Assisted Same-Sex Reproduction: The Promise of Haploid Stem Cells?

Same-sex couples, not unlike their heterosexual counterparts, would prefer having a genetically related child. However, assisted same-sex human reproduction has heretofore been deemed infeasible absent haploid cellular analogs of human gametes. The closest theoretical analog to assisted same-sex reproduction might have been nuclear transfer if and when applied to a prospective female couple. Recent developments, however, may have overcome the absence of haploid cellular analogs of human gametes through the derivation of haploid embryonic stem cells (hapESCs). Early reports of this feat spotlighted hapESCs from several mammalian species, including a nonhuman primate [1]. The generation of human parthenogenetic and androgenetic hapESCs followed suit before too long [2,3]. Undifferentiated, pluripotent, self-renewing, and stably haploid, hapESCs have also displayed germline competence [4].

It is in this capacity that murine hapESCs, doubling up as de facto gametes, gave rise to bimaternal and bipaternal progeny [5]. Herein we argue that assisted same-sex human reproduction, although potentially attainable at this time, is still years away from the clinic. In support of this perspective, we note the significant technical, regulatory, statutory, and societal hurdles that stand in the way of near-term implementation.

The technical challenges associated with assisted same-sex human reproduction remain substantial. Human androgenetic hapESCs, the cellular analogs of round spermatids, proved capable of “fertilizing” oocytes as well as of supporting embryonic development to the blastocyst stage [3]. Human parthenogenetic hapESCs, the cellular analogs of oocytes, have yet to be assessed for their capacity to instate and sustain embryogenesis [2]. It follows that significant preclinical research is yet to be carried out to assess the inherent gametogenic competence of human parthenogenetic hapESCs. Close attention will also have to be paid to the genomic imprinting status of human hapESCs in advance of potential deployment in assisted same-sex reproduction. Murine precedent suggests that assisted same-sex human reproduction may require the deletion of select differentially methylated regions (DMRs) of hapESCs [5].

The deletion of 2 to 7 DMRs and the imprinted genes thereof proved critical to the ability of murine hapESCs to effectuate bimaternal and bipaternal reproduction [5]. The uncompromising safety of this and related interventions in the human context would have to be meticulously scrutinized if iatrogenic harm is to be avoided. Then, and only then, might regulatory consideration be given to the prospect of uterine transfer of bimaternal or bipaternal embryos. Apart and distinct from the aforementioned limitations, note must also be made of the rate of hapESC establishment and the maintenance thereof, the matching of the cell cycle parameters, and the developmental efficacy of semi-cloned embryos. Yet other limitations have to do with the reality that the science of imprinting in the human lags behind that of its rodent counterparts.

A responsible regulatory course toward the approval of assisted same-sex human reproduction must build on a rigorous body of in vitro and in vivo preclinical studies. The requisite guardianship of this investigative phase is the domain of Institutional Animal Care and Use Committees. Similar rigor should be applied to in vitro preimplantational research involving human hESCs, gametes, and embryos. It is here that Institutional Biosafety Committees as well as Embryonic Stem Cell Research Oversight and Embryo Research Oversight Committees will play a central role. In time, it will fall to the US Food and Drug Administration (FDA) to assess the safety and efficacy of the first-in-human uterine transfer of bimaternal or bipaternal embryos. Precedents suggest that bimaternal and bipaternal human embryos will be classified by the Center for Biologics Evaluation and Research of the FDA as “Human Cells, Tissues, and Cellular and Tissue-Based Products” that have undergone “more than minimal manipulation” [6].

In so doing, the FDA will have deemed bimaternal and bipaternal human embryos to comprise biological drugs the regulatory course of which is comparable with that of traditional chemical counterparts [6]. It follows that the uterine transfer of bimaternal or bipaternal embryos will be conditional upon the approval of a Biologics License Application (BLA) by the FDA [6]. Absent a detailed “guidance for industry” from the FDA, the precise safety and efficacy expectations for assisted same-sex human reproduction may only be surmised at this time. All the same, nothing short of impeccable safety and efficacy will do if heritable harm is to be forestalled.

