Bioethics Forum Essay
Why Human Germline Editing Might Never Be Legal in the U.S.
A Russian scientist recently announced his intention to use the gene-editing tool CRISPR to edit and implant human embryos—a revelation that met with international outcry similar to the condemnation of the Chinese scientist He Jiankui last year when he announced that he had created the first gene-edited babies. Jiankui’s actions — deemed unethical for several reasons – led to a call for a moratorium on editing human germline cells (sperm, eggs, or embryos) to produce genetically modified babies.
Even the signatories of the moratorium, however, suggest that CRISPR might one day be safe enough for ethical, clinical use on the germline. What would it take for the first case of germline editing to proceed under applicable U.S. law and ethical standards?
Germline editing would be regulated as a gene therapy by the Food and Drug Administration. To comply with the relevant regulations, germline editing must undergo clinical testing to demonstrate safety and efficacy and win FDA approval before coming to market. Currently, federal law prevents the FDA from reviewing or approving any application involving manipulated human embryos. However, if and when this ban is lifted, the first case of germline editing would take place in the context of a clinical trial and therefore would be subject to the laws and ethical standards applicable to research.
Specifically, Subpart D of the Common Rule, which pertains to research involving children and is incorporated into FDA’s regulations, would probably apply to germline editing research. Under this provision, research that entails more than a minimal risk must provide a prospect of direct benefit to the child.
The Common Rule states that minimal risk means that “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests”—a conservative standard that germline editing, for several reasons, is unlikely to meet.
First, CRISPR research has revealed relatively high frequencies of off-target edits (meaning that an untargeted gene is edited) and mosaicism (not all cells of an embryo are successfully edited) with the potential for significant deleterious effects. Risk of such inaccuracies cannot be completely ruled out in any embryo intended for implantation. Because a cell must be removed from an embryo in order to be sequenced, only a subset of an embryo’s cells can be tested for off-target edits and mosaicism. It is therefore practically impossible to confirm that a child produced from germline editing will be free from the more than minimal risks associated with these inaccuracies.
Furthermore, given the nascence of CRISPR gene-editing combined with our relative lack of understanding of the complexities of the human genome, there may be other, yet-undiscovered, greater-than-minimal risks associated with germline editing. It’s unclear how animal and lab testing could successfully identify all such risks before human trials are initiated.
Even assuming that all the technical risks potentially associated with germline editing can be resolved, the technology must be performed in conjunction with IVF. IVF, however, carries some risks, including multiple births and other complications. Even though IVF is routinely carried out in a clinical setting, as a procedure, IVF was not subject to FDA’s clinical research requirements and related legal and ethical standards. However, in the context of germline editing research, the risks associated with IVF may alone be enough to surpass the minimal risk threshold of Subpart D.
Because germline editing arguably involves more than a minimal risk, any related research must provide the prospect of direct benefit to the child-to-be. If gene-editing were applied to an existing child with a severe genetic disease, such as Tay Sachs, then such research would provide the possibility of direct benefit to the child, such as relief from suffering associated with the disease.
With germline editing, however, no sick child exists. Instead, there are embryos of a certain genetic makeup that if implanted would cause the existence of a child with a genetic disease. No such child needs to exist, however, given the other options available to couples affected by genetic disease.
For example, the vast majority of couples affected by genetic disease can produce and selectively implant some amount of healthy embryos using IVF and preimplantation genetic diagnosis. The relatively few couples who cannot produce healthy embryos, however, still have other options. Specifically, they can 1) use gamete donation to create a healthy child that is their partial genetic relation; 2) adopt a child; 3) or choose not to become parents. The unique benefit of germline editing over these existing options is to provide such a couple with the ability to have a genetically related child they likely otherwise would not have had. This benefit accrues to the parents, not the child-to-be.
The more than minimal risk that germline editing presents to the child-to-be is not outweighed by a direct benefit as required by relevant law. Therefore, even putting aside the many other ethical concerns associated with germline editing, it’s unclear that it could proceed in the U.S. under current law—a fact conspicuously absent from the CRISPR debates.
Jennifer M. Gumer, JD, is an attorney and adjunct professor of bioethics at Columbia University and Loyola Marymount University. She was a visiting scholar at The Hastings Center in July.
My impression is that there are many procedures that can be done without FDA approval, since FDA approval is mainly required for a new product or treatment that one intends to *market*. I also wonder about the scope of FDA approval: has the FDA approved the embryo selection that is currently taking place? I don’t believe the FDA reviews abortion procedures. I appreciate the arguments that follow the initial assessment regarding FDA approval, but I am not convinced that FDA approval is necessarily pertinent for a procedure that would take place in a fertility clinic and would not be marketed.
