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A*STAR SERC Thematic Strategic A*STAR SERC Thematic Strategic Research Programme on “Integrated Research Programme on “Integrated Manufacturing & Services Systems”Manufacturing & Services Systems”
APBioGrid, APBioBox, APBioGrid, APBioBox, APBioKnoppix, Laboratory APBioKnoppix, Laboratory Workflow Integration and Workflow Integration and
BioManufacturing Workflow in BioManufacturing Workflow in Life SciencesLife Sciences
PI: Tan Tin Wee, National University of SingaporeCO-PIs: I A Karimi (ChemEng), Lim Teck Sin (KooPrime), Lim Beng Siong (SIMTech)
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MilestonesMilestones
• 1997 SINGAREN - Internet2 link through STARTAP • 1999, elucidated the X-ray crystallographic structure of Bucandin, a
Malayan snake toxin (resolution of 0.98Angstroms)Remote access and control of goniometers at the beamlines in Stanford Synchrotron Radiation Lab (SSRL) from Singapore.
• By 2000, several SC demos illustrating how grid computing can achieved through distributed computation of FastDNAML in phylogenetic analysis
• SC2003 award of the most geographically distributed HPC Challenge Award for Global Analysis of Arthropod Evolution.
• 2001, we set up the APBioGrid and NUS BioGrid using Globus. • 2002 APBioBox - a toolbox of readily installable grid-accessible
bioinformatics software.• 2003 Collaboration with Sun Microsystem's Asia Pacific Science and
Technology Centre APSTC) - Sun BioCluster-Grid package for Sun Grid Engine.
• 2004 - Basis for a widely distributable software LiveCD containing APBioBox bioinformatics software and grid software called APBioKnoppix
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APBioKnoppix 1.0APBioKnoppix 1.0• This package contains a workflow integration system, KOOPlatform, for
applications integration in a life science research workflow.• Collaboration with KOOPrime Pte Ltd in prototyping a BioManufacturing
workflow for rapid development of diagnostic kits for emerging infectious diseases under a Pilot Project from our Agency for Science and Technology Research (A*STAR).
• Integration of workflow from computational and database servers from our collaboration with SCS Ltd and United Devices MPGrid deployed in NUS Campus as TCG@NUS of 800 UD-enabled PCs
• Our collaboration with IBM and Avaki to construct a datagrid.• Proposed project with Sun Microsystem on OpenSolarisBioBox • Blueprint Asia is also based in our NUS campus and their Seqhound and
BIND databank will be tapped on. • In addition, bioinstrumentation suppliers such as Attogenix and
automated DNA sequencing vendors will have devices connected as part of the manufacturing workflow.
• NovusGene, an oligonucleotide synthesis company, from Japan is also in the process of being integrated.
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RationaleRationale
• This biomanufacturing, computation and data workflow integration prototype expected to be demonstrated in the middle of 2005 will illustrate how workflow integration over grid computing and grid-enabled bioinstrumentation can be used to design and fabricate prototype DNA chips for rapid development of diagnostics in the event of a major outbreak of new strains of infectious diseases such as SARS or bird flu, and eventually for design of RNAi (miRNA/siRNA) therapeutics and DNA/peptide vaccines.
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UrgencyUrgency• Our Singaporean SARS experience• WHO warning on influenza pandemic• Warning signals in Thailand etc on bird
flu zoonoses• Conference for the Expert Group on
Biotechnology of Emerging Diseases, Feb 2005 Bangkok
• Urgency in extending high throughput life science research to biomanufacturing
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IMSSIMSS• A*STAR Science and Engineering
Research Council (SERC) funded a pilot project under the Thematic Strategic Research Programme (TSRP)
• Under this umbrella, our project is on “Integrated Biolaboratory Manufacturing and Services System” Group 9 Project 042-112-0020
• Tasked as 1 out of 10 pilot projects to look into how the broad canvass of integrated manufacturing and services systems (IMSS) can accelerate specific areas of manufacturing, in our case, biomanufacturing.
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What’s reality today in What’s reality today in the labs?the labs?
• Broadscale Database Integration technologies including Kleisli® of Wong Lim Soon in Genetixchange Inc (KRDL/BIC spinoff) (1995-)
• Pockets of Workflow Integration by KOOPrime Pte Ltd (BIC-CNPR spinoff) (1997-)
• Joint Center for Structural Genomics (1999-)• EoL, SDSC/UCSD and BII (2000-)• UK eScience’s Taverna-myGrid (2002-)• BioPipe (IMCB/GIS/TLL,SangerInst) (2003-)• VIBE, Anabench, etc.
