What happens when we make embryos from stem cells?
The science, ethics, and legal status of in vitro gametogenesis
Welcome, or welcome back, to The Science Fictional Now! A big part of what we do here involves looking back through the history of biology so that we can discuss new technical advances more fruitfully. Today, we’ll be diving headfirst into such an emerging technology, which helps create embryos from stem cells. It’s called in vitro gametogenesis (IVG) and is a reproductive technology in the lineage of in vitro fertilization (IVF), and stem cell research. In this article, we’ll break down the science behind how IVG works, and explore some of the most pressing ethical and legal questions that it gives rise to.
Let me know your thoughts on IVG by reposting or commenting below!
IVF and stem cell research were two of the most controversial biotech advances ever, so the fact that IVG is so closely related to both of them means that it’s bound to open up old fault lines and prompt new philosophical questions. IVF has become increasingly normalized since Louise Brown became the first person to be born via the procedure in 1978, and stem cell research is no longer the hot button political issue that it was during George W. Bush’s presidency.
Of course, neither of these issues has reached anything resembling universal consensus, within the United States or anywhere else. IVG debates to come will have the baggage of IVF and stem cells to deal with - and that’s in addition to the inherent weight that comes from dealing with a part of biology so profoundly important as reproduction.
Japan recently became the first nation to allow the creation of human embryos via IVG, though only for research use. There are tangible clinical applications for IVG however, and countries could permit the use of such embryos to start pregnancies in the future. Beyond near-term uses complementing existing IVF techniques, IVG could one day help same-sex couples and single parents have biological children. Before we discuss these very weighty (and for now, very theoretical) scenarios, let’s look at how IVG actually works.
The science of IVG
In traditional IVF, doctors take sperm and eggs from the parents-to-be and then combine them in a lab to create a fertilized zygote. Sperm and eggs are collectively known as germ cells or gametes - hence the “gametogenesis” part of IVG. The zygote is just a single cell but quickly begins to multiply, at which point it becomes known as an embryo. This embryo is implanted into the mother’s uterus to begin pregnancy.
In IVG, cells are taken from other parts of patients’ bodies and used to create the germ cells, which could then be used to start a pregnancy via IVF. This has been done in mice, but researchers haven’t been able to produce mature human germ cells from stem cells.
How are the germ cells actually made from other cells? This starts by obtaining stem cells, which are able to become other more specialized cell types through a process known as “differentiation.” The vast majority of cells in our bodies have differentiated enough that they’re too specialized to turn into germ cells. Thankfully, researchers have discovered ways to revert these cells back to earlier stages by exposing them to certain proteins - kind of like turning back the hands of a developmental biology clock.
This type of reprogramming was first demonstrated in 2006 by Shinya Yamanaka’s lab at Kyoto University.1 The proteins used for reprogramming are now called “Yamanaka factors” accordingly. After reprogramming, the cells are called “induced pluripotent stem cells” (iPSCs).2 In the context of IVG, “pluripotent” means that the cells have traveled back far enough in developmental time that they’ve gained the ability to become germ cells. After making iPSCs, researchers can then expose them to more proteins to help them differentiate into eggs or sperm. The foundational work here was done in Mitinori Saitou’s lab, also at Kyoto University.
What was actually approved in Japan?
We can see now that there are a few different ways IVG could be used, so let’s quickly go over what Japan’s recent decision actually permits. The core idea is that researchers are allowed to create human embryos using germ cells that began as stem cells. These embryos can only be used for research; starting pregnancies with them isn’t allowed. Researchers also have to destroy their cultures after 2 weeks, which is standard practice for human embryo research around the world.
What are the actual legal checkpoints for this though? What if someone figured out how to turn human stem cells into germ cells tomorrow and started a pregnancy in their garage? Japan has a few different laws that deal with embryos and Japanese bioethicists have drawn distinctions between stem cell-based fertilization products and other embryos. The idea is that laws and guidelines would beupdated if researchers are able to create mature germ cells from stem cells. If a lone wolf in Japan started an IVG pregnancy tomorrow, I doubt they’d get away with it, but the law doesn’t seem to be 100% clear on this either.
Japan has historically been a leader in stem cell research and regulation, which probably doesn’t come as a surprise given the prominence of Japanese scientists like Yamanaka and Saitou. Japan being at the forefront of stem cell-based embryo regulation is just one example of the country’s prioritization of stem cell research. Now that we’re up to date on IVG’s science and regulation, let’s look at how it might be used in the clinic.
