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 ph@musician.org– 2. Khee Teck kheeteck@yahoo.com– 3. Vijey vijey@solutionnet.net– 4. Loo Guan Wee guan-wee.loo@ap.equinix.com– 5. Khoo khoogc@pacific.net.sg– 6. Tan Swee Teck tanst_2000@yahoo.com

• IMSS ISS MTech Project Team 2BioInstrumentation, BioComputation and BioDatabase Interoperability– 1. San Zaw Maung sanzaw@singnet.com.sg, szmaung@starhub.com– 2. Lukman Salim lukman@aces.co.id– 3. Allen Teoh guanleng@yahoo.com– 4. Woon Siong wssik@yahoo.com– 5. Jagadamba@infineon.com,– 6. JoeWooWoo joe_adicio@yahoo.com

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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