My last blog post focused on existing assisted reproductive technology (ART) and how societal and legal heteronormativity harms queer couples trying to grow their families. I recommended that men who have sex with men be allowed to donate gametes, that gender-neutral language be adopted in parentage laws to give equal parentage rights to same-sex parents, and that all states require insurance to cover IVF treatments, including using donated gametes, for all parents pursuing ART to grow their family.

In this blog post, I will explain the science behind a possible new scientific development that could revolutionize reproductive medicine and fertility treatments, allowing same-sex intended parents and trans-intended parents to have genetic children without the need for donor gametes. This technology will also help intended parents experiencing infertility due to chromosomal abnormalities, lack of viable eggs or sperm, age, and others. I will explain where the science is so far and what more needs to be studied in order to understand how this technology could influence offspring health. Finally, I will briefly describe how policy around insurance may influence how this technology is used by the public if research is able to develop this tool and it is safe and available.

Making sex cells in the lab

Making induced pluripotent stem cells (iPSCs) was a landmark discovery in biology that reprograms a cell, most likely a fibroblast taken from skin or connective tissue, into a stem cell. Stem cells can then be differentiated into most other cell types, and used to study nearly all areas of cellular biology, cell types, and organs in culture without starting out with that given cell type. iPSCs have also helped us study stem cells, cellular differentiation, other processes, and revolutionized the field of regenerative medicine. The potential to run the biological mechanism for cell differentiation in reverse from what happens in vivo has allowed for extremely important discoveries.

Law professor and bioethicist Hank Greely describes one potential application of iPSCs related to reproduction, envisioning a potential future of ART that relies on in vitro gametogenesis (IVG) in his book The End of Sex[1]. (His argument also delves deep into the future of pre-implantation embryonic genetic screening and diagnosis, and how that will influence what embryos people choose to become their children[2]. While that leads to many interesting conversations about the use of clinical genetics with the future of ART, that is outside the scope of this blog post.) IVG takes a somatic cell from an individual, reverts it to iPSCs, and then re-differentiates the cell into a gamete (i.e., an egg or sperm cell) instead of another type of somatic cell. Greely’s argument is that one day, we will be able to take two cells from two intended parents in a minimally invasive manner and reprogram them into a desired gamete, and make offspring using these methods in order to prevent genetic diseases, allow parents with fertility struggles and chromosomal abnormalities to have genetic children, and allow homosexual intended parents to have genetic children[3].

While this may sound like science fiction, methods for IVG in mouse embryonic stem cells have been successful for developing both oocytes, or eggs, and sperm, and both types of IVG gametes have successfully produced fertile offspring in Professor Mitinori Saitou’s laboratory at Kyoto University[4]. The IVG oocytes are used directly for fertilization[5], and for sperm, spermatogonia (the cells that produce sperm) are developed in vitro and implanted into the mouse’s testes in order to propagate and make sperm[6]. While both IVG oocytes and IVG spermatogonia have been used to successfully produce fertile offspring, there are still issues with the quality of the gametes derived via IVG—the quality of the follicle (immature oocyte) is lower in that there are fewer mitochondria in the cell, more chromosomal abnormalities, and issues with the required meiotic arrest[7]; in the sperm derived from IVG spermatogonia, there is decreased spermatogenesis propagation potential and there are differences in epigenetic markers between in vivo sperm and IVG sperm[8]. Additionally, these IVG gametes that yielded fertile, healthy offspring were produced using embryonic stem cells. Thus far in research, iPSCs have been functionally equal to the embryonic stem cells they were developed to emulate, there are some important molecular differences between iPSCs and ESCs. Professor Saitou’s group did replicate their IVG work using mouse iPSCs successfully, though it requires more tinkering to overcome some molecular and epigenetic differences that cause decreased developmental potential[9]. Therefore, although the mice that were born using IVG gametes seemed healthy and fertile, further investigation is needed of the offspring and the generations that follow in order to understand if and how these differences in gamete quality impact the resulting offspring.

Exciting breakthrough allows for egg cells to be made from male mice using IVG

Perhaps most exciting, a paper came out last month, March 2023, in Nature, in which eggs were made successfully from a male mouse using IVG and successfully produced offspring, and these offspring did develop into adulthood[10]. This paper also confirmed that the gene expression of oocytes derived from male mouse iPSCs was not significantly different from in vivo oocytes; they reported that only one protein-coding gene was differentially expressed[11]. Therefore, mice were successfully made from two fathers, a huge scientific breakthrough. Up until this paper, in cases of successful IVG to make spermatogonia and egg cells, the original cells were derived from embryonic stem cells, and were derived from an embryo of the “correct” sex for the given gamete type—the oocytes were derived from a female mouse embryo and the spermatogonia were derived from a male mouse embryo[12]. The exciting 2023 paper in which two paternally derived gametes yielded mouse offspring did state that gametes derived from the same iPSC did not successfully produce offspring due to fertility issues with IVG-derived sex cells. Despite this exciting development, this paper did not investigate the epigenetic markers on these male-derived oocytes and did not report on the potential impact of differential expression of non-protein-coding genes that may make important RNAs in these oocytes compared to those derived from mice in vivo. Additionally, they did not report on the fertility of the mice that were born from these male-derived oocytes or any potential differences in gene expression of the offspring compared to those born via in vivo-derived gametes. More research is needed in order to identify how healthy and fertile offspring are using IVG gametes from the opposite sex.

