Abstract
In the fall of 2018 Jiankui He shocked the international community with the following announcement: two female babies, “Lulu” and “Nana,” whose germlines had been modified by the cutting edge, yet profoundly unsafe CRISPR-Cas9 technology had been born. This event galvanized policy makers and scientists to advocate for more explicit and firm regulation of human germline gene editing (GGE). Recent policy proposals attempt to integrate safety considerations and public input to identify specific types of diseases that may be safe targets for human GGE (Sarkar forthcoming; Guttinger. 2019. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy; Lander et al., 2019). This paper argues these policy proposals are inadequate in different ways. While Sarkar (forthcoming) intends to incorporate input from the disability community for the purpose of deciding the value of human GGE, I argue that his strategy for doing so is inadequate. I’ll argue that an iterative, deliberative process is a more appropriate framework for allowing the disability community to inform policy on human GGE. Further policy proposals have been framed in terms of monogenetic or single-gene diseases (Guttinger. 2019. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy. “Editing the Reactive Genome: Towards Postgenomic Ethics of Germline Editing.” Journal of Applied Philosophy; Lander et al., 2019). I argue that this way of conceptualizing disease is not what matters for deciding which disorders are viable candidates for human GGE. Instead, what matters is that (1) the disease in question must have (among its set of causes) genes that have a high degree of causal control with respect to the disease and (2) alternative nucleic acid sequences variants that are likely to produce traits deemed desirable must be identified. Previous policy proposals leave (2) unspecified. What conditions must be met for satisfying condition (2) should not be left to individual scientists to decide for themselves. The present proposal offers some guidance on this issue.
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Notes
I am grateful to a blind reviewer for this observation.
Jiankui He’s use of CRISPR-Cas9 to target the CCR5 genes in “Lulu” and “Nana” was performed at a time before the scientific community had proper understanding and control of the technology’s off-target effects. This was a violation of the temporary ban.
Whether it is morally permissible to destroy human embryos for research purposes is a topic that will not be explored in this paper. With that said, a number of countries abide by the 14-day rule, which states that human embryos may not be kept alive beyond the 14th day after fertilization. Recently there have been calls to extend the number of days research on embryos is permitted (Appleby et al. 2018).
Further developments in genome sequencing methods are also necessary for this sort of information to be possible.
I am grateful to a blind referee for suggesting an ethical and conceptual contrast between human GGE and somatic stem cell gene therapy. The problem of unintended consequences is a more serious concern in the case of human GGE than in somatic cell gene therapy. This is due to the former introducing genomic modifications that will be inherited by all the cells of an individual, which in turn will influence development over the course of an individual’s lifetime. The problem of unintended consequences in the case of somatic stem cell therapy will be more contained to specific cell lineages and developmental stages and, thus, will be less serious than in the case of human GGE.
A common concern expressed about human germline gene editing is its impact on human evolution (Doudna et al. 2017). The social, political, and epistemic considerations that are relevant for the evolutionary impact human germline gene editing might have on human populations deserves its own treatment. In this paper, the focus concerns the social, political, and epistemic considerations that are relevant for clinical trials with human germline gene editing. This is a noteworthy distinction as gene editing technologies alone are not sufficient for influencing human populations on an evolutionary scale. Further technological advancements (such as a method for editing the germlines of early-stage embryos in vivo) are likely to be needed for this sort of effect.
Indeed, there is a burgeoning and unregulated market for implementing CRISPR technologies in fertility clinics in which a number of scientists are financially invested (Kirksey 2020).
Broad societal consensus was originally one of two requirements for the responsible use of human germline gene editing included in the statement issued by the first International Summit on Human Gene Editing in 2015; however, this requirement has since been removed from more recent statements issued by the International Summit. (For criticism of this revision see Baylis 2019).
This proposal is compatible with other communities from the public having a say in deciding the value of human germline gene editing.
The view I am proposing is similar to the idea of a critical standpoint found in feminist epistemology (Wylie 2012) and Rolin’s (2015) concept of a scientific/intellectual movement.
This characterization of ableism applies Alison Jaggar’s characterization of sexism to the issue of disability (Jaggar, 2008, pp. vii).
The process outlined by Lander et al. (2019) is a more adequate model for enabling representatives of the public to inform the value judgments of human GGE; however, as I’ll argue in Sect. 5 their proposal falls short in other ways.
Incorporating the perspectives of disabled individuals – especially individuals with cognitive impairments – requires its own theoretical framework as such individuals may not be able to communicate their perspective in a standard format (see Warren 2016). For this reason, it may be that caregivers and allies also be included as representatives of disabled communities.
In fact, study of the CCR5-Δ32 mutation marked the beginning of this sort of integrative research program (see Jackson, 2015).
The number of alternative variants will depend on whether one is removing a functional element entirely or simply replacing a deleterious functional element with a different one. Nevertheless, a sequence that is n-nucleotide bases long, will have ~ 4n number of possible alternative sequences from which scientists may choose. That is, for each nucleotide base in a sequence, there are four possibilities (adenine, thymine, guanine, cytosine). For an average protein coding gene, the number of alternative possible sequences is ~ 4900.
This framework only works for genetic variants present in human populations. Whether it is safe to introduce variants from non-human species is a question that raises its own unique set of epistemic challenges and, thus, requires a separate treatment.
Theoretical knowledge of how a gene edit is likely to influence health and development may (in some cases) be more justified than theoretical knowledge concerning how a novel pharmaceutical will influence humans. This is due to conditions (1) and (2) requiring scientists limit their theories and predictions to genetic determinants actually present in human populations. Consequently, researchers may have access to more evidence as to the outcomes of germline edits than researchers may have for a genuinely novel pharmaceutical drug.
Sarkar (forthcoming) is sympathetic to the disability community having a say in human GGE policy and Lander et al. (2019) also advocate for public input on the matter. However, both sets of authors advocate for the restriction of human GGE to monogenetic diseases alone independent of what the disability community (or broader public) might have to say.
Even though complex diseases may be candidates for human germline gene editing, there are pragmatic reasons to limit the number of genome edits to as few as possible. It is challenging enough to successfully introduce a single edit to germline cells so that the change is inherited by all cells of the organism. Performing multiple edits at this stage risks mosaic effects – an effect where only some cell lineages carry a desired edit and others don’t – as well as premature cell death and chromosomal rearrangement (Chari et al. 2017).
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I have Anya Plutynski, Lauren Ross, Zina Ward, Katie Kendig, and Stephan Guttinger to thank for helpful comments on earlier drafts of this paper.
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Baxter, J. When is it Safe to Edit the Human Germline?. Sci Eng Ethics 27, 43 (2021). https://doi.org/10.1007/s11948-021-00320-x
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DOI: https://doi.org/10.1007/s11948-021-00320-x