Standard IVG and IVF
IVG’s most immediate clinical use case is probably as part of an infertility treatment for people who can’t produce their own germ cells. Creating eggs or sperm outside the body would address issues not solvable with IVF alone. Taken on its own terms, I don’t think that this use case is meaningfully different from standard IVF either. Of course, that means that it won’t be palatable to IVF’s staunchest opponents, who oppose the procedure on philosophical or theological grounds. Albert Mohler, President of the Southern Baptist Theological Seminary and noted stem cell critic, summed up this view on a recent news briefing:
“marriage, the union between the husband and the wife, the gift of life and pregnancy, the creation of the embryos, that is something that by God’s design was a composite whole. When you separate that and you alienate the goods…one from the other, you create an awful lot of moral risk.”
Mohler’s view isn’t nearly as common as it used to be, and I don’t anticipate this flavor of criticism being a huge barrier to IVG development. I’m personally totally okay with creating embryos in a lab and would have no problem extending that to embryos made from stem cells, provided that the procedure is still safe. What constitutes “safe enough” isn’t always a simple question though - we’ll come back to this later.
Overall though, this type of IVG application has been uncontroversial enough to inspire the founding of multiple companies. Tokyo-based Dioseve is working to generate eggs from iPSCs in order to treat female infertility. Their technology is based on research from Katsuhiko Hayashi’s lab at Osaka University; Hayashi led the aforementioned work that created the first germ cells from iPSCs while in Mitinori Saitou’s lab. Berkeley-based Conception in Berkeley is also working on creating eggs, as is Ovelle Bio, a spinout from George Church’s lab at Harvard.3
IVG could also allow post-menopausal women to have kids without ever storing their eggs. I could see this happening if IVG ends up working really well, but I doubt that it’s sufficient to drive IVG’s development since egg storing already has established infrastructure.
IVG could become more controversial if used in concert with artificial wombs or other emerging reproductive technologies. Imagine a scenario where parents’ stem cells are converted into germ cells and used to create an embryo, which then develops inside an artificial womb. Many would be emotionally averse simply because this sounds like Brave New World, but I’m guessing that doing the whole reproductive cycle outside of the body would be more philosophically controversial than the sum of its parts. Discussing this in full would take more time than we have today, but should absolutely be done.
Further out applications
There is also potential down the road for IVG applications that could create new family structures. Given the cellular reprogramming we’ve talked about so far, you might reasonably wonder if one person’s stem cells could be used to make both sperm and eggs. This is no easy feat but if possible, would open up the possibility to create embryos using two germ cells from the same donor (usually called auto-reproduction)4 or from two separate donors of the same sex. These advances will take years or even decades, but discussing them now is a key part of proactive bioethics.
First though, let’s discuss how to even go about generating both types of germ cell from the same parent. Katsuhiko Hayashi’s lab figured out a way to create mice with two dads in 2023: they made iPSCs from each of the fathers, then turned one set into sperm and the other eggs. The latter was accomplished by isolating the small number of cells that spontaneously lost their Y chromosomes upon becoming iPSCs, then treating them with a chemical that causes errors in cell division to duplicate the single X chromosome. Their IVF success rate was quite low, with only 7 births from 630 attempts, though both of the adults that they tested for fertility passed (one male and one female). Despite other attempts, their method is still the best so far.5
Female parents might have an even harder time since an external Y chromosome would need to be introduced for them to have sons. Overall, it’s unlikely that creating germ cells to allow auto-reproduction or same-sex biological reproduction will ever be as easy as introducing a few Yamanaka factors.
Things are also asymmetrical for male and female parents at the stage of pregnancy. Female donors could become pregnant after IVG and IVF, but male donors would need to enlist the help of a surrogate or an artificial womb. Surrogacy was used in the mouse studies described above but is much more ethically and legally complicated in humans. Meanwhile, artificial wombs are a separate technology with their own technological and regulatory timelines; they can’t be counted on to offer an easy way out.
Male and female parents having access to different IVG applications isn’t ideal but will have to be weighed against the rest of the issues at play as science continues to advance. What’s clear is that emerging reproductive methods shouldn’t only be judged alone, but also within the broader technological landscape that they occupy.
Regulation worldwide
Regulation has come up a few times now, so let’s take a minute to discuss IVG’s legal status before wrapping up. The International Society for Stem Cell Research (ISSCR) creates ethics guidelines to help countries develop their own laws. In fact, the ISSCR guidelines’ latest update deals specifically with stem-cell based embryos. Still, laws governing stem cells and reproductive biology vary between nations and sometimes even within them, especially for emerging technologies like IVG.
To illustrate how this might look in practice, let’s look at an especially futuristic scenario where someone uses IVG to “clone” another person without their consent. They could theoretically do this by taking the other person’s skin cells, creating iPSCs, differentiating those into both eggs and sperm, and then starting a pregnancy. Kind of like what happens in the Black Mirror episode “USS Callister” but with no computer involved.
