This editorial appears in the March 2025 issue of the American Journal of Bioethics.
Heritable monogenic maladies, the byproduct of single gene mutations, comprise a broad range of over 10,000 inborn afflictions. Some of the more common monogenic disorders in question include Cystic Fibrosis, Tay-Sachs disease, and Sickle Cell Disease. A substantial contingent of subjects is inevitably affected worldwide. Lifelong incapacitating morbidity is all too frequently a common outcome. Heavy loss of life often follows. Effective palliation, let alone cure, remain distant goals in many of the cases in question. In the eyes of many, the universe of congenital monogenic disorders is rife for transformation by remedial germline editing of the human embryo at or around the time of In Vitro Fertilization (IVF). Failure to proceed along these lines once procedural safety has been established, is to forego an opportunity to tackle the global burden of genetic disease. A report of the Nuffield Council on Bioethics on the subject put it plainly when stating that “the desire of people…to secure…the welfare of their children by using genome editing to influence their inherited characteristics gave rise to a morally powerful claim”. Stated differently, the replacement of a mutant gene with its wild-type counterpart, can and should be seen as beneficent, and thus, as equivalent to other “morally permissible” or “morally imperative” health-restoring interventions on the part of the healing profession. In this Commentary we advance the notion that Hippocratic beneficence comprises the ethical grounding for the all-important mission of remedial germline editing and the profound salutary future effects thereof.
It was the Nobel Prize-winning discovery of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 that saw to it that remedial germline editing could, in time, be finally realized. Though hardly infallible at this time, remedial germline editing of the human embryo is being continuously refined with an eye toward reversing monogenic afflictions. “Prime editing” is a case in point by dint of its potential to “search-and-replace” and thereby address the lion share of the genetic variants associated with human disease. Powerful and precise, “Prime Editing” enables targeted genomic insertions and deletions absent the generation of a double-strand DNA break. Similar plaudits apply to the near-PAM (protospacer-adjacent motif)-less CRISPR-Cas9 variants, all-purpose base editors, as well as to Cas transposons and Cre recombinases. Nothing short of flawless editing efficiency, specificity, and uniformity will do if credible clinical trials with safety and efficacy in mind are to follow.
The precept of beneficence in biomedical ethics is all but a given in that medicine, by its very nature, constitutes a normative benevolent undertaking. The very core of the Hippocratic “Primum Non-Nocere” (first do no harm) pledge all but assures that practitioners of the medical art will strive to secure a favorable balance of health while avoiding, to the extent possible, unintentionally exacted harms. As referred to herein, Hippocratic beneficence draws on the reality that medicine, at its core, is a beneficent pursuit intent on promoting the “good” of others absent the infliction of harm.
The notion of germline remediation as a byproduct of Hippocratic beneficence is hardly a novel one. Scholarly contributions spanning the latter part of the last century and its present day counterpart, attest to this moral therapeutic imperative of the medical profession. Pioneering biologist Robert L. Sinsheimer came out in strong support of “designed genetic changes” with an eye toward mending the woes of diabetes.Nobel Laureate Joshua Lederberg, for his part, couched the “amelioration of genetic defect” by “genetic engineering” as tantamount to “humane containment”. Similar sentiments were articulated by Stanfield Rogers of the Oak Ridge National Laboratory in whose view gene therapy comprised “a potentially invaluable aid to medicine and mankind”. Yet others, such as Nicholas M. L. Wade, characterized “genetic engineering” as a “beneficent technology” and “human germ-line therapy” as a prima facie “moral obligation of the medical profession”.
More recent articulation of the imperative of Hippocratic beneficence was offered by John Morley Harris who laid claim to the view that remedial germline editing is all about lightening the “burden of human existence”. Julian Savulescu, for his part, concluded that the “moral case in favour of pursuing germline gene editing” is “morally permissible and indeed morally desirable”. Bryan Cwik, taking stock of the state of the art as it stood in 2020, made it plain that “clinical utility” and “clinical justification” of germline gene editing is to be supported in that significant benefits are bound to be accrued. Yet others, such as G. Owen Schaefer, framed their support for heritable genome modification in purely utilitarian terms intent on “life-saving” and the institution of “healthy new lives”.
Proponents of remedial germline editing make it plain that amended gene mutations are hardly limited to the index case, but, inevitably, also apply to his/her progeny for generations to come. Stated differently, remedial germline editing is in a position to interrupt, in perpetuity, long-standing chains of heritable familial afflictions. It is for these reasons that future remedial germline editing of monogenic afflictions can and should be seen for what it is, namely, an act of Hippocratic beneficence. In its ultimate expression, Hippocratic beneficence is all about upholding the best interests of the patient under one’s care. Viewed in this light, Hippocratic beneficence is as relevant today as it was in times long gone by. In other words, Hippocratic beneficence was and remains a central pillar of the ethical and moral values of contemporary medicine. Its application to the imperative of remedial germline editing reflects the continuity of a value chain that must not be interrupted.
At the time of this writing, the implementation of the yet-to-be perfected remedial editing of affected human embryos is prohibited in the European Union, the United Kingdom, and the United States. Recent efforts on the part of a “citizens jury” to persuade the British Parliament to liberalize the extant law fell short. In standing its ground, the British Parliament drew heavily on Reports of the International Commission on the Clinical Use of Human Germline Genome Editing and of the World Health Organization. It follows that not until such time that remedial germline editing is deemed safe beyond any reasonable doubt, will extant laws be revisited. Then, and only then, can one assume that remedial germline editing has “arrived” replete with the inherent Hippocratic beneficence thereof. It was poet and novelist Victor-Marie Hugo who said it all when noting that “There is nothing more powerful than an idea whose time has come.”
Disclosure Statement
Professors Adashi declares no conflict of interest. Professor Cohen is a member of the ethics advisory board for Illumina and the Bayer Bioethics Council. He was also compensated for speaking at events organized by Philips with the Washington Post, attending the Transformational Therapeutics Leadership Forum organized by Galen Atlantica, and retained as an expert witness in health privacy lawsuits.