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High level Knowledge-High level Knowledge-based Grid Services for based Grid Services for
BioinformaticansBioinformaticans
Carole Goble, University of Manchester, UKmyGrid project http://www.mygrid.org.uk
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IMSSScreenshot of Carole Goble’s talk (2004)
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IMSSScreenshot of Carole Goble’s talk (2004)
Taverna, GUI for myGrid is a collaboration between the European Bioinformatics Institute (EBI), IT Innovation, the Rosalind Franklin Centre for Genomic Research (RFCGR), Newcastle Computer Science faculty, Newcastle Centre for Life, Manchester Computer Science faculty and the Nottingham University Mixed Reality Lab.
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Exemplar 1:Database + Computational + Grid Computing Integration
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Extending that reality to biomanufacturing
• The “Database IntegrationComputational IntegrationVirtual BioLab ?? BioEmanufacturing” platform aims to connect the current broad based of Life Science Research more closely that to limited, but specific Life Science manufacturing areas and translate the technological knowhow and research output into designs and manufactured products.
• Why further research is needed in this area of Virtual BioLab environment.
• Where does Bio-E-Manufacturing come in?• “Life Sciences research is headed towards Industrial scale operations”
TW Tan, 2003• Therefore to leapfrog, we need to ask, how to connect that to the next
step, to Bio-E-Manufacturing
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Relevance to Singapore’s Relevance to Singapore’s Life Science IndustryLife Science Industry
• The life science pharmaceutical industry in Singapore has been growing for the past few decades. Today besides GlaxoSmithKline giant in Jurong manufacturing billions of dollars worth of drugs, Singapore has clinched manufacturing investment by Schering Plough, Merck etc over the years. In addition, pharmaceuticals and biotech companies have started to invest in Singapore not just in manufacturing, but also in R&D.
• Recent R&D examples include Chiron in S* Bio (2000), Genset, Norvatis in Norvatis Institute for Tropical Diseases, Eli Lilly's Lilly Systems Biology Institute, Johns Hopkins, etc. At the same time, Singapore is fostering Good Manufacturing Practice GMP plants via the Bioprocessing Technology Centre. The tie-up between the Post Genome era of technologies in genomics and proteomics with information and network technologies is increasingly important. The link between high-end high value-added manufacturing and R&D must be strengthened to ensure sustained investment into Singapore by these sunrise industries
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© John Wooley, JCSG/UCSD 2003
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PDB
HT Pipeline Processes, Bottlenecks and Leaks
purificationexpressioncloning
struc. refinementstruc. validationannotationpublication
phasingdata collectionxtal screening tracingbl xtal mounting
crystallizationimagingharvesting
targetselection
The Industrial Scale Discovery The Industrial Scale Discovery PipeLine of JCSGPipeLine of JCSG
© John Wooley, UCSD 2003
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HT StructureDetermination2nd Generation
HT Data Collection1st Generation Prototype3rd Generation Software
TargetSelection
HT Imaging
1st Generation Hardware6th Generation Software
StructureValidation & Deposition
Autosubmission of electronic publication
Info/Data Flow Info/Data Flow parallels the parallels the experimental experimental
pipeline, harvestingpipeline, harvesting~300 parameters ~300 parameters from 25 stagesfrom 25 stages
HT Crystallization2nd Generation
HT Purification2nd generation
HT Expression4th Generation
© John Wooley, UCSD 2003
Exemplar 2: Large scale Bioinstrument/Device Integration possible
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To prepare for the next bio-tsunami• Attempting to build the interface between life science manufacturing
that might benefit from the advances in R&D. To date, most of the work has focused on linking genomics, proteomics and bioinformatics with the drug discovery process. The knowledge generated from data-analysis and data-mining feeds into the design and discovery of new drugs and their clinical trials. Another interface that is developing is the feed into the life science manufacturing industry. In this regard, there are at least three areas:
a.BioSequence-based Therapeutics for drug therapy (AntiMicrobial Peptides, RNAi)
b.Diagnostics for rapid diagnosis (DNA chips, PCR primers, peptide antigens)
c.DNA vaccines/Peptide Vaccines for prevention of disease• The design and manufacturing that goes into these areas are highly
sequence-dependent, that can immediately profit from genomics, proteomics, bioinformatics and computational biology include the direct manufacture of peptide antimicrobials, or biochips for bioactivity screening, or for microarray diagnostics, or peptide vaccines, and the IT control of processes for their manufacture in the GMP plant.