In Japan and a number of other countries, this would be illegal. The United States doesn’t actually have a national law against human cloning though: it’s technically legal if you’re not using federal dollars to do it. There are individual states that ban it but they define cloning differently, complicating things even further. States like Michigan limit their definitions to somatic cell nuclear transfer - the process famously used to create Dolly the Sheep.
Other states define cloning more broadly. For example, Illinois outlaws “attempt[s] to transfer to a uterus anything other than the product of fertilization of an egg of a human female by a sperm of a human male,” meaning that the method above would be illegal simply due to the single donor. Most interestingly though, Maryland bans “the replication of a human being through the production of a precise genetic copy of nuclear human DNA or any other human molecule, cell, or tissue.” Since the clone wouldn’t be exact, this one would probably need to be decided in court.
It’s clear though is that IVG applications can fall into ambiguous areas of the law. Recent changes, including the ISSCR and Japan’s updates, are steps in the right direction, but further work is necessary to deal with all eventualities. Science is decentralizing and we don’t want a rehash of the Jiankui Affair.
IVG in social context
Regardless of what specific uses of IVG become most popular, the technology is likely to increase the number of embryos created for fertility treatments and scientific research wherever it’s approved. The most obvious reason is that IVG makes it easier to obtain eggs from mothers-to-be, which makes it easier to create a lot of embryos for IVF. This is useful when there’s a risk of genetic disease: doctors can essentially screen as many embryos as they want to find one that looks good. If and when embryonic genome editing is approved, IVG will similarly make it easier to find embryos with exactly the desired edit(s) and nothing else.
None of this would be obvious if we simply focused on deciding whether or not creating human embryos from stem cells is ethical in and of itself. Evaluating technologies on their own terms is important, but should be complemented by consequentialist ethics rooted in the proper social context.
Following this line of thinking, we arrive at an even larger question: how will IVG challenge or reinforce our understanding of familyhood? It’s clear from an evolutionary psychology perspective why humans prioritize having biological children. But is it really rational to maintain this attitude in such a highly developed world? As University of Warwick bioethicist Heather Draper put it:
“An obsession with biological connectedness tends to make non-biological parents be seen as second-best parents, and I think that’s actually quite offensive.”
With over 100,000 children eligible and waiting for adoption in the United States alone, now is no time to denigrate non-biological parents. It’s possible that technologies like IVG could even reinforce preferences for biological families - within specific groups like the LGBT community and/or society at large. I don’t think this is a reason to halt IVG research. In fact, I think that thoughtful discussion of new reproductive technologies could actually help us re-evaluate how we think about familial structures. IVG won’t be here tomorrow, but when it does arrive I’m hoping that we’ll have thought long and hard enough to be ready for it.
Thanks to Heather Cook for discussions on the legal aspects of IVG.
As with most of the research discussed here, Yamanaka’s group started in mice, turning mouse cells into iPSCs before trying the same with human cells. By the end of 2007, both the Yamanaka Lab and James Thomson’s group at the University of Wisconsin, Madison had shown that iPSCs could be made from human cells.
iPSCs are different from other types of cells that come up in research, ethical, and political discussions around stem cell research. These include embryonic and adult stem cells, both of which exist in the body as stem cells and don’t require the use of Yamanaka factors. Embryonic stem cells (ESCs) are pluripotent and are sourced from developing embryos; these were at the center of the US political controversies over stem cell research during George W. Bush’s presidency. Adult stem cells (ASCs) are found in the bodies of mature organisms but are typically more differentiated than iPSCs and ESCs. Both ESCs and ASCs could be used in some of the IVG applications here but we’ll focus on iPSCs since they make the procedure so much easier.
For those curious, there are some other companies working on related issues that aren’t exactly within the purview of IVG. Another Church company, Gameto, has a product called Fertilo that can be combined with eggs in a dish to help mature them. The product contains ovarian support cells differentiated from iPSCs. Renewal Bio wants to make synthetic embyros to act as organ donors, based on mouse work from co-founder Jacob Hanna’s lab.
This is highly reminiscent of technologies imagined by feminist science fiction writers in the 1970s. Check out the short stories “When It Changed” by Joanna Russ and “Houston, Houston Do You Read?” by Alice Sheldon (writing as James Tiptree, Jr.).
Wei Li’s lab at the Chinese Academy of Sciences recently published a paper where they also made mice with two dads, creating the eggs by inactivating a bunch of genes and then transferring those nuclei to egg cells from other mice (this approach isn’t strictly dependent on IVG). They achieved a slightly higher birth rate than the Hayashi lab but their mice had developmental issues and were infertile so I’d characterize their approach as less successful overall. In his own article on IVG, UC Davis stem cell biologist Paul Knoepfler said he doesn’t think this will ever be safe in humans.