Genomics Research & Development Initiative: Supporting Regulatory & Operational Mandates of the Canadian Government Ivy Moffat1, Julie Bourdon-Lacombe1, Carole L. Yauk2 & Andrew Atkinson3

1Regulators: Water and Air Quality Bureau, 2Research Scientist: Environmental Health Science and Research Bureau, 3Policy: Science Policy Directorate, Health Canada, Ottawa, ON, Canada

Council of Canadian Academics: Independent policy advice • Identified genomics as a global strength area for Canada (State of S&T, 2006)

Genome Canada: Funding body for non-gov’t institutions • To advance university-led large-scale genomics research & technology platforms ($840 million since 2000) • Leveraged >$900 million co-funding with partners

Genomics R&D Initiative (GRDI): Funding body for gov’t labs • Solutions to issues important to Canadians ($20 M/yr since 1999) • Build genomics capacity & research to support regulatory & operational mandates individual departments • Supports interdepartmental collaborations, sharing strategic priorities of national importance

Government of Canada’s Support for Genomics

GRDI Departments & Agencies

1.  Health Canada 2.  National Research Council 3.  Natural Resources Canada 4.  Agriculture and Agri-Food Canada 5.  Environment Canada 6.  Fisheries and Oceans Canada 7.  Public Health Agency of Canada 8.  Canadian Food and Inspection Agency (Shared Initiative)

http://grdi-irdg.collaboration.gc.ca/eng/index.html

GRDI Funding Process

Treasury department approval •  Mandate, benefits, shared initiatives, risk if projects not conducted •  Continuously funded for five 3-yr phases; April, 2014 reapproved for

5 years

Strategic review of research priorities & peer-reviewed competitions to allocate funds (each phase)

Evaluations: •  Independent (2006, 2010): GRDI process is well-managed,

effective & efficient. Integral to genomics governmental research

•  Cabinet/Strategic & Operating review (end of each phase) •  Annual performance reports on GRDI funded projects: e.g.

collaborations, R&D capacity, outreach & publications

Expert and end-user opinions

•  In support of GRDI funding renewal, a targetted survey of genomics researchers and end-users was conducted within Health Canada to:

•  Assess the current state of genomics issues •  Examine allocation of funding (e.g., departmental vs

shared; generation of new knowledge vs high through-put testing)

•  Examine opportunities for knowledge translation & engaging end-users

1. Interview (2013)  Health Canada genomics users: Researchers & Risk Assessors  Interview guide: ensure uniform data collection  10 questions: genomics issues relationg to impact, capacity, challenges, horizontal, needs & leveraging of funds  notes shared with respondants to ensure accuracy

100% response rate (underscored level of interest)

2. Analysis of responses: Common responses were grouped into categories when appropriate

Expert and end-user opinions

Groups Number of

Researchers Number of Risk

Assessors environmental contaminants & consumer products

6 4

health & food products 6 3 pesticides 0 2

12 9

Health Canada genomics users: Researchers & Risk Assessors

Findings

1.  Applications & impacts of genomics to mandates 2.  Capacity for genomics 3.  Challenges to the application of genomics 4.  Horizontal issues addressed by genomics 5.  Needs & foresight for genomics application 6.  Leveraging of funds

1. Applications & impacts of genomics to mandates

0 20 40 60 80

Researchers Risk assessors

Perc

enta

ge o

f st

akeh

olde

rs

n=12 n=9

Economic Impact (annually)   GRDI Projects  

>$30B trade chemicals   - Regulatory toxicology tools  - Complex mixtures  

$10B health care due to foodborne-pathogens/chemicals  

- Causing food allergy  - Short-term cancer assay fungal toxins  - Foodborne isolates: Campylobacter & Listeria  

Drugs 2nd largest health care cost  

- Stem cell based health products  - Interferon-induced hepatic injury  

Multi-million $ wireless industry   - Radiation risk assessment  $0.5B colorectal cancer   - Dietary fibre/Prebiotics  $68B Chronic disease; ensure GM foods don’t contribute to this  

- Multi generation study of soybean products  

Researcher & Risk Assessor Collaborations Toxicogenomic signature to classify genotoxic vs. non-genotoxic chemicals (Environ. Mol. Mutagen., submitted)

• Application of the HESI TGx-65 genomic biomarker for compounds requiring metabolic activation in human cell culture

• HTS of chemicals for hazard ID & MOA

Case  study  on  data  rich  compound  Tradi'onal   Tradi'onal  &  

Toxicogenomics  Toxicogenomics  

MOA   MOA   MOA  

Human  relevance   Human  relevance   Human  relevance  

POD   POD   POD  

Comparison

Case Study: Toxicogenomics & traditional approaches - Both approaches ID a genotoxic MOA - Similar regulatory values (Crit. Rev. Toxicol., accepted)

BMD/BMDLs

Approach Liver Lung Fore-

stomach Traditional •  Tumors 1.8 /1.2 0.8 0.8/0.5 •  Mutations 7.2/4.8 2.2/1.4 0.5/0.3 Toxicogenomics • Key event before committed step 8.1/1 14.8/3.7 11.4/7.4 • Lowest MOA-associated pathway 8.1/1 14.8/3.7 11.4/7.4 • Lowest pathway (Thomas et al., 2011) 0.3/0.2 15.7/2.1 16.1/4.5

Lessons Learned: Integrating toxicogenomics into human health risk assessment (Crit. Rev. Toxicol., accepted)

