The INFRAFRONTIER Research Infrastructure Preparatory Phase . ... The INFRAFRONTIER Research Infrastructure . ... IMPC report published on how it …

The INFRAFRONTIER Research Infrastructure

Michael Hagn, Helmholtz Zentrum München INFRAFRONTIER-I3 metabolic phenotyping workshop, 10 October 2016

INFRAFRONTIER Research Infrastructure

www.infrafrontier.eu

Agenda

• RIs and ERA

• ESFRI process

• INFRAFRONTIER RI

• INFRAFRONTIER RI resources and services

• Quality and reproducibility

• Technology development

• Outreach & networking

• INFRAFRONTIER2020 / sustainability

• CORBEL / Collaboration of BMS RIs

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Infrastructures and grand challenges

‘research infrastructures’ refers to facilities, resources and related services used by the scientific community to conduct top-level research Examples: databases, biological archives, clean rooms, high-capacity/high speed communication networks, research vessels, satellite and aircraft observation facilities, telescopes, synchrotrons and accelerators RIs may be ‘single-sited’ (a single resource at a single location), ‘distributed’ (a network of distributed resources), or ‘virtual’ (the service is provided electronically).

www.infrafrontier.eu 3

Horizon 2020 and infrastructures


Biomedical Projects selected from 150 proposals:

BBMRI – biobanking

EATRIS – translational research

ECRIN – clinical trials

ELIXIR – bioinformatics

INFRAFRONTIER – animal disease models

INSTRUCT – structural biology

(up-dated in 2008 and 2010 for additional projects)

European science policy background


ESFRI – The European Strategy Forum on Research Infrastructures

First roadmap in 2006

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INFRAFRONTIER Mouse Clinics

Archiving / Distribution

Systemic Phenotyping


Access to scientific platforms, data, in vivo models and training

Mouse Production

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INFRAFRONTIER Preparatory Phase

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 …

2009 – Germany prioritises INFRAFRONTIER

2010 – Establishement of the Inter-Ministry Working Group for INFRAFRONTIER

2011 – ESFRI-Chair Vierkorn-Rudolph confirms German Lead in INFRAFRONTIER - Memorandum of Understanding, between DE, GR, FI, FR, CZ and EMBL

INFRAFRONTIER GmbH

2012 – Business plan and legal founding documents for the INFRAFRONTIER GmbH

2008 – 2012 – INFRAFRONTIER Preparatory Phase, coordinated by HMGU

INFRAFRONTIER PP

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INFRAFRONTIER GmbH


Based on INFRAFRONTIER MoU

Partners:

• DE – HMGU 11 Apr 13 • FR - CNRS 05 Dec 13 • CZ – IMG 05 Dec 13 • FI – U OULU 05 Dec 13 • GR - Fleming 05 Dec 13 Interested to join: SWE, NL, IT

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INFRAFRONTIER Research Infrastructure


INFRAFRONTIER RI is an ESFRI Landmark


INFRAFRONTIER-RI


https://www.infrafrontier.eu

central interface to community

EMMA integrated in new portal

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INFRAFRONTIER-RI informatics and database https://www.infrafrontier.eu/knowledgebase/bibliography




• 14 European countries + EMBL + Canada

• Mouse clinics

• EMMA archiving and distribution nodes

• Bioinformatics

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INFRAFRONTIER RI - mouse clinics


INFRAFRONTIER phenotyping capacities and expertise

• Systemic phenotyping Top down projects (INFRAFRONTIER-I3 / EUMODIC / IMPC) and bottom up projects

• Secondary phenotyping

• Collaboration / fee for service

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INFRAFRONTIER-RI / EMMA repository


5500 mouse mutant lines are displayed

on the public EMMA strain list

Major collections • 2640 mouse strains from IKMC resource

• 611 ENU strains

• 268 Cre expressing strains

• 86 mouse strains from Lexicon / Deltagen

collection (Wellcome Trust KO mouse resource)

• 46 strains with Tet expression system

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INFRAFRONTIER RI - EMMA repository

EMMA – 3rd largest mouse repository worldwide

Major collections:

• IKMC / IMPC mice: 2640 Industry access via Genoway

• Cre driver lines: 268

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INFRAFRONTIER-RI / EMMA repository


Number of shipments / year

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World-wide distribution of INFRAFRONTIER users


Industry access




INFRAFRONTIER-I3 Transnational Access


Transnational Access (TA) activities: • WP8: Mouse production service / 30 access units

Production of heterozygous mice carrying the targeted gene of choice from the corresponding validated gene-targeted ES cell clone(s)

• WP9 Mouse phenotyping service / 22 access units

Comprehensive, customizable first line phenotyping of a mutant line with appropriate control Access provision to TA services and definition of evaluation process 5 TA calls // 206 applications across EU // 55 selected TA projects

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INFRAFRONTIER-I3 TA / WP8 disease models


Production centre

Call Gene of interest

Research area and project objective of finalised projects

Fleming 1 Lpar1 Chronic inflammation: Role of lysophosphatidic acid (LPA) receptor 1 function in diseases like rheumatoid arthritis and idiopathic pulmonary fibrosis

Oulu 1 Caspase1 Infectious diseases: Study role of caspase-1 (via a cond. Caspase1 specific KO) in infectious and non-infectious disease

Oulu 1 Shb Use cond KO to study cell specificity of effects seen in KO line relating to reproduction, angiogenesis and hematopoiesis

VUW 1 Pdcd5 Cancer research: Investigate the role of PDCD5 in autophagy and as a modulator of p53

