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

**

*

**

*

*

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

20

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