The MRC DNA Bank: the story so far

1. The MRC DNA Bank:the story so far ESF Workshop on Biobanks: practical, ethical and legal aspects Uppsala 13 September 2002

2. 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

3. Medical Research Council 50 Institutes and Units UK Human Genome Mapping Project Resource Centre: an MRC Unit with three divisions

4. Unit Divisions UK HGMP RC www.hgmp.mrc.ac.uk Research Bioinformatics MRC geneservice • Functional • genomics • Software • development • Research products • and services

5. 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

6. 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 Key Points

7. Business Model • Short term • Products and contract research • R&D 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

8. Organisation • Moved to Babraham: July 2001 • Non-profit government organization • Bioinformatics and R&D support at Hinxton • Commercial infrastructure • 32 staff • Operations/IT/Finance/Business Development Cam Ba Hi

9. 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

10. 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

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

12. 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

13. 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

14. R R R R 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

15. DNA Service: work in progress • Planning and starting to build a DNA bank

16. 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

17. 13 collections funded by MRC in October 2000 • Age-related macular degeneration families • Colorectal cancer cases, relatives, matched controls • Hypertension nk • Parkinson’s 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 Alzheimer’s 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

18. 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

19. 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

20. 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)

21. Cambridge application for MRC DNA Bank: July 2001 Institute of Public Health + other Cambridge groups including Sanger Institute

22. Overall bank organisation DoH/MRC/ MRC COREC WT DNA BANKERS Materials Operations and Methods Committee Group OPERATIONS

23. Operations organisation IPH UK HGMP RC ECACC Operations Systems and Cell and Genotyping Services Data Group DNA Group Group Research Group

24. 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)

25. MRC DNA BANKING AND GENOTYPING INITIATIVE Combined Application: Plan of Work and budgets ·MRC geneservice ·Centre for Integrated Genomic Medical Research ·European Collection of Cell Cultures MRC selects centres: March 2002

26. MRC DNABankingNetwork

27. Combined application: June 2002 The MRC DNA Bank service will comprise: ·organising 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

28. 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

29. 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

30. 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?

31. 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

32. 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

33. 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.

34. 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.

35. 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.

36. 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.

37. 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