Inside a decade, the U.S. Food & Drug Administration (FDA) will approve clinical trials for the genomic modification of a viable human embryo in order to prevent disease.
That seems a real possibility in light of significant developments in policy and research this year. While such trials are currently barred in the United States by federal law, the prospect of future trials gained key support from the National Academies of Sciences, Engineering, and Medicine (NASEM) in a lengthy report published in February. Privately funded research is advancing at such a rate that it seems only a matter of time before a team is able to demonstrate an adequate degree of precision and safety in repairing an objectively harmful mutation in viable embryos. The next ten years may well bring our first foray into genomically modified humanity.
What is human germline modification?
Human germline modification (HGM) refers to the modification of DNA in human sex cells or, more commonly, in early-stage embryos. In both cases, molecular devices are used to add, edit, or remove DNA in the targeted cells, with the goal of propagating the change to all cells as the embryo divides and grows. This is distinct from gene therapy, which refers to the genetic modification of somatic cells in a living patient, often a specific type of cell that is functioning abnormally. Genome-editing techniques are often divided into groups based on the enzymes used. The most recently developed group, CRISPR/Cas9 and its variations, provides the cheapest, most efficient, and most customizable method yet, enabling, in principle, any arbitrary change at a known spot in the genome.
These techniques offer tremendous therapeutic potential. For example, researchers have identified many single-nucleotide polymorphisms (SNPs)—single DNA-letter variations—that cause or contribute to disease, and which could be targeted for repair with CRISPR/Cas9. However, with the ability to make precise alterations to our increasingly well-understood genome rightfully come concerns regarding its use for non-therapeutic, even nefarious, purposes, as well as questions about the moral implications of genome editing in any form.
Current law and recent developments
In the United States, clinical trials of HGM are effectively barred by a rider to the appropriations bill that Congress passed for fiscal year 2016. The rider’s provisions prevent the FDA from using appropriated funds to evaluate proposals for clinical investigations of any technique causing heritable genetic changes. By effecting a ban in this way, however, lawmakers must decide annually whether to extend it. Considering the pace of advancement in privately funded research, the annual expiration provides a useful mechanism for revisiting the question regularly.
The international scientific community seems to agree that it is premature to attempt modification in viable embryos intended for implantation and pregnancy. In early 2015, Chinese researchers became the first to use CRISPR/Cas9 in (non-viable) human embryos, sparking international concern. Later that year, NASEM co-hosted the International Summit on Human Gene Editing with the Chinese Academy of Sciences and the U.K.’s Royal Society in order to foster dialogue and collaboration. The official statement published at the close of the summit endorsed the idea of future use in a narrow range of cases, but only if certain conditions regarding safety, oversight, and social consensus are met.
The NASEM report published in February of this year further spurred research by reiterating conditional endorsement of clinical trials and providing a roadmap for institutional governance. In August, Nature published the first study in the U.S. of CRISPR/Cas9 use in human embryos, aimed at replacing a mutated gene linked to a potentially fatal heart condition. In October, researchers at MIT published their investigation into “base-editing,” whereby individual DNA base pairs are chemically converted without cutting the DNA strand itself. Their investigation converted A-T pairs to G-C pairs, the reverse of which, according to their study, accounts for half of all known disease-causing, single-base pair mutations. We are seeing the tip of an iceberg.
Future challenges and the road ahead
The technical capability seems inevitable. Research teams in the U.S., China, and elsewhere are actively refining the genomic engineering toolkit and pushing the boundaries on precision, efficiency, and overall safety. In addition, medical science, aided by ever-improving analytical tools, including artificial intelligence, will continue to expand our knowledge of the human genome, providing researchers a growing list of pathogenic mutations to target and a better understanding of the effects of doing so.
Social consensus is harder to predict, as commentators have pointed to many legitimate ethical concerns and thorny practical issues that could dissuade policymakers from wading into these murky waters. Can and should we limit use of HGM to disease prevention? How do we distinguish therapeutic applications from those that might be termed enhancement or cosmetic? Will disparate access to this technology exacerbate social inequality? Will it commodify human life or trigger renewed interest in eugenics?
There are also credible arguments that the combination of in vitro fertilization (IVF) and pre-implantation genetic diagnosis (PGD) is already adequate to screen for and prevent transmission of heritable diseases from parent to child, perhaps even superior in most cases. However, while HGM techniques may be unnecessary to prevent certain diseases for certain patients, the hypothetical parents’ genetic makeup may render the probability of producing an embryo lacking the harmful mutation too remote to be feasible, even if PGD were able to confirm its absence.
Such legitimate concerns notwithstanding, it is difficult to envision a future in which germline modification is entirely abandoned, if only because we know about it and have glimpsed its potential. History offers little support for the prospect of humankind, finding itself on the cusp of potentially transformative technological innovation, collectively backing away out of humility and caution. We’ve tamed fire. We’ve sailed across oceans and flown through skies. We’ve split the atom and left the planet. In all likelihood, we will eventually, though not without incident, engineer our genome.