CRISPR: Opportunities and Challenges Webinar
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CRISPR: Opportunities and Challenges Webinar
Your Personal Research Assistant
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Webinar Host
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Medical Lead Scientist at PreScouter, Inc.
Ph.D. Biophysical Sciences from the University of Chicago
Charles Wright, Ph.D.
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What is CRISPR/Cas?
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CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats): repeating palindromic sequences of
DNA in prokaryotes; unique spacer DNA sequences matching to foreign DNA are found between each repeat
Cas (CRISPR Associated protein): enzymes needed to identify and cut the targeted DNA sequence
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What is CRISPR/Cas?
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CRISPR/Cas: form of acquired immunity in prokaryotes that confers resistance to foreign genetic elements
CRISPR/Cas9: simplified, programmable version of CRISPR/Cas modified to edit genomes
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How the CRISPR/Cas9 system works
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sgRNA (single guide RNA): synthetic RNA molecule that contains the components needed to target the desired
genomic DNA sequence(s) and to complex with a Cas protein
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How the CRISPR/Cas9 system works
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Cas9: a Cas endonuclease protein that can cleave almost any DNA sequence complementary to its guide RNA
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How the CRISPR/Cas9 system works
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How the CRISPR/Cas9 system works
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials11
CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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CRISPR Timeline
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1987
2002
2005
2006
2007
2010
2012
2013
2014
2015
2016
2017
CRISPR repeats first observed in bacterial genomes
CRISPR elements and associated genes identified and named
CRISPR spacer identified as foreign DNA
CRISPR proposed to be a bacterial adaptive immune system
Discovery that CRISPR/Cas imparts resistance to specific phages
CRISPR/Cas identified as bacterial and archaeal immune system
CRISPR/Cas9 developed as gene editing tool
CRISPR/Cas9 used to edit targeted genes in both human and mouse cells
First use of CRISPR/Cas9 in plants
CRISPR/Cas9 used to cut HIV out of genome of infected humans cells
Monkeys with CRISPR-engineered targeted mutations are born
CRISPR/Cas9 used to develop virus-resistant tomato plants
CRISPR/Cas9 used to edit human embryos (but many off-target effects observed)
International moratorium proposed on making heritable changes to the human genome
USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs
First human trial to use CRISPR gene editing gets NIH approval
US patent office awards key CRISPR/Cas9 patents to the Broad Institute
National Academy of Sciences report outlines criteria to be met for germline editing clinical trials
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Potential Applications of CRISPR
Biomedical research:
we are creating new animal models
to understand disease and to aid in
drug discovery
Agriculture:
we can edit the genes of crops to
make them tastier, more nutritious,
pathogen-resistant, or more robust to
extreme environmental conditions
Gene drives:
instead of modifying just a single
organism, we could modify an entire
species
New antibiotics and antivirals:
we could use this system to eradicate
specific bacteria and viruses
New tools to stop genetic diseases:
we could edit the human genome to
eliminate genetic diseases like
Huntington’s disease, sickle cell
anemia, or cystic fibrosis
Designer humans:
we might one day edit the human
genome to eliminate disease or select
for desirable traits
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3 Step Process
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STEP 1
Describe your questions Meet with your PreScouter-managed
Scholar team 2–3 times over 4–6 weeks
to review what they have found
STEP 2
Make smarter decisions,
based on the
Scholars’ report
STEP 3
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CRISPR Panelists
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John G. Doench, Ph.D.
Associate Director of the
Genetic Perturbation
Platform at the
Broad Institute
C.B. Gurumurthy,
Ph.D., Exec. MBA
Associate Professor at the
Department of
Developmental
Neuroscience, Munroe
Meyer Institute for Genetics
and Rehabilitation
Shuibing Chen, Ph.D.
Assistant Professor in the
Department of Surgery and
Biochemistry at Weill
Cornell Medical College
Questions
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What enhancements to the CRISPR/Cas9 system do
you think will be the most impactful?
1
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Of the current technical limitations facing the CRISPR technology,
which do you think are most important?
2
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What are the lessons we can learn from the obstacles faced by
CRISPR’s predecessors? In what ways is CRISPR unique from
these systems?
3
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What are the main technical challenges of applying CRISPR to
animal models? How will CRISPR-based development of
animal models allow us to create better disease models and
aid in drug discovery?
4
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5
How can CRISPR aid in research involving pluripotent stem cells?
What translational/therapeutic use cases do you foresee? What are
the hurdles to achieving these applications?
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CRISPR and Pluripotent Stem Cells (PSCs)
Neuron Blood Cells Cardiomyocytes β cells Liver Cells
Modified from Regenerative Medicine. August 2006
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Research Tools
• Create reporter line.
• Evaluate the biological function of certain genes or mutations in human development and human cells.
hPSCs definitive endoderm
pancreatic progenitor
glucose-responding cells
Isogenic hPSCs
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Therapeutic Application
Patient
Corrected
hPSCs
Reprogramming
Patient-specific
hPSCs
Directed
differentiation
Replacement
therapy
Patient
Corrected
tissue or organs
Isogenic
hPSCs Patient-specific
tissues or organs
Drug screening
Drug candidates for
precision therapy
Fo
ld C
ha
ng
e o
f IN
S+ C
ell
De
ath
Ra
te
#of INS+ cells
0.01
0.10
1.00
10.00
-100 100 300 500 700 900 1100 1300 1500
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What are the greatest challenges (technical, regulatory, or ethical) to
broader applications of CRISPR within biomedical research, drug
discovery, agricultural enhancements, or therapeutic applications?
6
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What applications of CRISPR are you most excited to see in the next
few years? What about the next 10–20 years?
7
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Future Direction of CRISPR in Pluripotent Stem Cells
1. Gene/Mutation Specific Drugs
Patient-specific
tissues or organs
Drug screening
Drug candidates for
precision therapy
Fo
ld C
ha
ng
e o
f IN
S+ C
ell
De
ath
Ra
te
#of INS+ cells
0.01
0.10
1.00
10.00
-100 100 300 500 700 900 1100 1300 1500
2. Isogenic iPSC-based Genome-Wide Association Study
Genome-Wide Association Study Gene-Environment Interaction
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