When Perfection Causes Imperfection: A Potential Non-Genomic Complication Of Germline Editing

There is wide consensus that we should not only treat but also try to cure genetic conditions that cause profound suffering. CRISPR and related technologies have descended on us like a deus ex machina from the heavens and made it possible to “cure” genetic diseases through germline editing. Precision molecular microsurgery has stimulated provocative discussions about which diseases are serious, where we draw the line, the acceptance of people who are different in appearance and abilities, increasing the disparities between wealthy and poor, religious concerns, etc. I don’t have any helpful insights into these issues but I hope that vigorous debate continues and that if germline editing becomes a reality, we proceed veeerrrrrryyyyy slowly, cautiously, and incrementally.

The more ardent “germline utopians” envision a world where all fertilized embryos undergo germline editing to prevent the resulting offspring from developing genetic disorders. Of course, this will never happen universally. Even in a fantasy world of full acceptance of, and unrestricted access to, germline editing, pregnancies have a habit of, well, happening on their own. But for argument’s sake, let’s make the unlikely assumption that many parents will utilize germline editing to prevent their children from developing genetic conditions. Given that Western societies place great value on individual autonomy and considering the conditions that are currently screened for through prenatal diagnosis and carrier screening, it is likely that prospective parents would choose to “correct” traits ranging in severity from hearing loss to profound physical and developmental disorders, and all points in between. And to twist the complexity we might see the reverse scenario where deaf parents choose to “correct” a hearing-abled embryo. Should genetic enhancement – adding a few IQ points, tacking on centimeters of height, a slimmer habitus, Faye Dunaway zygomatics – become a reality then a goodly number of parents will take advantage of that as well (please I hope never because it will bring out the worst in us).

Of course, this model of genetic disease prevention depends on whether the technique actually works and that it is safe. There is reason to believe that germline editing and “correction” of genetic conditions are technically achievable. Safety, however, is more open to question. Off-target genetic effects, among other safety issues, could relegate germline editing to the What If category of debate.

But let’s posit a world where efficacy is proven and off-target effects are negligible. There would still be another safety issue, unrelated to genomics. Germline microsurgery requires in vitro fertilization/intracyoplasmic sperm injection (IVF/ICSI) in order to gain access to the gamete or the fertilized egg and to achieve a pregnancy. And therein lies the rub – IVF/ICSI is associated with a higher risk of complications in singleton and multiple gestations, such as prematurity, low birthweight, small for gestational age, perinatal mortality, and congenital anomalies. It reminds me of the introduction of a phenylalanine-restricted diet to reduce the impact of PKU that eventually created the phenomenon of maternal PKU, in which maternal hyperphenylalaninemia produced babies with microcephaly, heart defects, and intellectual disabilities. The attempt to cure one problem can create a whole new set of problems.

Now maybe the complications of IVF/ICSI are in part due to the underlying causes of the parental infertility, and thus fertile couples may have lower complication rates. Maybe. Perhaps IVF/ICSI will become safer. Perhaps. Still, it is likely that some parents will be willing to accept the risks of pregnancy complications in return for not having a child with Tay-Sachs disease or severe ichthyosis. But are the pregnancy risks worth it to prevent genetic hearing loss, increase a child’s IQ, or create a child with movie star beauty?

You might understandably say “My God, we finally have the chance to prevent serious genetic problems and improve people’s lives. How can we not take advantage of it? We are just trying to do good in a world full of suffering.” Indeed, the goal of reducing suffering is as old as the field of Medical Genetics. But when we march beneath the banners of Cure, Good Intentions, and Highly Ethical Motivations, and throw in an unhealthy dose of hubris, our enthusiasm may blind us to the harm that we might do. Perfection comes with a price.