The MRC DNA Bank: the story so far

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The MRC DNA Bankthe story so far

• ESF Workshop on Biobanks
• practical, ethical and legal aspects

Uppsala 13 September 2002
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• Mission statement
• The MRC's mission is set out in its Royal
  Charter
• To encourage and support high-quality research
  with the aim of maintaining and improving human
  health
• To train skilled people, and to advance and
  disseminate knowledge and technology with the aim
  of meeting national needs in terms of health,
  quality of life and economic competitiveness
• To promote public engagement with medical
  research

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Medical Research Council
50 Institutes and Units UK
Human Genome
Mapping Project
Resource Centre an MRC Unit
with three divisions
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Unit Divisions
UK HGMP RC www.hgmp.mrc.ac.uk
Research
Bioinformatics
MRC geneservice

• Software
• development

• Research products
• and services

• Functional
• genomics

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MRC geneservice mission

• To develop and provide at cost-recovery
  innovative functional genomic products and
  contract research services
• for the European academic and commercial research
  community
• to improve human health

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Key Points

• Objectives
• Non-restricted access
• Unique genomic resources
• Enabling technologies
• Cost recovery
• Value for money
• Invest in infrastructure

• Offering
• Products and services
• Functional genomics
• Translational research
• Market
• Academic and commercial
• Public/private partnering

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Business Model

• Short term
• Products and contract research
• RD via collaborations/grants
• Strengthen products and service offering
• Increase volumes/market share
• Full cost recovery by 2006
• Long term
• Growth in internal research
• Partnering/Joint Ventures
• Develop IP portfolio

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Organisation

• Moved to Babraham July 2001
• Non-profit government organization
• Bioinformatics and RD support at Hinxton
• Commercial infrastructure
• 32 staff
• Operations/IT/Finance/Business Development

Cam Ba Hi
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Recent highlights

• Commercial Development
• Business Plan Feb 01
• Premises at Babraham July 01
• Commercial team in place Dec 01
• MRC Board accepts budget and business strategy
  Apr 02
• MRC geneservice launched May 02

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Recent Highlights

• Product and Service development
• RNA Service
• 1st academic and commercial Affymetrix Microarray
  service provider in UK Dec 01
• 1st commercial deal May 02
• Quantitative PCR validation of microarray
  results July 02
• Cloning Service
• Pilot production line of expression ready clone
  (mouse cancer ORF set) Aug 02
• DNA Service
• 1st commercial SNP genotypng deal April 02
• National DNA banking award July 02
• Reagents
• C. elegans RNAi clones, ScFv library, RIKEN FL
  mouse clones, MGC FL Human cDNAs

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Global distribution
gt 11,000 users in gt 40 countries Web ordering
system Online product description 3 day
turn-around
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DNA Service

• DNA extraction
• Fresh frozen whole/separated blood
• Mutation Detection and SNP Validation
• PSQ WAVE HPLC sequencing
• Genetic studies
• Linkage and association studies
• HTP microsatellite SNP typing pipeline
• Provide access to
• Technology and analysis tools
• Training
• Genetics network
• 18 collaborations
• Immunology, cardio-vascular, neurological, cancer
  studies

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Genotyping platform - TaqMan
Liquid handling Water bath PCR
Acquire data analyse
Current daily throughput 1 FTE 100 x 384-well
plates 38K assays 95 call rate (variable DNA
quality) 100 concordance
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Laboratory Information Management System
4R
replicating re-arraying recording reporting

• Allows users to create a system to track a
  laboratory process
• Allows users to define annotations for samples
• Provides a repository for results
• Provides reports
• Provides an audit trail
• Maintains need-to-know security

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DNA Service work in progress

• Planning and starting to build a DNA bank

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Milestones on road to DNA Bank

• October 2000 MRC funds 13 collections
• December 2000 MRC calls for proposals for a UK
  network for DNA sample banking and genotyping
• May 2001 MRC workshop on its initiative
• July 2001 MRCg et al submit proposal
• July 2002 MRC selects MRC geneservice as a DNA
  banker

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13 collections funded by MRC in October 2000

• Age-related macular degeneration families
• Colorectal cancer cases, relatives, matched
  controls
• Hypertension nk
• Parkinsons disease nk
• Multiple sclerosis cohort
• Asthma and eczema family collection
• Acute coronary event families
• Type 2 diabetes nuclear familial
• Acute leukaemia MRC clinical trials patients
• Unipolar depression case control study
• Glomerulonephritis cases
• Breast cancer affected sib pairs
• Late onset Alzheimers disease case control study
• 40K samples being collected
• Each applicant already has appropriate ethical
  approval
• Grant conditions require collections to be placed
  in MRC DNA banking centres
• Most collectors have well-supported labs and
  international reputations

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MRC call for UK network Dec 2000

• The MRC
• recognises importance of genetic epidemiology in
  the post-genome era
• announces its aim of establishing a network of
  centres
• envisages network as part of the Biobank
  infrastructure
• the network will
• have custody of large DNA collections
• manage the collections
• integrate data systems across the network
• common standards and practice
• pilot high throughput genotyping
• Network resources to be made available to UK
  scientists