I found this essay particularly intriguing given the recent overturning of Roe v. Wade and potential consequences of that ruling. The argument that germline gene editing benefits the parents, not the child-to-be given that no child yet exists could be challenged by arguments on when life is thought to begin. Is possible that some could argue that it would actually benefit a child rather than just an embryo to prevent a genetic disease, potentially outweighing the risks outlined in Subpart D? Or, if further restrictions on IVF are enforced, is the possibility of germline editing even more dismal than when this essay was originally published due to federal regulations?
While IVF was not subject to the FDA’s clinic research requirements, it is interesting to consider your argument that someone other than the child-to-be benefits from these technologies whether that be IVF with PGT or germline gene editing in the context of HLA typing for HSCT for a sibling. Germline editing could potentially be used for HLA typing in an embryo with the intention to create a well-matched donor sibling. If FDA regulation was enforced for clinical trials in this context, I doubt the benefits to the sibling would outweigh the risks to the child-to-be.
This article introduces a series of intriguing questions and raises significant issues surrounding germline editing that warrant thorough examination. While I generally acknowledge the merits of the arguments presented in this article, I seek to offer alternative viewpoints to foster a more comprehensive discussion.
First, the article asserts that the vast majority of couples affected by genetic diseases have the option of using in vitro fertilization (IVF) coupled with pre-implantation genetic diagnosis (PGD) to selectively produce a healthy embryo. A relatively small portion of couples who are unable to produce a healthy embryo through IVF and PGD, such as when one partner is homozygous for a dominant disease, may still opt for gamete donation to produce a healthy embryo with a partial genetic relation. However, one essential aspect not covered in this article is the rare scenario in which a couple, due to both individuals being homozygous for the same dominant disease, is incapable of producing a healthy, at least partially related child through IVF coupled with PGD or gamete donation. In these cases, germline editing emerges as a technology offering a unique benefit unmatched by existing biotechnologies. It can be argued that such instances represent an exceedingly small fraction of the population and thus seem to limit the practical applications of germline editing. Nevertheless, they do exist and deserve not to be overlooked. Consequently, further discussions are needed to analyze whether these exceptional couples should be afforded the same opportunities as others, allowing them to equally pursue the possibility of having a healthy, genetically related child.
Second, the article points out that germline editing using the CRISPR technology carries relatively high risks of off-target edits and mosaicism, potentially leading to deleterious effects. However, from a biological perspective, our DNA constantly undergoes random, naturally occurring mutations throughout our entire lives, which can pose a threat arguably greater than that posed by germline editing. As the American biochemist Jennifer Doudna, who received the Nobel Prize in Chemistry in 2020 for her co-discovery of the CRISPR gene editing technology, noted in her co-authored book A Crack in Creation, “Every person experiences roughly one million mutations throughout the body per second, and in a rapidly proliferating organ like the intestinal epithelium, nearly every single letter of the genome will have been mutated at least once in at least one cell by the time an individual turns sixty.” Thus, setting aside the additional risks associated with its conjunction with IVF, it is unclear whether the potential off-target edits and mosaicism resulting from germline editing alone can form a compelling argument against the legal use of this technology.
Third, the article further argues that due to the limitation of testing only a subset of an embryo’s cells for off-target edits and mosaicism, it is practically impossible to ensure that a child resulting from germline editing will be free from the risks of associated inaccuracies. However, research conducted in mice has demonstrated the possibility of growing eggs and sperm from stem cells in a laboratory setting and using them to establish pregnancies. With the rapid pace of scientific advancements in this field, it is plausible that this procedure may soon become applicable to humans, allowing us to edit primordial egg and sperm cells and perform pre-fertilization screening to eliminate off-target mutations altogether. Thus, as this technology continues to evolve, this argument presented in the article will likely warrant re-evaluation.
In summary, the article presents a range of thought-provoking arguments highlighting the challenges faced by germline editing in terms of legal acceptance in the U.S. However, these challenges do not inherently imply that germline editing should be unequivocally rejected for all time, particularly in light of the alternative perspectives proposed above. As the technology advances, it is imperative to maintain an ongoing open dialogue involving a diverse cohort of scientists, clinicians, bioethicists, government agencies, and the general public. This will ensure periodic re-evaluation of the ethical and practical dimensions of germline editing. More importantly, the alternative arguments presented above aim to promote a mindset of societal openness towards germline editing and an ability to adapt to new scientific possibilities. This includes a willingness to engage in constructive discussions and recommend pertinent policies where appropriate. In the words of the Nobel-winning scientist David Baltimore, “I fully agree—and the whole group of us involved in the summits agree—that we’re not ready to be doing germline modification of humans, if we ever are… But the important point is to be flexible going forward… With a science that’s moving forward as rapidly as this science is, you want to be able to adapt to new discoveries, new opportunities and new understandings.”