January 25, 2021

The Niche

Trusted stem cell blog & resources

The big blind spot on CRISPR for human embryo editing: PGD

blind spot on CRISPR of human embryos
There’s a blind spot on heritable CRISPR of human embryos.

There is a big old blind spot in the discussion over germline gene editing in humans: preimplantation genetic diagnosis (PGD).

There’s been a lot of talk in 2015 about worries over how gene editing technology such as CRISPR might be used prematurely in the clinic in an unsafe or unethical manner in humans in the germline to try to prevent genetic disease.

This is a very serious concern and I share it.

However, in a way the dialogue on this usually misses a crucial, more basic question.

Why would anyone even try human gene editing in the germline given the existence of the very powerful, already proven safe technology of PGD?

In a match up of say CRISPR versus PGD, PGD would win almost 100% of the time as by far the best choice to tackle genetic disease. It would be both safer and more effective. Again, we are talking about germline editing here, not gene therapy in children or adults where gene correction is a logical option.


Using PGD, anywhere from one to a few cells (depending on embryo stage) are plucked from early human embryos for genetic analysis. In this way, almost any genetic disease imaginable in principle and a huge number already in practice today can be detected. Right here in Davis and Sacramento, for example, the local fertility clinic called California IVF offers embryo screening for testing for a huge number of genetic diseases (see image).

Embryos lacking genetic disease can then be used for pregnancies. PGD can even be used to detect mutations in genes that do not always cause disease, but lead to disease predisposition such as BRCA1 mutations.

PGD also has the advantage of picking up other, random genetic problems.

This week has been abuzz with two papers related to the use of gene editing technology to prevent human genetic diseases. We saw the paper out of China on the use of CRISPR to genetically modify human embryos for a hypothetical future path to treat beta thalassemia. Then there was the Salk paper on the use of TALENs to prevent human mitochondrial disease.

The authors in both cases talked about potential future clinical applications of gene editing, but realistically why go that route?

If you think about it, as awesome as CRISPR-Cas9 is as a tool it seems like it would nearly always be far riskier and less effective than PGD for clinical applications. Same for use of TALENs for gene editing. PGD would win out as the choice by a mile.

Sure, PGD is not perfect.

It does not always work and some biopsied embryos fail due to the cell(s) being plucked off. There are also ethical concerns over the use of PGD for sex selection or potentially in ways that are eugenic.

Still it’s a generally safe and effective technology.

In fact it works for the diseases focused on in this week’s two gene editing papers: beta thalassemia and mitochondrial diseases.

If given all the facts, why would parents who are genetic disease carriers pick gene editing over PGD?

Perhaps if both parents-to-be were carriers of mutations? Then it would be only a rare instance that PGD could effectively find an embryo lacking a mutation so instead try gene editing? Seems like some pretty unlikely scenarios would have to be invoked.

And even then, it still would come back to PGD even if one chose a gene editing route because you would need to do PGD in order to validate that you achieved the mutation correction and hopefully there was no off-target activity in the embryos.

In the end, even in a hypothetical future scenario with an essentially perfectly accurate gene editing technology, going with PGD instead is going to be the wiser choice for parents and doctors almost every time.

Why is almost nobody mentioning PGD?

Neither the Baltimore, et al. nor Lanphier, et al. commentary pieces on germline editing mentioned PGD. Also, one of the top reviews on the potential therapeutic use of gene editing never mentioned PGD even once either. In my own ABCD plan for managing human germline editing, admittedly I also didn’t mention PGD. I should have.

The reality of PGD as a powerful, more often preferable option for prevention of human genetic disease needs to be an integral part of the therapeutic gene editing discussion today. Its inclusion in the dialogue would also further temper imprudent consideration of rapid clinical use of CRISPR or other gene editing technologies in the germline in humans.

Update: Hank Greely rightly pointed out in the comments that his recent blog post did mention the important element of PGD in the discussions. Hat tip to him.

%d bloggers like this: