Reproduction reimagined

Thomas Samuel Kuhn, Ph.D. (1922-1996), plausibly the leading philosopher of science of our time, maintained that science proceeds through periods of steady growth punctuated by emendational revolutions. His 1962 book, The Structure of Scientific Revolutions, one of the most quoted bodies of academic work of all time, maintains that the progress of science is not linear, let alone invariant (1Kuhn T.S. The structure of scientific revolutions. University of Chicago Press, Chicago1962Google Scholar). Rather, the progress of science is episodic, that is, marked by alternating periods of “normal” and “revolutionary” gains. In a word, breakthrough science transpires apart and distinct from the stepwise continuity of “normal science,” sometimes referred to as “development-by-accumulation” of agreed upon facts and conjectures. It follows that revolutions attributable to transformative unforeseeable notions that play havoc with accepted thinking, comprise singularly significant and therefore rare events in the history of science. Not since the introduction of in vitro fertilization (IVF), a Kuhnian leap if ever there was one, did the field of reproductive medicine witness a truly revolutionary breakthrough. Herein we describe what we believe to be three truly astounding scientific developments that are all but certain to disrupt the field of reproductive medicine as we know it. Viewed through a contemporary lens, the derivation of nature’s requisite reproductive elements, the egg and the sperm, relies on their inborn endowment. Sperm, generally readily available and in abundance, uncommonly constitute a rate-limiting step. The recovery of eggs, however, depends on a far more elaborate sequence entailing ovarian stimulation followed by transvaginal retrieval. Alternatives to this state of the art have been sought by many investigators. Organ cultures of human gonadal substrate, constrained by inaccessible starting material and limited gamete output, are unlikely to replace current technology. Eggs and sperm from a buccal smear, or for that matter from any other somatic cell source, the heretofore unthinkable Kuhnian solution, can be counted upon to rise to the occasion. The by-product of the Nobel Prize-winning discoveries of stem cells of the embryonic and induced pluripotent (iPSCs) varieties, eggs and sperm from a somatic cell source have now been the subject of active investigation for some time (2Cohen I.G. Daley G.Q. Adashi E.Y. Disruptive reproductive technologies: the prospect of in vitro gametogenesis.Sci Transl Med. 2017; 9: 1-3Crossref Scopus (36) Google Scholar). Rodent studies make it clear that embryonic stem cells or iPSCs constitute legitimate gamete antecessors (3Hikabe O. Hamazaki N. Nagamatsu G. Obata Y. Hirao Y. Hamada N. et al.Reconstitution in vitro of the entire cycle of the mouse female germ line.Nature. 2016; 539: 299-303Crossref PubMed Scopus (333) Google Scholar). The in vitro specification of human primordial germ cell-like cells and of oogonia has since been accomplished as well (4Yamashiro C. Sasaki K. Yabuta Y. Kojima Y. Nakamura T. Okamoto I. et al.Generation of human oogonia from induced pluripotent stem cells in vitro.Science. 2019; 362: 356-360Crossref Scopus (129) Google Scholar). However, the in vitro generation of human sperm or of fertilizable meiosis II oocytes, now well within reach, remains to be accomplished. The attendant regulatory, legal, ethical, and societal challenges notwithstanding, at present it appears likely that stem cell-derived human gametes will thoroughly disrupt the current world order. One distinct outcome might well be that the clinical practice of IVF as we know it will be no more. Absent the need for ovarian stimulation, egg retrieval, or egg donation, IVF may well transform, in time, into a laboratory-based enterprise wherein the import of clinical input is markedly diminished. The recent origination of haploid embryonic stem cells (hESCs) afforded the scientific community with a highly versatile tool. Studies of the role of imprinting in embryonic development were markedly enhanced. Loss-of-function screens were equally well served. Little did anyone suspect that hESCs may also, in time, enable what has long been deemed infeasible, namely, the crossing of the same-sex reproduction barrier. In hindsight, this possibility could well have been foretold had hESCs been seen for what they are, that is, haploid cellular analogues of gametes. It took the Kuhnian insights of Anton Wutz, Ph.D. (professor of genetics at the Eidgenössische Technische Hochschule Zurich), to note the “germline potential of parthenogenetic haploid mouse embryonic stem cells” (5Leeb M. Walker R. Mansfield B. Nichols J. Smith A. Wutz A. Germline potential of parthenogenetic haploid mouse embryonic stem cells.Development. 