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IMSSEmerging Platform for Life Science Industrial IT
Manufacture of Therapeutics
Manufacture of Diagnostics
Manufacture of Prophylactics
•Peptide Antimicrobials•Peptide Inhibitors•siRNAs, miRNAs and other RNAi, etc
• PCR Primers diagnostics for SARS detection, etc• DNA Microarray Chips for bioterrorism agents• Peptide BioChips
• Peptide Vaccines• DNA vaccines
Life Science Industry
Drug Design & Discovery
Pre and Clinical Trials
Drug Screening
LIMSAIMSProprietaryBuilt s/w
Interoperate
VirtualDistributedBioIndustrialIT Platform
Traditional Areas
Genome Dbs
Proteome Dbs
Bioinformatics Dbs
Computational
BioinstrumentationSignals Processing
DNA synthesizer
Peptide synthesizer
Microarray FabricatorMaterials RequirementsSupply Chain Manufacturing
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VirtualDistributedBioIndustrialIT Platform
RDFXML Schema
SOAPUDDIWSDLOGSI
OGSAGlobus
Grid
Java Wrappers
InterFormatExchange
InterWebServices
ComputationalResources
BioinstrumentationAPIs
OntologyKnowledgeResources
LSID
BioManufacturingDevices
Material Requirements AnalysisSupply Chain Manufacturing
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Pipedream or Pipedream or Possibility?Possibility?
• When the next pandemic hits us, we ain’t going to have a choice.
• If we don’t get the diagnostics to the terrified thousands, or the prototype therapeutic to the dying dozens, or the vaccine to the vulnerable field workers, the consequences are unthinkable.
• What is our community’s response-time-to-a-design; time-to-a-product?
• How to balance the bioethics is a big question mark for me
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Proof of ConceptProof of Concept
Automated DNA Sequencing
Automated DNA Sequencing
UnknownInfectious
Agent
UnknownInfectious
Agent
Complete Genome/ Sufficient Data
Complete Genome/ Sufficient Data
Semi-AutomatedOligonucleotide
Design
Semi-AutomatedOligonucleotide
Design
AutomatedOligonucleotide/Probe Synthesis
AutomatedOligonucleotide/Probe Synthesis
Lead Primer Targets
Lead Primer TargetsNucleotide ProbesNucleotide Probes
Automated MicroarrayFabrication
Automated MicroarrayFabrication
PrototypeDNA Chips
PrototypeDNA Chips
Semi-AutomatedDiagnostic
Assays
Semi-AutomatedDiagnostic
Assays
Re-Designof Probes
Re-Designof ProbesNo
Yes
Large ScaleManufacture of
DNA Chips
Large ScaleManufacture of
DNA Chips
DeployableDiagnosticDNA Chips
DeployableDiagnosticDNA Chips
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Proof of ConceptProof of Concept
Workflow Pipeline
Data/Information Flow Layer
Control Layer
Materials Layer
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• A System that automates the DNA Sequencing process
• A user friendly system for users to submit samples
• Users track status of submitted samples through web
• User gets email alerts once the results are ready
• Users has flexibility to download output files through web
• Mapping tool for lab operator to fill the well plate by mouse clicking
• Automatic sorting of output files generated by sequencer
• Detail statistics are maintained on usage of system
DNA Sequencing System (DSS)
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IMSSKOOPrime ProductsKOOPrime ProductsLaboratory Services SystemLaboratory Services System
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Analysing DNA SequencesAnalysing DNA Sequences
User AdminLivePortal
Sequencer
DB / File System
KOOPlateMapping
KOOPAgent
Submit formsDownload Results
Check StatusManage UserPost Message
UpdateDB
Query DBUpdate DB
Monitor Output
Lab Tech
OutputFile
Create PlatesSubmit Jobs ABI files
Quality Check
VectorMasking
VectorTrimming
ContigsAssembly
HomologySearch
SequenceAnnotation
ReFormatFor Search
LiveBASE
Gene SplicingGene Cloning
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IMSSReportsReports
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Scope of DMSScope of DMS
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Integration of ApplicationsIntegration of Applications
Analysis
