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.
I find it difficult to understand why somethings are prohibited and some others are not. I’m doing a presentation for a labmeeting right now about all of these discussions. What comes to my mind is: why isn’t PGD a concern and genome editing is? Why is it ok to store and throw away embryos after a certain amount of time and there are so many discussion about using those same embryos for research? (I’m from Brazil). For me, PGD is a nice thing but can be used for eugenic purposes as well. What’s the difference on ethical concerns for you in this case Paul? Would it be that genome editing adds new genes? When you do PGD and only chose those that don’t have the disease you´re doing the same thing as PGD…Is the concern be related to “improving” natural genes?
@Natassia,
PGD is a concern. It can be misused and as you said it definitely has the potential for use in Eugenics kind of ways. In a comparison between PGD versus human genetic modification, I guess one might say that PGD seems far safer at least.
Paul
I agree. But I believe that it´s genetic human breeding… it´s not GMO but it´s what agronomists do to plants in other to select traits…I’m not sure if I’m favor or against it, but for me, is a concern as well. Thanks!
Well that is a difficult question to answer given that there aren’t that many proven function enhancing alleles out there (at least too my layman’s knowledge). But surely someone must be considering using CRISPR to remove the CCR5 gene and confer HIV resistance at the germline level? PCSK9 could be another possibility.
PGD only allows for the selection of embryos without negative genes/alleles. CRISPR can add in alleles not in the parents gene pool.
Hi Jim,
That’s right re: PGD only selection against undesired genetic states. What kind of gene would you want to therapeutically add in via CRISPR to patients?
Paul
Hank: This is an excellent point. I have now included an update in the post in this regard and linked to your post.
Cheers,
Paul
My first post on the topic does talk about PGD as an alternative and discusses the very few situations where CRISPR modification might be necessary to two people having child without a specific known genetic disease. http://blogs.law.stanford.edu/lawandbiosciences/2015/04/04/of-science-crispr-cas9-and-asilomar/ (Go about 60% down the long post.)
Personally, I think the even bigger blind spot is the non-human uses. I’m a GM crops fan, but a fan of regulated GM organisms, not of unregulated genomic modification of the biosphere.
Hi Paul
You’re right – it’s a very good observation and well worth addressing given the latest IVF technology. I’ve posted on the PGD topic quiet often, given a biospied pre-embryo has the potential to yield viability data & patient specific pure ES cells for medical interventional use without immune rejection.
The process of pre-embryo selection is very important to best-effort birth outcomes and adds the necessary filter for possible issues for parents. This is here and now technology, as you point out. Success ratios vary depending on many factors in the IVF process – not just biopsy techniques & their timings. In addition, which many seem to overlook, is nature’s own system which even in normal reproduction, with all things looking good, doesn’t guarantee success at all. It hit and miss at best.
If parents going through IVF use PGD as a recommended medical procedure there might well be significantly reduced cases of elective abortions for reasons of mutated genes. That I believe would help considerably and perhaps all stakeholders can get behind that.
On the issue of increasing the success ratios of IVF pre-embryo selection that too can be improved as a result of PGD, as genetically compromised & non-viable implantations would be avoided. Perhaps it would even reduce the need to create as many fertilized pre-embryos, as they can be screened and not implanted in multiples to raise success ratios… Knowing what it’s like to be a parent of a single and twins I would say it’s easier to have one at a time!!
If as you say it’s not possible to screen for a viable pre-embryo due to parental mutation loads, or the extent to which it would be necessary to pressure the IVF process to produce a viable option, then perhaps there is indeed a case for alternatives. If you take the concept further the idea that you can assist reproduction via IVF opens many possibilities to add technology to the process.
My question on this is related to gene editing later in the cell division / fetal / post-birth cycle. If PGD was integrated in the IVF process wouldn’t it be possible to identify cellular system targets for later intervention? This of course wouldn’t be germline editing but if the targets have known solution options then the development course of fertility could go ahead in those cases where there is an proven solution and then interveen safely and effectively later down the development path to correct any specific problems. This of course would be in only those cases where there is no fertility alternative. Some would argue perhaps that it would be unethical to attempt implantation with a known mutated pre-embryo, perhaps… but I suppose all of us started out with some errors in our code, it depends on the error I guess & solution effectiveness… Does it defeat the purpose of gene editing if you have to do that again & again given the same problems will surface in the next gen cycles. Yes, but by then we should have mastered the art and allowed for a step wise introduction of the technology into human practice, which is always preferable.
I’d say Basic Research, IVF & PGD are fundamental to this conversation in so many ways…
Thanks for bringing the issue up.
Cheers
PS – I had added a comment on PGD in your Blog: “Proposed Moratorium on Genetic Modification of Human Germ Cells” as below. (https://www.ipscell.com/2015/03/pausehumangmo/#comments)
“Important issue not discussed in comments, as far as I could determine, which Dr George Church touched on is the possible reduction of IVF failures & parental hard choices when dealing with genetic issues.
In addition, and perhaps the most divisive & unspoken issue in the room, being the potential resolution to the need to create millions of extra supernumerary pre-embryos…..
Not the topic of gene editing of Sperm or Egg but is a PGD fix good 4 Life!?
Embryo Therapy in Patent Law is ok btw…
A step in the right direction perhaps?
Cheers”
I don’t disagree that PGD is by far the preferred method of identifying and implanting disease-free embryos. However, it does not slow down the race to go where no man/woman has gone before – slipping and sliding the whole way.