in vitro gametogenesis in the time of DeSantis et al
From my latest New Yorker.
In 2016, two Japanese reproductive biologists, Katsuhiko Hayashi and Mitinori Saitou, made an announcement in the journal Nature that read like a science-fiction novel. The researchers had taken skin cells from the tip of a mouse’s tail, reprogrammed them into stem cells, and then turned those stem cells into egg cells. The eggs, once fertilized, were transferred to the uteruses of female mice, who gave birth to ten pups; some of the pups went on to have babies of their own. Gametes are the cells, such as eggs and sperm, that are essential for sexual reproduction. With their experiment, Hayashi and Saitou provided the first proof that what’s known as in-vitro gametogenesis, or I.V.G.—the production of gametes outside the body, beginning with nonreproductive cells—was possible in mammals. The mice that had descended from the lab-made egg cells were described as “grossly normal.”
…This March, Hayashi, who is not currently trying to make a human egg, had another announcement: his lab had repeated the I.V.G. process in mice, but this time it had produced fertilized embryos whose egg cells had been developed using stem cells from male mice—“mice with two dads,” as the headline in Nature put it. Futurists have speculated about broader possibilities, such as an embryo formed with the DNA of four people instead of two, or even a so-called “unibaby,” the result of a person reproducing with herself…
In late January, I visited the headquarters of Conception, in Berkeley. The company was founded in 2018, and has since raised almost forty million dollars in venture capital in pursuit of in-vitro gametogenesis. The staff was temporarily based in a single-story co-working space near Aquatic Park, and things had gotten crowded. Conception’s C.E.O., a thirty-one-year-old entrepreneur named Matt Krisiloff, was working from an armchair wedged between two desks. Krisiloff first tweeted about his interest in I.V.G. in 2017. At the time, he was the director of a nonprofit wing of Y Combinator, the startup incubator, established to fund technological research “for the benefit of the world,” as the company put it. Sam Altman, who was then running Y Combinator, told me that he and Krisiloff were both interested in what he called “hard-tech companies that invest a long time in developing a difficult technology first and then don’t bring a first product to market for many, many years.” Krisiloff had helped out in the early months of OpenAI, which went on to invent ChatGPT, dall-e, and the transcription service Whisper, an experience he has cited as formative in learning how to set up a research-oriented company with an ambitious end goal.
Krisiloff has close-cropped hair and a gap-toothed smile, and on the day of my visit he was dressed in jeans, a black crew-neck sweatshirt, and sneakers made by the Swiss brand On. He does not have a degree in the hard sciences—as an undergraduate, he majored in Law, Letters, and Society at the University of Chicago—and was still in his twenties when he and two scientists founded Conception, which was initially known as Ovid Research. Krisiloff’s interest in I.V.G. was partly personal: he is gay, and liked the thought of one day being able to have biological children with a male partner. (Krisiloff once dated Altman; he is now in a relationship with Lucas Harrington, the co-founder of Mammoth Biosciences, which is focussed on the gene-editing technology crispr.)…
While visiting Hayashi’s lab in Japan in 2018, Krisiloff met Pablo Hurtado González, a Spanish biochemist who was a visiting scholar there. Over dinner at a ramen restaurant in Fukuoka one evening, the mission of Conception began to take shape. Hurtado González, who is thirty-two, is also gay, and has a Ph.D. in reproductive health and a particular interest in male-male reproduction. (The bio on his Instagram profile reads “Trying to make genetic gaybies at Conception Bioscience.”) After placing an ad in Nature, Krisiloff and Hurtado González hired their third co-founder, Seres, who was born in Romania and raised in Hungary. She had worked as an embryologist at a fertility clinic in England before completing her Ph.D. at Cambridge University under Melina Schuh, a German cell biologist who is an expert in meiosis, the type of cell division unique to reproductive cells, which leads to the production of eggs and sperm. “Coming from I.V.F., in-vitro gametogenesis was the single most important solution to not having enough eggs,” Seres told me. Seres, who is thirty-six, has a daughter conceived without assisted reproductive technology, but her experience working at fertility clinics had made the issue personal to her: she had seen many patients with infertility issues for which no clear cause could be found…
The timing gives one pause, given the increasingly vitriolic (up to eliminationist) anti-LGBTQ+ rhetoric these days.