Database
ResourcesInstrument Apps
Hardware
Operating System
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IMSSMicroarray Analysis Module Microarray Analysis Module Hierarchical ClusteringHierarchical Clustering
Array ID
Gene ID
Gene annotation
Experiment clusters
Gene clusters
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IMSSIn a Nutshell:In a Nutshell:WOrkflows for LiFe sciencesWOrkflows for LiFe sciences
Services Portal Sequencing,
Array Tracking
IMCB Singapore, NUS Singapore (proposed)
Proteomics Integration
BTI Singapore (proposed)
Post Analysis SystemsPatent Search,
BioPathway System
DNA Microarray Fab and Data Analysis
NCC Singapore, BTI Singapore
Oligo Probe Design
Novusgene Japan
Intranet Internet
KOOPrime WOLFPACK
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Plan for next 2 monthsPlan for next 2 months
• Details of Tasks:1. Task A: Integration of Automated DNA
sequencing with Oligonucleotide Primer Design and Synthesis
2. Task B: Integration of Microarray Fabrication
3. Task C: Materials Requirement Analysis and Construction of Prototype Supply Chain management system for multi-integrated systems
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Initial Project CollaboratorsInitial Project Collaborators• Current Collaborators (from other IMSS projects):
1. Prof Karimi (Project 10) – Integrated Supply Chain Management System - Chemicals
• Current Collaborators (from others):1. KOOPrime Pte Ltd [WorkFlow Integration System]2. SCS Ltd (Ong GS)&United Devices (TCG@NUS)
[ComputationalGrid]3. IBM (Krishna/David Lim) and Avaki (GIZ@NUS) [DataGrid]4. Sun Microsystems Asia Pacific Sci and Tech Centre APSTC (Dr
Simon See) [BioClusterGrid]5. NovusGene (Japan) [Semi-Automated Oligonucleotide design]6. Synamatix (Malaysia) [Semi-Automated Primer design]7. Attogenix Pte Ltd, DMERI/NTU (Dr Farid) [DNA chip fabrication]
• Collaborators (from other IMSS projects):1. Prof Robert Gay (Project 1)2. Open to other interested groups
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Project Team BuildupProject Team Buildup• TCG@NUS Mr Ong Guan Sin• GIZ@NUS Mr Krishna• IMSS ISS MTech Project Team 1
Workflow Integration in BioManufacturing– 1. Chew Phuay Hern [email protected]– 2. Khee Teck [email protected]– 3. Vijey [email protected]– 4. Loo Guan Wee [email protected]– 5. Khoo [email protected]– 6. Tan Swee Teck [email protected]
• IMSS ISS MTech Project Team 2BioInstrumentation, BioComputation and BioDatabase Interoperability– 1. San Zaw Maung [email protected], [email protected]– 2. Lukman Salim [email protected]– 3. Allen Teoh [email protected]– 4. Woon Siong [email protected]– 5. [email protected],– 6. JoeWooWoo [email protected]
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IMSSWhat do we hope to deliver in What do we hope to deliver in
2005?2005?
• Expected Deliverables: 1. Deliverable A: Proof of Concept
prototype for integrated workflow system and technique for DNA chip diagnostics
2. Deliverable B: Proposal for TSRP3. Deliverable C: Workshop on
Bioworkflow integration systems – postponed to May 2005 during LSGrid 2005 at GridAsia 2005, Biopolis
4. Deliverable D: Complete model on the global supply chain for chemicals
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Join us!Join us!
• In 1990, my colleagues wished me luck when I wanted to push biocomputing in Singapore. Look at today!
• In 1996, my boss nearly fell off the chair when I drafted a $100M project for advanced networking and APAN. Today, we have SINGAREN, and are linking to Lambda networks.
• In 1998, in my spare time, I decided to change the basic fundamental of the Internet and every one said it was impossible. Today we have IDN internationalized domain names standards in IETF and implementation discussed in ICANN, ITU, WIPO and UN.
• We can choose the safe, well-worn path, but it gets boring after a while. Stuff like this is risky, but combines fun with the sombre responsibility for saving lives should a bio-tsunami pandemic hit us.
• “In times of peace, prepare for war” – our role in biodefence