CRISPR-Cas9

As we know, modern genetic research continues to generate new technology at a staggering pace, bringing us

new possibilities for healing as well as new moral challenges. Recently, with the 2012 debut of CRISPR-Cas9

technology, the engineering (think correction) of faulty human genes in vivo or in vitro has been made much easier. But alongside the specter of healing genetic diseases is another scenario, one that has haunted

biologists since the dawn of the Genomic Age—the evil scientist custom-crafting a human being with test tubes

and petri dishes. Since NCER has a special interest in monitoring technological research on human embryos, we

have assembled this powerpoint presentation as our position on prospective uses of CRISPR-Cas9.

PART ONE: WHAT IS CRISPR-Cas9?

CRISPR Cas9 is a genetic editing technique used to alter or “edit” (snip and splice) faulty genes in adult body

cells or, as an IVF technique, to genetically edit early animal and, most recently, human embryonic cells with

the end of correcting genetic diseases.

Previously, scientists have made enormous strides in their ability to do things with genes: modifying them, moving them from cell to cell, even animal to animal. It’s been

possible, in theory, to treat genetic diseases like sickle cell anemia or beta-thalassemia by removing a patient’s bone

marrow, repairing the damaged gene, and then returning the repaired cells to the patient.

But that approach has not been successful in clinical praxis. Now, with CRISPR, the cost and the ease for

making the necessary genetic editing is such that it’s really feasible to tailor therapies to the genetic errors of the

patient’s own cells and essentially to correct their genetic disease.

The contents of the editing tool injected into the cell--the CRISPR-Cas9 complex--includes:

(1) An RNA guide molecule that is programmed to match the mutated gene of interest; (2) the enzyme, Cas9, attached to the

RNA molecule which cuts both strands of the DNA at the mutation point

so that (3) a DNA moleculethat is a copy of the genetic correction can be inserted.

The CRISPR enzyme (green and red) binds to a stretch of double-stranded DNA (purple and red), preparing

to snip out the faulty part.

Distinguish between the uses of CRISPR-Cas9

Genetically engineering somatic or body cells (SCGE)

Genetically engineering germline cells or early embryos (GLGE)

Genetically engineering spare embryos for research purposes (GESE)

o SCGE: the genetic changes end with the patient, they are not transmitted

to the patient’s descendants.CRISPR once proven safe and effective for use in SCGE in adult

humans would be therapeutic, would not alter the human genome, would be within acceptable clinical safety and efficacy standards,

and would, therefore, be morally acceptable.

o GLGE: not only affects the embryonic patient but all of his/her descendants.

CRISPR used for GLGE, i.e., in embryonic or germline cells for reasons cited below is morally unacceptable.

o GESE: genetic editing of spare embryos to better understand early human development.

Although the decision to alter a human germline cell or the cells of an early embryo may be valuable

to the embryonic patient, as the altered inheritance is carriedinto new genetic combinations,

uncertain and possibly undesirable consequences may ensue. And these

inheritable genetic changes cannot be erased.Good or bad, they will afflict all subsequent generations

of the edited patient.

GESE—the use of CRISPR-Cas9 to genetically engineer

spare embryos—might lead to increased knowledge

of early human embryonic development,but this research is intrinsically immoral:it constitutes an utilitarian, experimental use of embryonic human life resulting in

the direct destructionof endless numbers of spare human embryos who will be used for this

research.

PART TWO: HOW IS CRISPR-Cas9 USED?

(1) To correct genetic diseases

in adult animal models

The CRISPR injection resulted in the normal Fah gene being expressed in 1/250 liver cells in the treated mice. Because these cells were much healthier than the

cells that still expressed the mutated Fah, they divided and produced more daughter cells. Thus, the percentage of healthy cells in the livers of the treated mice was rapidly increased, up to 33% over 30 days. The treated mice also had

significantly less liver damage than untreated mice.

CRISPR ADULT ANIMAL STUDIES PAVETHE WAY FOR CRISPR’S

THERAPEUTIC USE IN HUMAN ADULTS (SCGE).

