JAMA Forum: Heritable Genome Editing: Edited Eggs and Sperm to the Rescue?

By Eli Adashi, MD, MS, and I. Glenn Cohen, JD

“[We] might anticipate the in vitro culture of germ cells … coupled with recognition, selection and integration of the desired genes…”  Nobel Laureate Joshua Lederberg, PhD (1963)

Heritable genome editing is widely predicted to render inborn afflictions a thing of the past. Topping the list of edit-worthy maladies are single-gene disorders for which preimplantation genetic diagnosis is unworkable. In addition, an insufficient number of viable embryos without the disease mutation is an important limitation in preimplantation genetic diagnosis, and in such cases, heritable genome editing might offer an alternative strategy.

Constraints along these lines have frequently undermined some families’ attempts to have a baby—a “savior sibling”—who could serve as a stem cell donor to a sick older sibling who might benefit.  Heritable genome editing could also be brought to bear on disease-predisposing gene variants, such as a variant of the APOE gene that contributes to Alzheimer disease risk; a variant of the LPA gene that contributes to atherosclerotic cardiovascular disease; a variant of the MYPBC3 gene that causes hypertrophic cardiomyopathy; and variants in BRCA genes that increase breast and ovarian cancer risk. Currently, the focus of preclinical research, with safety and efficacy in mind, heritable genome editing remains years away from the clinic.

Preclinical research efforts to replace mutant alleles with wild-type counterparts have thus far been limited to human embryos. Such efforts have formidable technical challenges, including  introduction of unintended genomic insertions, deletions, and rearrangements, which cannot be tolerated in the clinical context. Nothing less than unyielding editing precision is required to preclude cross-generational harm. An additional challenge to editing the human embryo is the uniformity imperative—ensuring that all the embryo’s cells are appropriately edited. Failure to edit the entire cellular complement of the embryo to exclude mosaicism (in this case, a mixture of edited and unedited cells) is clinically inviable. One final challenge of note is the required validation of edited embryos as transfer eligible. Impeccable editing fidelity as well as uniformity must be documented prior to embryo transfer. At present, however, such reliable assessment is technologically infeasible, and accomplishing this goal may require new technologies.

Apart and distinct from the technical hurdles, editing the genome of the human embryo is also subject to political and doctrinal opposition, which likely gave rise to the statutory federal moratorium now in effect. Under the Consolidated Appropriation Act of 2016, the moratorium prohibits the US Food and Drug Administration from addressing research “in which a human embryo is intentionally created or modified to include heritable genetic modification.” Expounding on the bill in question, Rep Harold D. Rogers (R, Kentucky) noted that it “preserves the sanctity of life,” adding “new provisions prohibiting genetic editing of human embryos.” Rep Robert B. Aderholt (R, Alabama), said that “prohibition on gene editing of human embryos … is a tremendous victory for those who are concerned about life.” Given that the prospect of editing of the human embryo genome is caught up in the debate over abortion, proponents of gene editing will be hard-pressed to secure the broad political support required for its actualization.  

In light of such technical, political, as well as doctrinal challenges, genomic editing in the human embryo thus faces an uphill struggle, and it is against this backdrop that the possibility of editing human eggs or sperm first came to the fore. Given that the editing of eggs and sperm is not mentioned in the statutory federal moratorium, limited political and doctrinal opposition to this approach may be assumed. An additional advantage of this tack is that it avoids the possibility embryonic mosaicism. The feasibility of assessing the quality of the editing process constitutes yet another upside.

During the 2015 International Summit on Human Gene Editing, scientists reported that editing of mouse spermatogonial stem cells corrected a cataract-causing mutation. Further progress, however, has been sparse. Held back by the requisite testicular transplanting of edited spermatogonial stem cells, only a limited body of experimental work followed. There has been a comparably modest body of work dedicated to the editing of maturing eggs.     

The successful editing of human gametes, it would seem, may have to await the materialization of a rapidly evolving scientific field, in vitro gametogenesis (IVG), which is poised to convert somatic cells (such as skin) to induced pluripotent stem cells, and thereupon to mature eggs or sperm. Editing of IVG-derived egg or sperm precursors and their validation by whole-genome sequencing should prove eminently feasible. Correctly edited clones of eggs or sperm could then be selected for eventual use during in vitro fertilization.

At this point, scientists have generated human primordial germ cell-like cells and of oogonia in vitro. However, the in vitro reconstitution of the entire cycle of the human germline remains to be accomplished. Given the  anticipated advantages of editing the genome of IVG-generated human eggs or sperm, this innovation may well be worth the wait.


About the authors:

Eli Y. Adashi, MD, MS, is a professor of Medical Science and the former dean of Medicine and Biological Sciences at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. (Image: Brown University)




I. Glenn Cohen, JD, is the James A. Attwood and Leslie Williams professor of Law and director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, Cambridge, Massachusetts. (Image: Martha Stewart)



About The JAMA Forum: JAMA has assembled a team of leading scholars, including health economists, health policy experts, and legal scholars, to provide expert commentary and insight into news that involves the intersection of health policy and politics, economics, and the law. Each JAMA Forum entry expresses the opinions of the author but does not necessarily reflect the views or opinions of JAMA, the editorial staff, or the American Medical Association. More information is available here and here.

Categories: Genetic Counseling/Testing/Therapy, Genetic Disorders, Health Policy, The JAMA Forum

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