , but also on externally funded projects with the NASA Information Power Grid , the Department of Energy's Visualization Interaction Environments for Weapons Simulation ( VIEWS ) , and the National Archives and Records Administration . BIOLOGICAL DISCOVERY While the project will require many new developments on the underlying technologies , the success of the project will be measured in part by how well the underlying infrastructure permits biology researchers to make new discoveries from the collections . For these users , the alpha project will provide a number of new resources and capabilities . First , the test codes run by the participants will provide both benchmarks and biological results . Second , the experiences of the participants will be captured in templates for performing similar analyses . Timings on resources , formulas for extrapolating from workstation runs to Legion runs , and other information will help determine the resources needed to answer a hypothesis and hence develop an NPACI allocation request . Eventually , the test codes and algorithms may be made available for execution , possibly via the Web . " In some ways , the biology community is depending on projects like this alpha project to keep up with the rapid growth of biology data collections , " Altman said . " Using the Grid to marshal the resources necessary to scan databases such as the PDB and GenBank , this project will make this kind of bioinformatics capability routine . " -- DH *