CRISPR Gene Editing: The Flashing Yellow Light of Caution!€¦ · CRISPR Scientific Risks...
Transcript of CRISPR Gene Editing: The Flashing Yellow Light of Caution!€¦ · CRISPR Scientific Risks...
CRISPR Gene Editing:The Flashing Yellow Light of Caution!
Arvin M. Gouw, Ph.D.
Lafayette- Orinda Presbyterian Church
September 16, 2019
Outline
• CRISPR Mechanism
• CRISPR Applications
• CRISPR Dangers
• CRISPR Regulations
CRISPR: Bacterial Immune System
http://sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/
Outline
• CRISPR Mechanism
• CRISPR Applications
• CRISPR Dangers
• CRISPR Regulations
CRISPR E.Coli and algae for climate healing
https://www.labroots.com/trending/microbiology/3441/scientists-engineer-e-coli-sugar-carbon-dioxidehttps://www.wur.nl/en/project/A-CRISPy-tale-of-microalgal-genome-editing.htm
CRISPR in agriculture
CRISPR Animals: from pets to food
“Hercules” $1,500 Micropigs HypoallergenicEggs
Anti-Malaria Mosquitoes
Myostatin deletion leads to increased muscle mass
https://science.sciencemag.org/content/361/6405/835
“Hercules”Duchenne’s Captain America
https://www.nature.com/news/new-life-for-pig-to-human-transplants-1.18768
The mosquitos’ range expands as more locations develop a “mosquito-friendly” climate.
CRISPR Mosquitoes & Climate Change: How Does Climate Affect Zika?
• As Temperatures Warm…
Aedes aegypti
There are more days when mosquitos are active and able to reproduce.
The mosquitos’ reproduction rate increases, so more generations are born each year.
The mosquitos’ metabolism accelerates, causing them to feed (bite) more often.
The virus incubates more quickly inside the mosquito, increasing the time available for transmission.
Image: 1905 Emil August Goeldi
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Zika Virus
Dengue Fever
Cryptococcus Gattii fungus
Chagas Disease
Chikungunya
Rift Valley Fever
West Nile Virus
*The exact point of origin of many diseases is uncertain
Tropical Diseases on the Move
© James Hastings-Trew
CRISPR Gene Drives
https://www.nextbigfuture.com/2015/11/gene-drive-can-propel-genes-throughout.html
How can genetic mouse models help us?
There are ~4,000 monogenic diseases
https://www.slideshare.net/adonissfera/schizophrenia-as-a-multifactorial-disorder
I went to Stanford for mice!
Molecular Cell 1999
Science 2002
Nature 2004
PNAS 2015
Sci Trans Med 2014
Oncogene Addiction Models
Dean Felsher
Oncogene Addiction Models
Richard Zare
Desorption Electro Spray Ionization Mass Spectrometry Imaging
(DESI-MSI)
Cancer specimen
Nanodroplets dispersed
Signature lipids that increase with RCC
progression & regression
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PG(22:6/22:6) m/z 865.500
“MYC & SREBP1 in lipogenesis” Cell Metabolism 2019
Unfortunately not everybody can afford a $100K
CRISPR Mouse
There are more than 7,000 rare diseases – affecting
more than 300 million people globally.*
*3 in 4 are children. 3 in 10 don’t
survive past their 5th birthday.
Why I’m at Rare Genomics Institute
The current top-down model for biomedical
research is not designed to address
so many diseases. As a
result, less than 5% of
rare diseases have any
type of therapy.
The Current Situation
We help families design and implement one-of-a-kind
research programs. We are
pioneering a new paradigm
for bottom-up, patient-
driven research.
How We Help
We partner with top medical centers and biotech
companies to provide for unique research programs
Combing all these elements,we create research projects
that would otherwise
not exist – tailored for
each individual and
each rare disease.
Research projects as unique as …
WINDSOR MAYA ROBERT SELAH
Well what about human CRISPR Gene Therapy?
Monogenic rare diseases & orphan drugs
First CRISPR human clinical trial
Outline
• CRISPR Mechanism
• CRISPR Applications
• CRISPR Dangers
• CRISPR Regulations
CRISPR Scientific Risks
• Off-target effects: The key to CRISPR targeting system is the sgRNA which is used to determine which gene gets edited. Given the fact that our DNA is long with 3 billion base pairs, it is a major concern to get the correct gene edited out of the myriad of base pairs in the genome.
• On-target effects: There could be unintended consequences of even an on-target gene therapy. i.e. sickle cell anemia confers resistance to malaria
• Chimerism: Not all genes get edited, leading to differential survival of cell subpopulations
• Epigenetic factors: Genetic modifications can have unintended effects due to epigenetic modifications
CRISPR: Next gen bioterrorism?
CRISPR Advent of Lulu and Nana
CRISPR designer Babies
• Design implies that genetic modification X will cause a change, X.
