Helen C. O’Neill has explored how the global reaction to the birth of genome-edited twins in 2018 echoed the condemnation surrounding the first successful use of in-vitro fertilisation (IVF) in 1978. Now regarded as a huge clinical success which has benefitted an estimated 16 million parents, at the time the development not only sparked moral outrage but led to political and legislative constraints.

Whilst many celebrated the birth of Louise Joy Brown, the first IVF baby, the news spurred the US to ban federal funding of research on human embryos, and the procedures remain illegal in research laboratories to this day. It’s argued that legislative restriction on human embryo and oocyte studies have impeded a deeper medical understanding of the adverse events that may affect implantation. For example, patients undergoing IVF may be presented with numerous assisted reproductive treatments purportedly increasing the chances of pregnancy. Such commercialised “IVF add-ons” often come at high costs without clinical evidence of validity. Additionally, long-term studies of children born through IVF have historically been scarce and inconsistent in their data collection. This has meant that potential genetic predispositions, such as increased body fat composition and blood pressure, as well as congenital abnormalities long associated with IVF births, lack proof of causality.

Dr O’Neill does not dispute that He Jiankiu’s case of clandestine editing of human embryos was both premature and morally reprehensible. However, she argues that the calls for a global moratorium on the use of CRISPR for germline genome editing could also be considered unethical.

Altering inheritance

The primary argument against germline editing is that it alters the genes inherited by subsequent generations, but Dr O’Neill argues that it is already commonplace in clinics today. Preimplantation genetic testing (PGT) for karyotype profiles has been used prior to IVF implantation for almost 30 years. By preferentially selecting embryos for implantation and destroying those which may carry a genetic disorder we already rewrite natural familial inheritance.

With PGT mutated embryos are automatically discarded, whereas CRISPR could correct mutations to increase the number of viable embryos for implantation. Moreover, in instances where all embryos in a given cycle are destined to develop with severe or lethal mutations, CRISPR could bring success for otherwise doomed IVF treatments.

Weighing it up: Natural inheritance v human suffering

Dystopian prophecies of a genetically engineered superior race that would forever cement the chasm between rich and poor still dominate the narrative around using CRISPR in humans. More rational opponents cite the risks of introducing new or unknown mutations into genetic code to be inherited by subsequent generations. Dr O’Neill, however, highlights the consequences of leaving certain family lines untouched. The burden of heritable disease in terms of disability, life expectancy, quality of life and somewhat callously financially, mean that it’s unjust to simply blanket ban a potential alternative.

For example, genetic screening programs offered to couples in hot-spot areas of carrier frequency of monogenic disorders have had huge success in alleviating regional disease burdens. Carried out since the 1970s these programs have altered the course of natural evolution, but few would dispute their benefits in preventing heritable disease transmission.

Mutations: A fact of life

Mutations are as inevitable as death and taxes. Whilst age is considered one of the largest factors in de-novo mutation generation, it appears that these are inherited primarily from the paternal line. Thus, the paternal age of conception predominantly determines the mutation frequency inherited by children. Whereas advanced maternal age is not associated with mutagenic allele frequency but (often more devasting) chromosomal abnormalities. The risk of aneuploidy, where cells don’t have a 46-set of chromosomes, rises steadily in mothers over the age of 26. Although embryos are screened for aneuploidy prior to implantation, with so many other factors simultaneously being screened the probability of having enough embryos remaining to allow for 50% rate of blastocyte development in-vitro are often fairly low.

Despite the treatment being used routinely for over 40 years now, it’s not abundantly clear if, or how often, IVF may introduce genomic alternations or off-target affects in embryos. Likewise, we are often unable to scrutinise changes produced through natural cellular processes including recombination and aging. So, is it right morally to delay using CRISPR to try and prevent multi-generational suffering, simply because it carries flaws, as nature and technology both innately do? As Dr O’Neill asks; “when will good ever be good enough?”