•  Communication: Improves experimental design, interpretation & use of data

•  Appropriate values for RA: standard method of selecting PODs

Basic technical guide for evaluating toxicogenomics data •  Guidance to evaluate & apply genomics data

Important Researcher & Risk Assessor Collaborations

Risk Assessors Are Beginning To Use Genomics

Risk Assessments Impact 3 drinking water guidelines Support for MOA pesticide active ingredients Support for MOA

2. Capacity for genomics: Funding ($000)

AAFC EC

DFO HC/PHAC

NRCan NRC

2. Capacity for genomics: Personnel

2. Capacity for genomics

Core genomics facility: leveraged from GRDI funds • 2 DNA microarray scanners • 1 next gen sequencer • Traditional apparatus • Collaborating labs: full proteomic analysis • Human resources: statisticians & 2 bioinformaticians – direct pipe from sample to analysis/interpretation

Outsourcing is important when no in-house capacity

3. Challenges to the application of genomics

0 10 20 30 40 50 60 70 80 90

Researchers Risk assessors

n=12 n=9

Perc

enta

ge o

f st

akeh

olde

rs

4. Horizontal issues addressed by genomics

Number of Collaborators

Genomics Working Group:

•  Advisory group: both regulatory & scientific experts for genomics applications & implications

•  Forum for knowledge exchange (cross-pollination) •  > 70 members

5. Needs & foresight for genomics application

Needs for Genomics Application

0 20 40 60 80

100

Researcher Risk Assessor

n=12 n=9

Perc

enta

ge o

f st

akeh

olde

rs

Foresight for Genomics Application

0 20

40

60

80

100

Researcher Risk Assessor

Perc

enta

ge o

f st

akeh

olde

rs

Other: antimicrobial resistance. Counter-bioterrrism, emergency prepardness/response

6. Leveraging of GRDI funds

Core genomics facility: •  Attracts collaborative national &international partnerships •  Attracts 4-times level of GRDI funding outside of GRDI •  No single policy approach /initiative could leverage

resources greater than current process

Encourage funding for collaborative projects •  Leverage horizontal support of non-GRDI agencies &

encompass a number of common issues among Bureaus •  Reduce barrier to collaboration & sharing of funds

Lessons learned from 15 years of GRDI funding:

Current State • Shared initiative projects are becoming important, but should not redirect funding from department projects • Genomics research is beginning to impact end-users

Capacity • Capacity must be developed before testing/data generation • Increased need for bioinformatic support, students & risk assessor training

Lessons learned from 15 years of GRDI funding: Cont’d

Needs

• Strong genomics research & user network to ensure effective knowledge translation (KT)

• Must demonstrate relevancy to programs through KT

• Collaboration, communication & training essential

Thank you

•  http://grdi-irdg.collaboration.gc.ca/eng/index.html

•  Please contact: ivy.moffat@hc-sc.gc.ca

For more information

Hazard  iden4fica4on,  dose-­‐response,  &  human  relevance  were  addressed  in  our  studies  

Annotate  affected  genes,  networks  &  pathways  

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 Quan'fy  &  compare    the  BMDs  of  genes,  pathways  and  apical  endpoints  

 Iden'fy  key  events  (lowest  BMDs,  plausible  biology)  

Build  mode  of  ac'on  (MOA)  

Derive      Point  of  Departure    

Process  'ssues,    generate  gene    expression  profiles  

Anchor gene

expression data to DNA damage & mutations to support

MOA

Human TK6 cells

exposed to BaP to

Confirm MoA & human relevance

       Expose  B6C3F1  and  MutaTMMouse  to    BaP  by  oral  gavage  

TRADITIONAL  TOXICITY  TESTING  Most  sensi)ve  toxicity  endpoints  

CURRENT  APPROACH  

TOXICOGENOMICS  Most  sensi)ve  perturbed  pathways  

NEW  APPROACH  

Toxicogenomic  POD  POD  

SCREENING,  MOE,  RISK  ASSESSMENT  AND  RISK  MANAGEMENT  

Targeted  tes4ng  

In  vitro  gene'c  toxicity  &  kine'cs/metabolism  tests,  In    silico,  HTS,  QSAR  

EXPOSURE  CHARACTERIZATION  

HAZARD  IDENTIFICATION:  Iden'fy  appropriate  endpoint(s)  to  determine  POD  

Refine    if  needed  

Obvious  toxicity/human  relevance?  

NO  YES  

Lower-­‐priority  

Lessons Learned from Research-Risk Assessor Collaboration for use of toxicogenomics data in risk assessments (Crit. Rev. Toxicol., final revisions)

Lessons  Learned   For  Both  Researchers  &  Risk  Assessors  

1.  Communica'on   Improves  experimental  design,  interpreta'on  &  use  of  data  

2.  Ease   SoZware  applica'ons  &  short  courses  are  now  available  

3.  U'lity  of  high-­‐content  info  

Wealth  of  info  can  be  generated  quicker/cheaper  than  standard  assays  

4  Biological  significance   Pathways  that  align  with  MOA  can  be  used  to  determine  BMDs  for  toxicologically  relevant  changes  in  known  biology  

5.  Human  relevance   Plausibility  of  animal  MOA  can  be  examined  with  cultured  human  cells  and  toxicogenomics  

6.  Support  MOA   Toxicogenomics-­‐based  MOA    target  which  test  are  necessary  

7.  Selec'on  of  PODs   Key  event  preceding  commibed  step  in  MOA  may  be  most  appropriate  POD  value  

8.  Great  poten'al   Toxicogenomics  provides  data  to  determine  MOA  s  &  PODs  for  data-­‐poor  chemicals