RDD Conf Day 1: Diseases: Models and Mechanisms, Phil Hieter
1. Rare Diseases: Models and Mechanisms
A Canadian National Network of Clinician and Basic
Scientists
March 30, 2017
CORD Meeting Vancouver
Phil Hieter
Michael Smith Laboratories
UBC
2. Rare Diseases: Models and Mechanisms
Main goal:
To catalyze connections/ collaboration between clinician
scientists (identifying rare disease gene variants) and
basic scientists (analyzing gene function/ mechanisms
in model organisms)
Launched December 2014
3. 1980- 2020
Constructing “A genetic anatomy of human disease”
Identify the genetic variants that cause human disease
2000- 2040
Addressing “The grand challenge”
Understand how genetic variants cause disease
Analyze gene/ pathway function
Translate knowledge of gene function to advancements in
prevention, treatment, and diagnosis of human disease
Human genetic variation and disease:
What the history books will say
5. Science 22 May 2015: Vol. 348 no. 6237 pp. 921-925
195 / 414 genes tested (47%):
Human gene functionally replaces yeast gene
6. The Model Organisms
(yeast, worms, flies, zebrafish, mouse)
are Nature’s gift to health research.
They will be critical in functionalizing human
genetic variants that cause disease
and in paving the way to developing rational
therapies, and disease prevention strategies
for decades to come!
7. 0
20
40
60
80
100
120
140
160
180
200
220
Number
of
Novel
Genes
Identified
by
NGS
Publication
Date
Novel
Disease-‐
Causing
Genes
Identified
by
WES
gene known
~4200
~3000 diseases
below the surface
x
Rare disease gene identification by whole
exome/genome sequencing (begin 2010)
8. 0
20
40
60
80
100
120
140
160
180
200
220
Number
of
Novel
Genes
Identified
by
NGS
Publication
Date
Novel
Disease-‐
Causing
Genes
Identified
by
WES
Canada has been a
leader in the field
gene known
~4200
~3000 diseases
below the surface
x
Rare disease gene identification by whole
exome/genome sequencing (begin 2010)
10. Model Organisms and Human Disease
Gene, pathway, network Function
Evolutionary conservation
Mechanisms of human disease, normal biology
Therapy, prevention
The keys:
Vibrant research communities
DiseaseGene identification, GeneFunction analysis
Collaboration, communication, exchange
Medical scientists Basic scientists
Genetics 198:443-445, October 2014
11. Canadian National Network:
“Canadian Rare Diseases : Models & Mechanisms Network”
Objectives:
1. Enable collaboration between clinician scientists (rare
disease gene discovery) and basic scientists (expertise in
the the cognate gene’s function)
1. Provide seed funding ($25K) to the collaborating scientists
to obtain functional data for publication or as preliminary
results for a larger grant application
2. Develop an information portal for resources, databases,
technologies, core facilitites, etc. available in Canada
12. Canadian National Network:
“Canadian Rare Diseases : Models & Mechanisms Network”
Core activity: “Rapid Response Grants” (seed funding)
Two types:
1) clinician scientists who discover a new disease gene seek
to establish collaborative connection to a basic scientist
1) clinician scientist/ basic scientist “pairs” who have
independently established a collaborative connection seek
seed funds/ network
Receive requests
Invite labs to apply (twice monthly)
Two page application + brief CV
One week to decision
$25,000 plus connection
13. Clinical Gene
Discovery
Applicants
Model Organism
Investigators
Register to
Join the
Network
Generate Functional
Data
Give Insights into
Disease Pathogenesis
Validate Clinical
Gene Discoveries
Suggest
Therapeutic Targets
Entry Points
Foster Longer
Standing
Collaborations
Decision Points Connections Destinations
Submit a
Connection
Application
Clinical
Advisory
Committee
Scientific
Advisory
Committee
Catalyst
Grants
Registry
Network Routemap
From the RDMM website (have a look!)
http://rare-diseases-catalyst-network.ca
14. Canadian National Network:
“Canadian Rare Diseases : Models & Mechanisms Network”
Major Challenges:
Establishing the best mechanisms for catalyzing connections
between clinician scientists and basic scientists
Creating a national database of model organism PI’s
Recruiting participation from the entire Canadian scientific
community
Communication within each of the communities
15. Canadian Rare Diseases : Models & Mechanisms Network
http://www.rare-diseases-catalyst-network.ca
(Mar 30, 2017)
48
of ~560
280
439
5091
16. Network Catalyst Grants:
Canadian Rare Diseases : Models & Mechanisms Network
Dr. Clara van Karnebeek (BC Children’s Hospital)
Dr. Sarah Hughes (University of Alberta), friut fly
Dr. Xiao-Yan Wen (U. of Toronto, St. Michael’s Hospital), zebrafish
Gene for severe developmental delay and skeletal dysplsia disorder
Drosophila model (“humanized” fly to test variants)
Zebrafish model (knockdown of zebrafish ortholog to model phenotype)
Dr. Pranesh Chakraborty (CHEO Research Institute, University of Ottawa) Dr.
Adam Rudner (University of Ottawa)
Gene for SIFD (Sideroblastic Anemia with Immunodeficiency, Fever, and
Developmental Disability)
Yeast model (“humanized” yeast to test variants, genetic suppression screens
Dr. Jacques Michaud (CHU Ste-Justine)
Dr. Mei Zhen (Lunenfeld-Tannenbaum Research Institute, U of Toronto
Gene for Intellectual disability with ataxia and arthrogryposis
Worm model to examine the patholical effects of identified NALCN mutations
18. Canadian National Network:
“Canadian Rare Diseases : Models & Mechanisms Network”
Anticipated direct outcomes:
1. Functional validation of disease gene identification
2. High impact publications of disease gene discovery through
inclusion of functional data
3. Potential rationale for treatment (eg, identification of
candidate drug targets) via knowledge of disease gene
pathway
4. Increased success in obtaining subsequent grant funding to
support future basic and/or applied research.
19. Network Catalyst Grant:
Canadian Rare Diseases : Models & Mechanisms Network
Additional (indirect) effects:
1. International recognition of Canadian leadership in
addressing ‘the grand challenge”: model systems to gene
function and mechanisms of disease to therapies
2. Increased awareness of the importance of basic research in
model systems (funding agencies, government, scientific
community, general public)
20. Network Catalyst Grant:
Canadian Rare Diseases : Models & Mechanisms Network
Current activities:
1. Recruitment
Goal: 100% participation Canadian scientific community
-Registration and contact information (basic scientists)
-Submission of novel disease genes (clinicians)
2. Newsletter (launched Oct 1)
3. Collaborations/ funding contributions from NGO’s
e.g., TTP, Dravet
4. International collaborations
e.g., Australia, NHGRI (U.S.), Europe
Please join/ interact with RDMM
http://www.rare-diseases-catalyst-network.ca/