The statutory obstacles faced by assisted same-sex human reproduction are multiple and considerable. First, owing to the Dickey–Wicker Amendment, research concerned with assisted same-sex human reproduction will be ineligible for funding by the National Institutes of Health (NIH) [7]. As written, the amendment precludes public funding of “the creation of a human embryo…for research purposes…in which a human embryo or embryos are destroyed” [7]. Comparable constraints are delineated by the NIH “Guidelines for Human Stem cell Research” [8]. It follows that private funds would have to be secured to underwrite research concerned with the generation of haploid human embryos, the derivation of hapESCs, and the origination of bimaternal or bipaternal embryos.

Second, due to the Aderholt Amendment, BLAs for bimaternal or bipaternal human embryos are unlikely to be vetted by the FDA in the likely event that the embryos in question were subject to “heritable genetic modification” [9]. A rollback of the aforementioned language of the statue may well be necessary to enable the regulatory adjudication of bimaternal or bipaternal embryos the genomic imprinting of which may have been modified. Thirdly, by dint of state variance in US surrogacy law, the prospect of assisted same-sex human reproduction of men may be compromised in some states. A case in point is the Louisiana surrogacy law (Act No. 494), which requires that “the parties who engage the gestational surrogate not only are married to each other, but also create the child using only their own gametes” [10]. Louisiana apparently intended to use this language to block same-sex couples from using gestational surrogacy, although one might wonder whether hapESCs (unlike gametes) might not be covered by this language.

Outside the US many more countries restrict same-sex access to reproductive technologies in ways that will likely block the use of hapESCs. In a world where assisted same-sex human reproduction is successfully consummated, a significant measure of “medical tourism” is to be anticipated [11].

Societal challenges to the notion of assisted same-sex human reproduction draw on sectarian objections to nontraditional family constructs. As per a recent Pew Research Center poll, the proportion of white evangelical protestants who favor same-sex marriage stood at 29% [12]. The corresponding figure for unaffiliated Americans stood at 79% [12]. Additional dispositional concerns are rooted in the national schism over reproductive rights. Leading this front would be unease over the derivation of hapESCs from erstwhile haploid human embryos. Additional solicitude could well focus on the very notion of bimaternal and bipaternal reproduction. On the legal front, there has been much progress on the matter of same-sex marriage and same-sex parenthood. In a landmark civil rights case, Obergefel v. Hodges, the Supreme Court of the United States guaranteed same-sex couples the right to marry [13].

In a related ruling, Pavan v. Smith, the Supreme Court mandated the listing of same-sex parents on birth certificates [14]. Corresponding shifts in public opinion are equally noteworthy. A recent YouGov poll reveals the majority of Americans (55%) to affirm that “heterosexual and homosexual couples can be equally good parents” [15]. However, the Supreme Court has yet to weigh in on whether even heterosexual couples have a right to use assisted reproductive technologies or when a state might constitutionally limit their use. Similar judicial silence understandably applies to the constitutional status of possible bimaternal or bipaternal reproduction [16]. Should US states seek to prohibit assisted same-sex reproduction, constitutional challenges appear likely.

The recent generation of human hapESCs afforded the scientific community with a highly versatile tool. Studies of the role of imprinting in embryonic development were markedly enhanced [2]. Loss-of-function screens were equally well served [2]. A role for hapESCs in crossing the same-sex reproduction barrier, however, was least anticipated. Now within reach, the notion of same-sex reproduction is the subject of ever-growing attention. Comprising but the latest disruptive reproductive technology-in-waiting, assisted same-sex human reproduction is joining the likes of in vitro gametogenesis, remedial germline editing, and mitochondrial replacement therapy. Viewed in this light, the notion of “reproduction rethought” bears the mark of prescience [17].