2012; 139: 3301-3305Crossref PubMed Scopus (62) Google Scholar). The race to effectuate assisted same-sex reproduction has been underway ever since. In a first, murine hESCs, doubling up as de facto gametes, produced bimaternal and bipaternal progeny (6Li Z.K. Wang L.Y. Wang L.B. Feng G.H. Yuan X.W. Liu C. et al.Generation of bimaternal and bipaternal mice from hypomethylated haploid ESCs with imprinting region deletions.Cell Stem Cell. 2018; 23: 665-676Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). With human parthenogenetic and androgenetic hESCs at hand, the realization of assisted same-sex human reproduction must now be assumed to be just a matter of time. In support of this contention, human androgenetic hESCs, the cellular analogues of round spermatids, proved capable of “fertilizing” oocytes to form zygotes capable of embryonic development to the blastocyst stage (7Zhang XM, Wu K, Zheng Y, Zhao H, Gao J, Hou Z, et al. In vitro expansion of human sperm through nuclear transfer. Cell Res. In press.Google Scholar). Although significant technical, regulatory, and statutory hurdles are doubtlessly ahead, the prospect of assisted human same-sex reproduction can no longer be dismissed. It is time for ethics and policy to catch up. Some of the polling suggests that this arena is fertile ground for change. A recent Pew Research Center poll reveals that the proportion of religiously unaffiliated Americans who favor same-sex marriage now stands at 79%. A recent YouGov poll reveals the majority (55%) of Americans to affirm that “heterosexual and homosexual couples can be equally good parents.” It remains to be seen whether these attitudes will extend to bimaternal or bipaternal reproduction. Mutant mitochondrial deoxyribonucleic acid underlies a wide range of incurable inborn afflictions. Prevention now appears possible by substituting the mutation-carrying mitochondria of zygotes or oocytes at-risk with donated unaffected counterparts. Strictly therapeutic in its orientation, mitochondrial replacement therapy (MRT) must be viewed as the leading front of the germline remediation of genetic disease. This Kuhnian insight, the brainchild of Donald S. Rubenstein, M.D., Ph.D., and his colleagues (then at the Stritch School of Medicine, Loyola University Chicago), may now be on the cusp of realization (8Adashi E.Y. Cohen I.G. Mitochondrial replacement therapy: born in the U.S.A.Am J Obstet Gynecol. 2017; 217: 561-563Abstract Full Text Full Text PDF Scopus (5) Google Scholar). More recently, the world was introduced to yet another breathtaking Kuhnian sagacity in the form of CRISPR-Cas9, a highly versatile gene-editing enzyme with endless possibilities. The inspired discovery of Jennifer A. Doudna, Ph.D., and Emmanuelle Charpentier, Ph.D. (then at the University of California, Berkeley), CRISPR-Cas9, not unlike MRT, stands to be applied to the germline remediation of genetic disease (9Jinek M. Chylinski K. Fonfara I. Hauer M. Doudna J.A. Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.Science. 2012; 337: 816-821Crossref PubMed Scopus (9424) Google Scholar). This unique melding of genetics and reproduction holds the potential to do nothing less than relieve the global burden of genetic disease. As of 2020, the prospect of responsible editing of the human germline must still be deemed to be years removed from the clinic due to notable methodological, judicial, and regulative roadblocks. Appreciable societal and ethical disquiet have yet to be confronted as well. None can be underrated. Still, one must not lose sight of the fact that for the first time in human history, the unrelenting generational scourge of heritable maladies may be effectively tackled. The melding of human genetics, regenerative medicine, and assisted reproduction, now all but inescapable, is rewriting the rules of what may be possible. Coalescing as they are, these mutually enhancing paradigms can hardly be ignored. Several examples follow. Heritable infertility could be redressed through in vitro editing of stem cell-derived gametes. Germ cell failure pursuant to azoospermia, premature ovarian failure, and chemotherapy might be overcome by stem cell-derived gametes. Autologous mutation-free stem cell-derived oocytes could plausibly augur a donor-independent approach to MRT. The process of securing “savior siblings” could potentially be facilitated as well. And remedial gene editing could be applied to iPSC-derived gametes of probands compromised by heritable infertility. Whichever direction one turns, one inference is inescapable. Assisted human reproduction will never be the same again. Kuhnian disruptions saw to it. It was the celebrated American poet Anthony E. Hecht who said it best in his evergreen Prospects “We have set out from here for the sublime; I have no doubt we shall arrive on time” (10Post J.F.S. A thickness of particulars: the poetry of Anthony Hecht. Oxford University Press, New York, NY2015Google Scholar).