Counterpoints to Lovell-Badge & Daley’s CRISPR baby rationales

Two prominent scientists, Robin Lovell-Badge and George Daley, have been amongst the most outspoken proponents of leaving the door open to heritable human genetic modification via CRISPR. While they each have articulated their reasons in somewhat different ways at times, their core reasons arguing in favor of future heritable CRISPR appear largely the same.

In this post I tackle each of these arguments in favor of leaving the door open to “CRISPR babies” with science-based counterarguments. I also raise larger risks to going down this path including social justice issues and unintentionally paving the road to trait enhancement. There may also be one insurmountable technological hurdle here too in terms of safety.

This past week Lovell-Badge outlined the main reasons he thinks producing CRISPR babies (and hence people bearing heritable genetic modifications) may be beneficial. His position was included in a very interesting piece where he systematically goes through the unfolding of the He Jiankui CRISPR baby situation.

Science journalist Antonio Regalado helpfully annotated the piece (including his own views) with red text in the margin, highlighting some of the key Lovell-Badge arguments to leave the door open to human CRISPR (see screenshot from Twitter.) Below I’ve concisely summarized these points and my counter arguments to Lovell-Badge’s. A HT to Antonio for his thoughtful take on this, with which I generally agree.

1. Argument #1. If one or especially both parents are homozygous for serious disease-causing mutations then PGD won’t work. Counterargument. It is true that under those extremely rare and sometimes hypothetical circumstances that embryo screening methods such as PGD by itself would be impossible or close to impossible to use to yield a healthy new baby. However, in my view, CRISPR gene editing is likely to be impossible or close to impossible in that context too. Why? If both parents-to-be are homozygous for disease-causing mutations that means all embryos will be homozygous mutant too so you’d then have the extremely tough hurdle of CRISPR’ing both alleles in each embryo somehow back to WT. Also, according to Shoukhrat Mitalipov lab’s work, early human embryos often may not utilize exogenously introduced homology-directed repair templates meaning repair of homozygous mutations in human embryos may be impossible in some cases.  Also keep in mind that you must be able to do PGD on your CRISPR’d human embryos or what you are doing won’t be safe because you’d be “flying blind.” Finally, the potential parents-to-be who have disease-causing mutations may produce embryos that may already much less viable to start with, interfering with gene editing and PGD. If only one parent has a homozygous or heterozygous mutation then PGD is almost always going to be a more effective and definitely safer option (more below).
2. Argument #2. We can give prospective parents who are mutation carriers more WT IVF embryos to try to use to make a healthy baby (or some say even to deal with infertility in a non-life threatening genetic disease context). Counterargument. I’d dispute the notion of needing to do CRISPR when only one parent carries a mutation because in that case PGD probably will work better. The notion that CRISPR’ing a mutation will safely and effectively give you significantly more WT embryos to work with for reproduction is unrealistic in my view at this point and for the foreseeable future given the state of the technology. Also, keeping it real, there may be an insurmountable hurdle here: is it really possible to rule out risky mosaicism in any specific CRISPR’d embryo without destroying the embryo? Not that I know of. Can someone resolve this roadblock? Finally, as to infertility, should we be promoting human genetic modification specifically to try to deal with just infertility itself outside the context of a life-threatening genetic disease? I’m skeptical that is a wise thing to start doing.
3. Argument #3. We’ll need heritable CRISPR of babies to make ‘savior siblings’. Counterargument. Savior siblings are children produced by parents mainly or only because they have a small chance of being useful in saving an already existing family member with a fatal illness such as a brother or sister who desperately needs a stem cell transplant, but there’s currently no identified living donor who’s a match. It’s true that there are cases where producing the needed savior sibling will only be potentially achievable via genetic modification of embryos with CRISPR, but this is a very ethically complex path to go down. Even conceiving non-gene-edited children for the sole reason to possibly serve as savior siblings is itself ethically complicated, although I personally can see circumstances where for I would definitely be supportive of that. However, throwing in genetic modification into this future hypothetical scenario makes things far thornier in my view. There would definitely be risks to the potential savior sibling and making a healthy savior sibling with CRISPR may be technologically nearly impossible in many cases.

There are some larger issues that make heritable human CRISPR very problematic.

Cost. At just a practical level, cost is going to be a major problem. Being able to safely and effectively use CRISPR to make children with beneficial genetic changes, assuming it’s possible and there is societal consensus in coming decades) will cost a fortune for each attempt. The price of PGD (embryo screening) is roughly $10K-$20K USD, but often way more, and this is already a barrier to families wanting to employ it to try to prevent transmission of genetic diseases. However, making CRISPR babies in the needed meticulous, regulatory-compliant manner could easily be about 100-times more expensive at millions of US dollars each. There are many problems associated with this kind of astronomical cost including social justice issues.

Enabling attempts at trait modification. Finally another bigger picture thing to contemplate is whether it is wise to heritably genetically modify a few children in the future with only hypothetical benefit to them, while at the same time you are likely enabling potentially broad use of CRISPR gene editing for attempts at other things that society is clearly against such as trait enhancement. He Jiankui’s misguided efforts are a perfect illustration that we cannot count on people being wise or even rational about the heritable use of CRISPR in humans.

Looking ahead. While I disagree with Lovell-Badge and Daley about heritable human genetic modification, it’s good to have healthy discussions and debates on this important issue. Unfortunately, recently the “big wig” meetings run by National Academies mostly seem to not include gene editing scientists or policy/ethics researchers who are more skeptical.

It’s unclear if the meeting organizers are truly open to other opinions any more (they sometimes seem to unfairly dismiss those who disagree with them as being motivated by ignorance, ideology or fear…or having watched too many sci-fi movies) or to pursuing societal consensus on the path forward.

Finally, I have yet to hear a strong argument against a temporary moratorium on implantation of CRISPR’d human embryos. It’s an imperfect step, but such a moratorium would do more good than harm.