“[...] we might anticipate the in vitro culture of germ cells and the direct control of nucleotide sequences in human chromosomes, coupled with recognition, selection, and integration of the desired genes (1).”
It was 1963 when Joshua Lederberg, one of the finest minds to grace American science (and a Nobel prize awardee for the discovery of bacterial conjugation), wrote those words in Man and His Future.
We can only speculate as to the functionality Lederberg envisioned, but it is likely that he had in mind what we would today call “word processing” – a system in which we replace one letter, word, or paragraph with another using simple commands such as “cut and paste.”
Transmuted to the genome editing arena, Lederberg’s construct would have permitted the substitution of one base (or gene) for another, using commands such as “delete,” which would give rise to a knockout, or “delete and insert,” which would lead to a knockin. The CRISPR-Cas9 endonuclease fits this bill perfectly. What sets CRISPR-Cas9 apart from its predecessors is its supreme targetability, fidelity, malleability, and versatility (2) – and that brings us to remedial editing of the human germline genome.
Genome Mapping Technology Case Study
Frances High explains how she used optical genome mapping to analyze structural variations in a large cohort of patients with congenital diaphragmatic hernia.
There are some basic questions we must ask ourselves when discussing such a therapy. For example, what is the objective of remedial human germline editing? Simply put, it is to prevent disabling and life-truncating heritable monogenic maladies – although there are formidable philosophical questions as to whether this is achieved by correction or substitution (in other words, is the pre- and post-edited embryo the “same person”). The deepest promise of this technology is transitioning from chance to choice – a lofty goal which, if taken to its logical conclusion, would rid humanity of the so-called “monogenic scourge.”
But what universe do we envision ourselves occupying with this new technology? Aside from the moral imperative of human germline editing, would we want to tackle the over 10,000 human monogenic disorders that are currently listed in Online Mendelian Inheritance in Man (3)? Indeed, we would be well-advised to assume a more focused approach, beginning with edit-suitable maladies for which peri- or postnatal medical therapy is infeasible, those for which peri- or postnatal somatic editing is ineffective, or those for which preimplantation genetic diagnosis is either associated with a rate-limited embryo complement or of no use at all. Preference should also be afforded to genes or alleles that are highly penetrant, ideally singular and, of course, CRISPR-accessible. It is worth emphasizing that we are discussing the desirability of this treatment for terrible monogenic diseases only, because bodies like the National Academies are appropriately wary of its extension to perfectionistic human enhancement (4).
The final question we should pose concerns the present state of remedial human germline editing. The simple answer is “nascent” – or, as the title would suggest, so near and yet so far. Much remains to be optimized in the process of gene editing – efficiency, specificity, and uniformity being top of the list (5). Once we overcome these technical challenges, safety and efficacy will be assured. Then – and only then – will remedial human germline editing become a reality in the service of the Hippocratic ideal.
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References
- J Lederberg, Man and His Future, 255. Little, Brown: 1963.
- M Jinek et al., Science, 337, 816 (2012). PMID: 22745249.
- Online Mendelian Inheritance in Man. Available at: https://bit.ly/362acBa.
- National Academies of Sciences, Engineering, and Medicine, “Human genome editing: science, ethics, and governance” (2017). Available at: https://bit.ly/2UYYGjK.
- MV Zuccaro et al., Cell, [Online ahead of print] (2020). PMID: 33125898.