Substantial research is needed before IVG is ready for human reproduction

It is possible that issues with fertility or offspring health would not show up until a few generations later, or that the first round of offspring can be born using IVG, but using IVG or other ART methods would not be successful from mice born using IVG-derived gametes. Further research also needs to investigate the impact of the problems with IVG-derived gametes on fertility and reproductive potential of these gametes—it is possible that the offspring are fine but successful in vitro fertilization, implantation of an embryo, or fetal and/or placental development differ or decrease with IVG-derived gametes, making a successful pregnancy less likely using these methods than sexual intercourse or using in vivo derived gametes.

The issue of the sex of the source material for developing the iPSC may remain the most difficult to overcome, despite the recent breakthroughs. When an embryo is formed, it undergoes a process known as “genetic imprinting,” which requires that certain genes be expressed on the chromosome that comes from the mother and other genes be expressed on the chromosome that comes from the father, and problems in genetic imprinting cause their own class of diseases[13]. More research is needed about imprinting, but there is already an association between ART and imprinting disorders[14]. It is clear that imprinting is important, but it is unclear whether the sex of the parent is important versus which type of gamete the cell is. There are likely to be even more issues with epigenetic markers and methylation on gametes derived from a source of the opposite sex able to produce that gamete than there are using IVG from a source that is of the sex that can generate that gamete in vivo. Ensuring that the epigenetic landscape of the IVG gamete is healthy enough to preserve the DNA demethylation, imprint erasure, and remethylation processes needed during gametogenesis to ensure proper imprinting and prevent disease may serve as the most difficult research challenge to overcome. Depending on which epigenetic markers are different between IVG gametes compared to in vivo gametes, it may even be possible that IVG gametes, especially derived from a different sex source than the sex cell itself, may introduce new diseases or issues with health and fertility. Again, these issues may not show up in the direct offspring born using IVG, and may appear in a subsequent generation.

IVG could be an amazing family planning tool that also supports the queer community

Despite all of these research challenges, as Greely, Saitou, and others have described, IVG could serve as an incredible tool in ART. If successful, IVG would help parents have genetic children despite many barriers, including lack of gamete combination for same-sex couples, and also chromosomal abnormalities, age, and infertility. People who want genetic children should be allowed to have them, which is why ART was developed. IVG technology would allow same-sex intended parents to have genetic children from both parents without the need for an outside genetic donor, which is currently impossible with the current state of ARTs. IVG could also allow for transgender people to produce the gamete that they choose, for example a trans woman would be able to produce an egg, which would likely be gender-affirming. In order for IVG to be able to help a trans man produce sperm, however, the technology would need to be developed for spermatogonia to propagate in culture instead of after implantation in testes, which would likely be doable.

There should also be legal oversight to limit using IVG in humans until further studies are done about fertility and health of IVG mouse offspring down several generations in order to ensure safety before using it in humans. Once it is established as safe, it should be made available to intended parents experiencing infertility in order to have genetic children. As things stand right now, with limited insurance coverage for ART, I don’t think we are close to Greely’s predicted future of the end of sex for reproductive purposes because ART is currently so expensive, and IVG would be as well. Greely’s argument claims that genetic screening using “easy pre-implantation genetic diagnosis” would be very cheap, but the rest of the procedures needed, including IVF, are not so inexpensive, have varying insurance coverage, and that cost-benefit does not apply in cases such as gay men, trans women, or women without uteruses, that require a gestational carrier to have a child. As discussed in my previous blog post about heteronormativity in ART, insurance coverage for ART does not cover all parents equally. State differences in policy currently discriminate against queer intended parents. If IVG becomes available, states should require insurance providers to let all intended parents experiencing infertility to have equal insurance coverage for IVG as an ART. With enough research to answer my scientific concerns and with complete insurance coverage to promote equity for all intended parents to use IVG, I could agree with Hank Greely’s prediction for the End of Sex, but a lot of intermediate steps in the research and in insurance policy need to “go right” for me to get there.

[1] Hank Greely, The End of Sex and the Future of Human Reproduction (2016).

[2] Id.

[3] Id.

[4] Mitinori Saitou & Katsuhiko Hayashi, Mammalian in vitro gametogenesis, 374 Science (80-. ). 1 (2021); Katsuhiko Hayashi et al., Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice, 338 Science (80-. ). 971 (2012); Yukiko Ishikura et al., In Vitro Derivation and Propagation of Spermatogonial Stem Cell Activity from Mouse Pluripotent Stem Cells, 17 Cell Rep. 2789 (2016).

[5] Hayashi et al., supra note 4.

[6] Ishikura et al., supra note 4.

[7] Hayashi et al., supra note 4; Saitou and Hayashi, supra note 4.

[8] Ishikura et al., supra note 4; Saitou and Hayashi, supra note 4.

[9] Saitou and Hayashi, supra note 4.

[10] Kenta Murakami et al., Generation of functional oocytes from male mice in vitro, 615 Nature (2023).

[11] Id.

[12] Hayashi et al., supra note 4; Ishikura et al., supra note 4.

[13] Yunqi Chao et al., Promising therapeutic aspects in human genetic imprinting disorders, 14 Clin. Epigenetics (2022).

[14] Id.; Hiromitsu Hattori et al., Association of four imprinting disorders and ART, 11 Clin. Epigenetics (2019).