As the article in Nature Biotechnology“Genome editing with Cas9 in adult mice corrects a

disease mutation and phenotype” concluded:

“Our study indicates that CRISPR-Cas9-mediated genome editing is possible in

adult animals and has potential for correction of human genetic diseases.”

(2) As

Genetic

Therapy

(GLGE)

In

Early

Human

Embryos

The Huang team injected 86 human embryos and then waited 48 hours, enough time for the CRISPR-

Cas9 system and the molecules that replace the missing DNA to act—and for the embryos to grow to about eight cells each. Of the 71 embryos that

survived, 54 were genetically tested. This revealed that just 28 were successfully spliced, and that

only a fraction of those contained the replacement genetic material. “If you want to do it in normal embryos, you need to be close to 100%, Huang admitted, “That’s shy we stopped. We still think

it’s too immature.”

What’s more, Huang’s team also found a surprising number of ‘off-target’ mutations assumed to be introduced by the CRISPR-Cas9

complex acting on other parts of the genome. This effect is one of the principal safety concerns surrounding germline gene editing

because these unintended mutations could be harmful. The rates of such mutations were much higher than those observed in gene-

editing studies of mouse embryos or human adult cells. And Huang notes that his team likely only detected a subset of the unintended

mutations because their study looked only at a portion of the genome, known as the exome. Huang admitted, “If we did the whole genome sequence, we would get many more [off-target

mutations].” Despite the troubling results, Huang and his team insist that the nonviable human embryos allow for a more meaningful

CRISPR model than an animal model or one using adult human cells.

CRISPR GLGE in early human embryos for

therapy paves the way for its

eugenics or non-therapeutic use in human embryos

(designer children).

PART THREE: What are the ethics of GLGE use of

CRISPR?

Altering the human genomewhen there is no guarantee

of safety and efficacy.

Paving the way for designer babieswhere parents’ rights trump all;

child’s rights are unequivocally denied(especially child’s right to lifeand the right to be conceived

within a marital act of his parents’ unitive love).

Creating a eugenics culture:destroying basic human equality (ubermensch vs. untermensch);

encouraging research hubris;allowing humans who happen

to hold the medical/political powerto design other

non-consenting human beings.

“Key to all discussion and future research is making a clear distinction between genome editing in somatic cells and in germ cells. A

voluntary moratorium in the scientific community could be an effective way to discourage human

germline modification and raise public awareness of the difference between these two techniques.

Legitimate concerns regarding the safety and ethical impacts of germline editing must not

impede the significant progress being made in the clinical development of approaches to potentially

cure serious debilitating diseases.”

PART FOUR: PROPOSED NCER POSITION ON CRISPR-Cas9

NCER’S POSITION ON THE USES OF CRISPR-Cas9:

Nebraska Coalition for Ethical Research encourages the continued use of CRISPR/Cas-9 in animal research and in adult human cell cultures as a means toward its eventual safe and efficacious use for the correction of disease genes in adult human beings.

NCER agrees with the calls for a self-imposed moratorium and an international meeting on the use of CRISPR/Cas-9 for germline genetic engineering on human embryos or human germ cells.

Regardless of the outcome of these initiatives, NCER strongly supports a permanent ban on the use of CRISPR/Cas-9 for germline genetic engineering because it:

• Irresponsibly alters the human genome;• Paves the way for designer human beings;• Denies the child’s right to give consent to an experimental technique;• Contributes to a eugenics culture that obliterates the basis for:

o Human equality, autonomy, and freedomo Medicine and research that serves the human person, ando Neighborly love and respect between persons

NCER also opposes the research use of CRISPR-Cas9 to edit genes in spare embryos. Despite its good goal—increased genetic knowledge of early embryonic development, this research constitutes an utilitarian, experimental use of embryonic human beings resulting in their direct destruction.

For further discussion of CRISPR-Cas9, please see NCER’s powerpoint presentation.

CRISPR-Cas9