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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
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
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
Model    Organisms
Multicellular
Biology
Unicellular
Biology
Human
Biology
Vertebrate
Biology
500  Myr
80  Myr
1,000  Myr The  “Security  Council”
HGP  ‘90-­’02
Science 22 May 2015: Vol. 348 no. 6237 pp. 921-925
195  /  414  genes  tested  (47%):  
Human  gene  functionally  replaces  yeast  gene
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!
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)
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)
Canada:  950  rare  diseases  through  pipeline  …
Known
gene
285
Novel	
115
0
50
100
150
200
250
203 138
Disorder	Solved Disorders	Unsolved
400
400  disease  
genes  found
42%  success
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
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
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  
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
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
Canadian  Rare  Diseases  :  Models  &  Mechanisms  Network
http://www.rare-diseases-catalyst-network.ca
(Mar  30,  2017)
48
of  ~560  
280
439
5091
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
van	
  Karnebeek et	
  al,	
  Nature	
  Genetics	
  2016;	
  48:777-­‐784
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.
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)
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/
END

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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
  • 4. Model    Organisms Multicellular Biology Unicellular Biology Human Biology Vertebrate Biology 500  Myr 80  Myr 1,000  Myr The  “Security  Council” HGP  ‘90-­’02
  • 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)
  • 9. Canada:  950  rare  diseases  through  pipeline  … Known gene 285 Novel 115 0 50 100 150 200 250 203 138 Disorder Solved Disorders Unsolved 400 400  disease   genes  found 42%  success
  • 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
  • 17. van  Karnebeek et  al,  Nature  Genetics  2016;  48:777-­‐784
  • 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/
  • 21. END