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MRC call for UK network

• Scope of network
• initial storage capacity 100,000 samples
• potential to expand to manage other studies
  funded by MRC - or others with cost recovery
• geographically clustered groups encouraged to
  form consortia
• long-term national HT genotyping service
• Assessment of bids
• Two stage review to differ from normal peer
  review process
• 1. consortia to express interest experts were
  to select a short-list
• 2. selected consortia to submit work plans that
  
• ? ensure users needs are met - including
  ready access to samples
• ? demonstrate commitment of hosts

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Expression of interest from Cambridge

• Summary of expertise available in Cambridge
• and of experience with large projects
• Submitted from
• 3 MRC units in Cambridge
• 11 University of Cambridge departments (including
  two MRC 13 collector PIs)

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Cambridge application for MRC DNA Bank July 2001
Institute of Public Health
other Cambridge groups including Sanger
Institute
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Overall bank organisation
DoH/MRC/ MRC
COREC WT
DNA
BANKERS
Materials Operations
and Methods Committee
Group
OPERATIONS
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Operations organisation
IPH UK
HGMP RC ECACC
Operations

Systems and Cell and
Genotyping Services Data
Group DNA Group Group
Research

Group
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Work flow
DNA
Bankers blood samples Blood
DNA Storage Retrieval Tests
Analysis

Archive WGA QC/QA
Lines
Operations
automated steps (to be introduced one at a time)
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MRC selects centres March 2002
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MRC DNABankingNetwork
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Combined application June 2002
The MRC DNA Bank service will comprise  organis
ing with the collectors the despatch of samples
from their subjects  receipt of subjects blood
or DNA samples (or receipt of samples from
ECACC)   extraction of DNA   housing of
DNA ? standard DNA concentration and DNA
quality determination
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Questionnaire to collectors

• Questionnaire probed status of collections
• - all at different stages some not started
• - some collectors query the custody status of
  samples
• - different protocols

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Current status of DNA Bank

• Final negotiations are underway
• MRCg and CIMR will use existing DNA extraction
  facilities
• Standardised sample storage systems will be used
• ECACC and CIMR will seek to improve EBV
  immortalisation
• MRCg will develop and implement WGA
• MRCg and CIMR will improve aspects of SNP typing
• MRCg hopes to acquire an advanced storage system
• Also MRC is to support a distinct collectors
  consortium

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Matters arising

• Should a national DNA bank be set up before or
  after collections have been funded?
• Should a strategic national project conceived
  centrally be selected from proposals conceived
  locally?
• Is it realistic to expect geographical clusters
  to form in preference to expedient clusters?
• Is there an overwhelming need for a network?
• In what ways might the network be part of the
  Biobank infrastructure?
• How can we overcome the reluctance of collectors
  to share even an aliquot of their sample plus
  associated phenotypic/clinical data?

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Should a national DNA bank be set up before or
after collections have been funded?

• Organisational factors
• If custody of samples and data sharing is not
  readily resolved, then fund collectors first
• Scientific factors
• Our data provide evidence that HT genotyping
  requires consistent quality DNA. As DNA/rx
  falls with UHT genotyping, we believe this will
  become an absolute requirement for high call
  rates and concordance

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Should a strategic national project conceived
centrally be selected from proposals conceived
locally?

• This depends on the extent to which the project
  will directly innovate or discover the more the
  amount of innovation / discovery anticipated, the
  greater the need for local proposals. A danger
  exists that local proposals may second-guess
  central conceptions so that the best guess wins.
• NB the distinction between vertical and
  horizontal projects is useful post hoc

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Is it realistic to expect geographical clusters
to form in preference to expedient clusters?

• Competitive bidding for funds will tend to favour
  the creation of clusters (i.e. consortia) that
  most readily create the strongest possible bid on
  scientific grounds. The Cambridge bid was mainly
  geographic but not in the sense MRC intended.
  The non-Cambridge applicant is located 200 km
  away.

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Is there an overwhelming need for a network?

• The trend in large pharma genotyping projects is
  toward out-sourcing and toward complete
  centralisation. This is for reasons of
  capital/labour costs and data quality
  respectively.

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In what ways might the network be part of the
Biobank infrastructure?

• The network will achieve harmonisation of
  procedures and ensure full interactivity of data
  systems. It is essentially a collaboration. This
  may meet some of the needs of Biobank.
• We are confident the MRC geneservice DNA bank
  will have the experience, processes and equipment
  needed to satisfy Biobank and others.

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How can we overcome the reluctance of collectors
to share even an aliquot of their sample plus
associated phenotypic/clinical data?

• There has to be a quid pro quo.
• Well-supported collectors are more independent in
  their operations than less well-supported
  collectors. For the latter, a bank network has
  more to offer. One may predict that in future
  collectors including the MRC 13 will all
  understand the virtues of a division of labour.

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Acknowledgements

• Nick Day Doug Easton - IPH Cambridge
• David Lewis Bryan Bolton - ECACC
• Bill Ollier Jane Worthington - CIMR Manchester
• Duncan Campbell Tom Weaver - UK HGMP / MRCg