Japanese regulators just quietly gave researchers there a historic OK to generate human embryos from stem cells in the lab — no ovaries or testes needed.
Scientists in Japan and around the world are quickly working toward making viable human eggs and sperm from stem cells, a process called in vitro gametogenesis, or IVG. Those stem cell-derived sperm and eggs could be used for vitro fertilization (IVF) to generate human embryos for research or, one day, making babies. Let’s call the potential new process stem cell IVF.
Why go down this path?
While researchers are now making increasingly accurate models of early human embryos in the lab from stem cells, research on actual human embryos is more relevant than just models. Stem cell IVF will also be far more scalable than studying embryos leftover from standard IVF. A team might easily be able to study hundreds of human embryos at time rather than just a handful.
This is not just about research, though. In principle, the same stem cell IVF process eventually could become the basis for a new, more flexible and efficient form of assisted reproduction.
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There is already great interest in using IVG and, eventually, stem cell IVF to better address infertility. For example, an American biotech called Conception Biosciences is exploring the development of IVG to produce human eggs to help some infertile couples.
IVG-generated eggs could be fertilized by “old-fashioned” donor sperm via IVF. Conversely, someday standard donor eggs might be fertilized by stem cell-derived sperm. I would call those hybrid approaches “partial stem cell IVF.”
Partial stem cell IVF has been successful at generating seemingly healthy baby mice, which will encourage advocates of trying similar things in people. Eventually, entirely stem cell-based IVF may successfully address cases where both parents-to-be are infertile.
I’m not inherently opposed to using stem cell IVF to help infertile people to try to become parents, but there are likely to be unintended consequences of the technology. For example, the same stem cell IVF could be used to try to generate gene-edited designer or cloned babies — possibilities we shouldn’t ignore.
Yet what’s actually most likely going to happen in coming years with stem cell IVF is more interesting than concerning. Under the new rules, Japanese researchers will be able to produce and then study stem cell-based human embryos for up to 14 days in the lab. It won’t be long before researchers in other countries, likely including the U.K., are allowed to follow suit.
Scientists will start by making induced pluripotent stem cells or IPSCs from ordinary donor cells (skin, cheek, blood, etc.) through cellular reprogramming. Then those human IPSCs will be differentiated into viable sperm and eggs, which in turn can be used for IVF to make human embryos. This could be the first time in human history that human embryos are made in a new way. However, most countries do not explicitly prohibit such research, so we can’t be sure.
For example, here in the U.S., there is no federal ban, and few state laws would be relevant. FDA officials have made statements about potential agency authority over IVG, but that remains murky, especially if stem cell IVF were used to make embryos only for research.
Let’s say you want to give it a try and there’s no law to stop you. The biggest technical challenge with the stem cell IVF process, in Japan or elsewhere, is to make those fully functional human eggs or sperm from IPSCs. Other complex issues could come into play, too, depending on characteristics of the IPSCs, such as their complement of sex chromosomes and genomic variants.
Despite such challenges, under the new provision in Japan, I expect that several researchers will collectively make scores of 14-day-old human embryos via partial stem cell IVG within five years, maybe much sooner.
The fact that Japanese regulators already just approved stem cell IVF suggests to me that they anticipate production of viable human eggs, sperm, or both from stem cells soon.
There have been other changes that open the door wider to this general area of research. Four years ago, the International Society for Stem Cell Research, or ISSCR, recommended dropping what has been called the 14-day rule, which had suggested limiting human embryo growth in the lab to two weeks. Back then, ISSCR also said stem cell IVF to make human embryos for lab research could be permissible in some cases. Still, as far as I know, no country specifically allowed that until Japan’s recent announcement.
This summer a group of international experts made the case for allowing eventual growth of human embryos for up to 28 days in the lab. While these policy shifts would mostly apply to research utilizing standard IVF embryos, they would likely apply to stem cell-derived embryos, too.
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New ISSCR guidelines released this week leave the door open to potentially using stem cell IVF technology to address infertility in the future if certain criteria are met, but at this point, only lab research on the human embryos is considered acceptable.
As such work now proceeds in Japan, it seems likely that at 14 days, some of the stem cell-based human embryos will be basically indistinguishable from the standard IVF-based human embryos using the best available assays. If that happens, I believe much more extended growth of the stem cell-based human embryos ultimately will be permitted in the lab either in Japan or elsewhere.
A limit of 28 days of laboratory human embryo growth is likely to become the norm overall, whether the embryos are produced by standard or stem cell IVF.
What happens then? More technological challenges. It’s almost certain that only a small subset of lab-grown 28-day human embryos will appear healthy at first even just starting with regular IVF embryos. It is even less certain whether any lab-grown 28-day human embryos made by stem cell IVF will seem healthy, but I believe eventually researchers will refine the technology to generate apparently healthy stem cell-based 28-day embryos.