• However, we at this point do not know the unintended consequences as well as off-target effects, and epigenetic effects.
Biological determinism
• BUT if we were to know them all, do we escape genetic determinism into genetic + environmental determinism?
• This is the approach of behavioral genetics and sociobiology and more recently evolutionary psychology
• If this were true, are we truly free? Or simply unconscious of our gene-environment predetermination?
Outline
• CRISPR Mechanism
• CRISPR Applications
• CRISPR Dangers
• CRISPR Regulations
CRISPR Democratization
ACMG on CRISPR
• American College of Medical Genetics and Genomics
• In January 26, 2017, ACMG published a report: “Genome editing in clinical genetics: points to consider.”(Acmg Board Of 2017)
• The report acknowledges great benefits of CRISPR in studying disease mechanisms, however it raises two major concerns: • off target effects and
• unknown epigenetic consequences of editing pathogenic variants.
The National Academies of Science, Engineering, and Medicine
• In February 2017, the National Academies of Science, Engineering, and Medicine also published a comprehensive report on CRISPR.
• They formulated three major advantages of CRISPR: • prevention of the inheritance of genetic diseases, • advancement of basic science research, and • improvements in CRISPR editing are making accuracy and efficiency better for clinical
applications.
• However, they also raised four major concerns:• chimerism, • off-target effects, • human gene pool effects, and • unknown long-term effects.
Several themes to consider
• Natural vs. modified
• External vs. Internal
• Therapy vs. enhancement
• Somatic vs. germline
• Permanent vs. reversible
Are we playing God?
• Should we alter nature?
• Is this a Promethean, Frankensteinian hubris? (Kass)
• There’s a reason why nature is the way it is. Don’t tinker with it! (Rifkin)
Hume’s guillotine
• Is nature how things should be?
• We are playing with God –created are co-creators (Hefner)
• Nature is incomplete (Deacon) and its fulfilment will be in the future. (Peters)
Blurry distinction:Revertant mutations vs. CRISPR editing
Wiskott-Aldrich syndrome (WAS)
Several themes to consider
• Natural vs. modified
• External vs. Internal
• Therapy vs. enhancement
• Somatic vs. germline
• Permanent vs. reversible
External vs. Internal
Where do we locate our essence?
• Are we our genes? Should we alter our DNA? Identical twins?
• Are we walking brains? Should we alter our neurons?
• Are we nodes within social infrastructure?
• Are we how we respond to God?
Several themes to consider
• Natural vs. modified
• External vs. Internal
• Therapy vs. enhancement
• Somatic vs. germline
• Permanent vs. reversible
Therapy vs. Enhancement: What is normal?
Bell Curve by Herrnstein & Murray promoted the idea that IQ dictates success.
Should we enhance our children?
• Will we be blamed if we edited their genomes?
• Will we blamed if we did NOT edit their genomes?
• If the technology is available, we are responsible to decide. To not act is to have decided.
Commodification of children
• But the real question is: is it truly for the baby’s benefit to be edited or for the pride of the parents? Have parents commodified their babies? • If gene editing goes wrong, do we get
discount on the kids?
• Are we going to suffer from the perfect child syndrome? Keep having babies till we have the perfect one
• At what point is the enhanced child ‘no longer our child’ due to the huge genetic differences?
Several themes to consider
• Natural vs. modified
• External vs. Internal
• Therapy vs. enhancement
• Somatic vs. germline
• Permanent vs. reversible
Germline vs. Somatic Gene Editing
Germline therapy arguments
Pro
• Medical utility: germline gene therapy offers a true cure for diseases
• Medical necessity: such therapy is the ONLY cure
• Prophylactic efficiency: prevention is less costly than lifetime treatment
• Parental autonomy: parents have freedom
• Scientific freedom: scientists have freedom
Con
• Scientific uncertainty and risks
• Slippery slope to enhancement
• Consent of future generations
• Allocation of resources: germline therapy may never be cost-effective
• Integrity of genetic patrimony: future generations have the right to inherit the ‘original’ genome
Eric T. Juengst
Several themes to consider
• Natural vs. modified
• External vs. Internal
• Therapy vs. enhancement
• Somatic vs. germline
• Permanent vs. reversible
Control MYC ON MYC OFF
Shachaf et al, Nature, 2004
Reversibility of Liver Cancer
Control MYC ON MYC OFF
Shachaf et al, Nature, 2004
Reversible MYC-induced Hepatocellular Carcinoma Mouse Model
Concluding Remarks
• CRISPR applications are very broad
• CRISPR dangers include off-target effects, on-target effects, and epigenetic factors
• CRISPR regulations are unclear on where to draw the line
• There are multiple dividing “lines” to consider:• natural/modified• External/internal• Therapy/enhancement• Somatic/germline• Permanent/reversible
Acknowledgments