VUW 1 Nr4a1 Develop a cond KO mouse model to study the role of Nr4a1 in retinitis pigmentosa the most common form of inherited retinal degeneration

CNB-CSIC 1 Il10 Develop a faithful mouse model for the lethal in childhood, cerebral inflammatory and demyelinating form of X-linked adrenoleukodystrophy

CNB-CSIC 1 Cpeb3 Develop a cond KO model to understand the role of CPEB3 in learning, renal cell differentiation and cancer

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INFRAFRONTIER-RI / Axenic service


• Generation of germ free mice

• Access to axenic mice, tissue or body fluids

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INFRAFRONTIER-RI Training


• Cryocourses: 36, 280 students

• Phenotyping courses: 4, 90 students

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INFRAFRONTIER RI / QM and reproducibility



Community challenges

• Trust in biomedical research / disease models

• Economics of irreproducible research Low reproducibility rates undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development

• Translational gap

The cumulative prevalence of irreproducible preclinical research exceeds 50% US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible (US alone)

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INFRAFRONTIER RI / QM and reproducibility


INFRAFRONTIER RI / IMPC deliver reproducibility


• EMMA repository guards health and genetic quality of deposited mice • IMPC IMPReSS (International Mouse Phenotyping Resource of Standardised Screens), contains standardized phenotyping protocols which are essential for the characterization of mouse phenotypes Validation of test robustness through reference lines IMPC report published on how it is ensured that ARRIVE guidelines are met. The ARRIVE guidelines, developed in 2010, aim to assure reproducibility and transparency in animal research

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INFRAFRONTIER RI / IMPC deliver reproducibility


It is also why the IMPC is so important - by detailing the function of each gene in a standard genetic background, it will provide a necessary source of information for researchers for many decades, and help in the effort to ensure that biological results are reproducible.

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• To continuously improve resources and services

• To reduce animal use

• To enhance operational efficiencies / cost reduction & sustainability

Refinement of Metabolic Phenotyping Cages with TSE

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INFRAFRONTIER technology development


INFRAFRONTIER technology development Cryo technology development achievements


Old cryopreservation approach • 2 cell embryo freezing (500 embryos),

70 animals, 6 weeks (+ 3-6 weeks QC) New approach (CARD methods) • Sperm freezing, 10 animals, 1 day, QC

via blastocyst genotyping Shipments Lifor importation of epididimydes Dry ice shipments (sperm) Animal use reduced 7x Cost reduction 6x Increased throughput User friendly services

Dissemination 20 protocols, training videos, 6 methods papers, 4 training courses / year (30 people) https://www.infrafrontier.eu/knowledgebase/protocols/cryopreservation-protocols

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INFRAFRONTIER-I3 / Outreach & networking Industry liaison meeting



• 80 participants

• INFRAFRONTIER / IMPC PIs, scientists, advisors

• IMPC Industry Sponsors

• BioPharma

• Research instrumentation developers

• CROs, suppliers and platform companies

• Funders

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International coordination


EC funded coordination actions:

• InfraCoMP (2011 – 2014) • IPAD-MD (2015 – 2019)

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• 2012 - InfraCoMP Workshop on IMPC Embryonic Lethal Phenotyping, London, UK

• 2012 - INFRAFRONTIER / IMPC Korea Meeting, Jeju Island, CO

• 2013 - INFRAFRONTIER / IMPC / IKMC Rome Meeting, Rome, IT

• 2014 - INFRAFRONTIER / IMPC Mouse Repository Workshop, Munich, DE

InfraCoMP workshops

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INFRAFRONTIER-RI / achievements


• Excellent network with expertise and capacities in cryobiology and phenogenomics, shaping ERA

• Network of network / health research, societies, policy

• Outreach to user communities and industry and collaboration with global networks: IMPC, FIMRe / IMSR, IRDiRC

• EC funding, 3 EMMA projects, 5 INFRAFRONTIER projects, 35 Mill €

• Resource development, EMMA 3rd largest mouse repository

• Global use, 1400 user projects

• Access to mouse model development and phenotyping capacities

• Axenic service unique among mouse infrastructures

• Technology development: cost reduction, increased throughput, use of fewer animals, improved user services

• Training courses, ~370 students

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INFRAFRONTIER2020 / towards sustainability


• Implement ERIC legal entity (members are states not institutions)

• Framework legal agreements of ERIC and operational nodes

• INFRAFRONTIER-ERIC business plan (new members) • Business models for sustainable operation

(independent of project funding)

• Quality management / certification

• Professionalise communication, dedicated comms manager

• Reengineer database, tool development

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INFRAFRONTIER2020 / towards sustainability


• Outreach: INFRAFRONTIER stakeholder conference, phenogenomics summer schools

Move mouse closer to clinical / human research • Customised service offers for model development and phenotyping

• CRISPR/Cas9 mouse and rat model development

• Metabolic phenotyping, behavioral phenotyping

• Late-onset phenotyping (develop intervention studies, biobanking)

• Microbiome research

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Coordinated Research Infrastructures Building Enduring Life-science services

www.corbel-project.eu

BACKGROUND

• 4 year project: 2015-2019, 35 partners in 11 BMS RIs

• budget: €14.8 million

• co-coordinated by ELIXIR and BBMRI-ERIC

OPEN CALLS


Michael Hagn, Helmholtz Zentrum München

Documents

The INFRAFRONTIER Research Infrastructure Preparatory Phase . ... The INFRAFRONTIER Research Infrastructure . ... IMPC report published on how it …