This line of research won’t stop there. In some sense the strongest driver here is not just research but inventing a new reproductive technology. However, even partial stem cell IVF — for example, combining IVG eggs with donor sperm to try to make human babies — will present major risks.
One of the most daunting hurdles to studying safety would be that stem cell-based human embryos at 14 or 28 days might seem entirely healthy by every assay we can try, but you wouldn’t know for sure until you implanted earlier versions of such embryos to try to produce babies. Then what if the resulting fetuses or even babies are seriously ill or die? I believe some researchers will want to take such risks even before all safety studies have been completed.
As much as I worry about possible dangers, I still find it fascinating that we humans seem willing to take those kinds of chances with research. Even with standard IVF, in the beginning researchers couldn’t know it was safe until they tried it in humans. Now, almost 50 years later, it’s wonderful that IVF seems like an ordinary way to help people become parents.
Something called mitochondrial donation is a more recent, relevant case of potential big risks and rewards with new reproductive technologies. Just a few weeks ago a team in the UK reported on eight apparently largely healthy babies produced using something called mitochondrial donation. It’s a new type of IVF involving genetic material from three people. Two parents provide the nuclear genomes, and a donor provides a mitochondrial genome lacking mutant mitochondria. The goal is to prevent inherited mitochondrial diseases.
The U.K. team and regulators there felt ready to try this new type of IVF based on encouraging animal studies, but it’s another one of those “you can’t know if it’s safe until you try it” kinds of human research. Encouragingly, the very early results look positive so far, even to me as someone who was previously vocal about its risks.
Five of the eight babies produced by this method had little or no detectable mutant, disease-causing mitochondrial DNA. No disasters have occurred so far, but there’s a long road ahead for this research, which I believe should span generations of follow-up to assess possible long-term risks.
While stem cell IVF could also potentially be used to address mitochondrial diseases or other genetic conditions that are due instead to mutations in the nuclear genome, its most likely first clinical use is going to be for infertility. For example, a 2024 workshop organized by the National Academies seemed upbeat about using IVG as a basis for addressing human infertility and more. “IVG could be a game changer for women and men dealing with infertility, women of advanced maternal age, and same-sex couples, allowing them to have genetically related children they could not otherwise,” the report said.
This is controversial territory. Just the report of researchers making seemingly healthy mouse babies from two moms or two dads seemed to unsettle some folks. Other researchers have successfully made eggs from male mice that way via IPSCs.
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If making human babies from stem cells becomes accepted for one or more reproductive applications, there are also major risks that some researchers will use this technology in other ways that are far more controversial. Even dangerous. For example, stem cell IVF probably would be the most practical way to attempt human cloning.
Stem cell IVF could also be the basis for attempts at eugenic human enhancement by gene editing the starting IPSCs. Think bigger muscles. More robust brains. We’re already seeing some fertility clinics marketing embryo screening for desired traits like intelligence. I have major doubts about what these firms can actually deliver now, but a potential next step for them could be to go beyond just screening embryos to trying to “write” certain traits such as with gene editing of embryos.
Skeptical that such things could happen in our lifetimes?
Biomedical science often radically changes in punctuated bursts. For example, the reprogramming technology to make IPSCs rapidly allowed just about anyone to essentially do cellular alchemy. What seemed almost like science fiction became a new reality of cell biology research within just a few years. Now, my lab and thousands of others can readily turn ordinary and easily isolated human cells like skin fibroblasts into just about any other kind of cell. Someday soon this will include eggs and possibly sperm, although the latter are more difficult to make. Similarly, CRISPR quickly empowered thousands of labs to readily gene edit cells from just about any organism including humans.
If stem cell-based human embryo production is similarly streamlined, hundreds of labs could eventually make human embryos that way too, where regulators allow it. This is likely to spark innovations but also new risks and almost certainly negative outcomes.
When multiple powerful technologies intersect, there will be even more innovation and perhaps less control. In a way, this is happening right now, which is both exciting and somewhat mindboggling. We’re at a unique moment in time where three revolutionary technologies — CRISPR, IPSCs, and IVF — are poised to come together to potentially change our species. Stem cell-IVF is just one approaching manifestation of this powerful intersection.
Coming back to the near future, I’m excited to see the human stem cell-IVF science unfolding once researchers in Japan or elsewhere soon master human IVG. At the same time, we need to be talking much more about the whole constellation of possibilities around human stem cell IVF and how that technology may synergize with others like CRISPR and artificial wombs.
We have less time to discuss all of this than you might think.
Paul Knoepfler is professor of cell biology and human anatomy at UC Davis School of Medicine.