Close on the heels of that article, my latest Science Magazine hit my mailbox. "Special Issue."
Not one word regarding IVG.
From the final article above (Assisted Reproductive Technologies):
Abstract
Assisted reproductive technology (ART) refers to processing gametes in vitro and usually involves in vitro fertilization. Originally developed for the treatment of infertility, culture of human embryos in vitro also provides an opportunity to screen embryos for inherited genetic disorders of the nuclear and mitochondrial genomes. Progress in identifying causative genetic variants has massively increased the scope of preimplantation genetic testing in preventing genetic disorders. However, because ART procedures are not without risk of adverse maternal and child outcomes, careful consideration of the balance of risks and benefits is warranted. Further research on early human development will help to minimize risks while maximizing the benefits of ART...
Outlook
ART has enabled millions of people across the globe to have children and to avoid transmission of genetic disorders. The potential for preventing diseases is greatly enhanced by recent progress in identifying causative variants of thousands of monogenic diseases (11). In relation to difficulty in interpreting trophectoderm-based aneuploidy screening for maternal-origin trisomy, the validated technique of polar body testing (22–25) avoids confounding effects of mitotic errors by directly analyzing the products of female meiosis. The benefit of an unambiguous diagnosis for at-risk women should not be underestimated when considering appropriate metrics of success. In cases where all eggs are aneuploid, a clear diagnosis would help women to avoid undergoing multiple futile and costly ART treatment cycles.
The use of ART procedures to reduce transmission of pathogenic variants in the mitochondrial genome offers hope to families affected by otherwise incurable disease. PGT has been used successfully to reduce the risk of mtDNA disease by identifying embryos with low variant loads (39). In cases where all embryos carry high levels of a pathogenic variant, recently developed MRT procedures can be used to reduce transmission (32). However, MRT may not be effective in all cases owing to the potential for resurgence of the maternal mitochondrial genome (32). Further research is required to understand the underlying causes and develop mitigation strategies. In the meantime, it will be important to counsel prospective patients that MRT cannot guarantee disease prevention. Moreover, given the invasive nature of MRT treatments, it will be important to define criteria for the use of MRT in the treatment of infertility. The rapidly advancing fields of single-cell transcriptomic and proteomic analysis provide an opportunity for improved diagnostics to underpin targeted clinical application of MRT for the treatment of infertility.
Finally, research on the earliest stages of human development will help to maximize the considerable benefits of ART while minimizing the risks. Exciting developments in stem cell–derived embryo models offer a powerful tool for investigating human embryogenesis, pregnancy loss, and early developmental anomalies (40). However, these models do not recapitulate the very earliest stages of human development. Progress on this front necessitates creation of human embryos specifically for research. Thanks to the brave and pioneering work of Anne McLaren and Mary Warnock (41), the legal and regulatory framework in the UK demonstrates that this type of research can be conducted within a robust regulatory environment. However, the creation of embryos for research is permitted in surprisingly few countries. In addition, many major research funding bodies have a blanket ban on funding research involving human embryos. Given progress toward validation of low-cost ART approaches to increase global access (42), it is estimated that ART-conceived children will account for 3.5% of the global population by the end of the century (1). With this in mind, it is perhaps time to reframe the ethical debate in terms of safeguarding the health of future generations.
Curious.
"MENTAL / COGNITIVE IMMUNITY" UPDATE
Regarding the books cited in the prior post.
Well into each book, Alternating between them chapter by chapter, back & forth. Extremely enjoyable and informative. My outset "metaphor / analogy" concerns are allayed. These are two substantive books.
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