There is growing interest in a possible new reproductive method based on something called in vitro gametogenesis or IVG.
Today’s post explains IVG including its potential pros and cons. I also discuss why its possible combination with gene editing is so potentially fraught, which is a big potential con.
Let’s start with an explanation of this technology and the more upbeat implications of IVG.
What is in vitro gametogenesis or IVG?
In vitro gametogenesis or IVG is a laboratory method to create gametes, meaning sperm or eggs, from stem cells. For thousands of years, humans have only been making sperm and eggs inside our bodies. However, new stem cell technologies have made laboratory or “in vitro” gamete formation possible. As an interesting side note, “in vitro” literally means “in the glass” in Latin. Like a test tube.
IVG utilizes especially powerful stem cells as a starting material, generally induced pluripotent stem cells or iPS cells. Going back a step, many types of adult cells can serve as the source for the iPS cells for subsequent IVG. Skin cells are a common choice for the reprogramming that makes iPS cells.
The idea behind IVG is that in the same way we can make heart muscle cells, neurons, or just about any other cell type from pluripotent stem cells, researchers could make human sperm or eggs from these stem cells too, do IVG, and then do in vitro fertilization or IVF.
Examples of how IVG might be used to assist IVF
For instance, in the simplest IVG scenario, instead of relying on both egg and sperm donors for IVF, researchers could make human eggs or sperm in a lab for reproductive use starting with female or male iPS cells, respectively.
Say a man is infertile, a team could make iPS cells from his skin cells, differentiate those iPS cells into sperm (or primordial germ cells (PGCs) from which sperm could be made) and then use the lab-produced sperm to fertilize a standard donated egg by IVF. Vice versa, much the same could also be done with stem cell-based, lab-produced human eggs made from female iPS cells, which are then mixed with donor sperm for IVF.
This type of IVG-assisted fertility is the main goal of biotechs that are working in this space, primarily focusing on egg production. Helping people have babies is the main potential pro of IVG.
IVG biotechs
Also on the positive, the main IVG firms right now seem like good citizens of our field to me.
Japan has been a pioneer in this space overall. The work there includes the research of leaders Mitinori Saitou and Katsuhiko Hayashi.
What about biotechs there? I see a Japanese start-up called Dioseve that looks intriguing. It talks about “directly induced oocyte” technology.
The main IVG biotech here in the U.S. is Conception Biosciences over in Berkeley, led by CEO Matt Krisiloff. Their focus is making human eggs from stem cells. The firm’s website says, “We want to help parents have kids, and we aspire to make future generations healthier.”
Vitra Labs is another SF Bay Area firm in this area. It is also working on making human eggs in the lab. I haven’t been able to find out much about it though and don’t see a website.
Other cutting-edge assisted reproduction biotechs
Then there is Gameto, a biotech focused on maturing human eggs outside the womb.
Some researchers are also working on bioengineering so-called artificial wombs.
Put it all together and in some future decade humans might be able to have kids entirely in vitro. That idea feels like something out of Star Wars.
As I mentioned, there are also some ethically complicated paths that people could take with IVG-type technologies.
Let’s discuss those and why some of them might raise concerns.
Another option: no gamete donors needed?
In a scenario entirely relying on IVG, researchers could try to make eggs and sperm each from two different human iPS cell lines (female and male, respectively), and then use these gametes for entirely lab-based IVF.
You can see this visually in my IVG diagram above. If the resulting embryo was implanted in a surrogate mother, the baby produced would be the offspring of the stem cell donors.
This could be a new approach to infertility not requiring an egg or sperm donor. Just stem cell donors. If safe and effective (no easy task to even do trials) I’m not sure I see any ethical issues with this per se.
IVG-based reproduction from one person: almost cloning?
Let’s say some researchers or physicians went further.
What if they potentially made both sperm and eggs from just one donor via IVG? Then IVF was performed using these nearly genetically identical gametes.
One person could be both biological parents in a practical sense. Are we ready for that?
The resulting child would not be a clone of this single stem cell donor but close to it. The donor would be an entirely new kind of”single parent”. This is easier said than done. Single-parent IVG-based IVF would likely require some major chromosomal alterations to the cells involved too (more to come).
Another unusual possibility came to mind for a friend I was talking to about IVG. In more of the sci-fi realm, they mentioned that someone could take some of your skin cells even without your knowledge, make iPS cells, and sort of clone you.
You can see that complex issues come up with the more unusual, ethically thorny scenarios related to IVG. These are definitely possible cons to IVG.
For more on human cloning see: If you lost a loved one, could you turn to human cloning?
Technical challenges for different kinds of IVG-based applications
Some of the above is hypothetical and may not ever be possible. Especially the single-donor parent thing.
Even for more standard IVG-based IVF, I do have safety concerns about getting the epigenetic state of stem cell-based human eggs and/or sperm just right via derivation in a lab. The only way to really know if it worked to produce a healthy baby would be to try it. Then what if it doesn’t work well? Disaster.
If the cell donor for single-donor IVG is female, the iPS cells produced wouldn’t have a Y chromosome unless some extra, complex steps were included in the process to try to make sperm. Even then getting functional sperm might be impossible.
Conversely, if you start with a male’s skin cells, make iPS cells, and then try to make eggs from those, will the eggs be healthy and functional? Some major interventions may be needed to even try to get there like removing the Y chromosome.
Adding or removing X and Y chromosomes while keeping human cells otherwise happy is not going to be easy. On the other hand, researchers have generated haploid pluripotent stem cells, which could provide another path.
Other issues are likely to arise even for more standard IVG-based IVF in humans.
How in vitro gametogenesis & CRISPR could be combined
If you combine IVG with CRISPR gene editing with reproductive intent, things could be seriously problematic. This could be another road to heritable human germline modification.
How might this work?
While most research efforts in this space so far have centered on gene editing of human embryos, it is likely that CRISPR of cultured reproductive cells like PGCs would be far more efficient.
For example, researchers may CRISPR cells such as primordial germ cells or gametes made by IVG in the millions. Then screen them over time. Cells validated to have precise editing and no other issues like spontaneous mutations or epigenetic changes could then be used for IVF to make new people with heritable edits in their genomes.
In my view, we aren’t wise enough to try such a thing even if the technical and safety issues were ironed out. Others are more bullish on giving it a try. What gene edits would be safe or useful to heritably introduce into people?
Who gets to decide?
I discuss all of this in my book GMO Sapiens.
Mice versus people
Some of the things discussed in today’s post like IVG for reproduction have been tried or achieved in mice, but making any of them happen in humans is far harder.
Imprinted genes pose an obstacle. In mice, researchers used CRISPR to delete those to do IVG for reproduction, but that’s not an option in people.
For example, just a few weeks ago researchers reported making offspring mice from just two male mice.
This was accomplished using a combination of reproductive technologies and CRISPR to target imprinted genes. I can’t imagine that approach ever being safe in humans. See: Mice with two dads have been created using CRISPR by Jessica Hamzelou over at MIT Tech Review.
Looking ahead
With all of this in mind, how do we think about IVG for people having trouble trying to have kids? It’s complicated.
I recommend checking out Hank Greely’s book The End of Sex for more details on possible new reproductive methods including using gene editing and stem cells.
In my view, IVG biotechs like Conception Biosciences can potentially have concrete positive impacts with their research and technologies. There are so many loving people out there who want to be parents but need technological help. In some ways today the nascent IVG field reminds me of what it must have been like in the lead-up to IVF.
So why even discuss the potentially more extreme or controversial possible uses of IVG? Not everyone is wise, has good intentions, or does things carefully. We saw that with the whole CRISPR baby thing a few years ago.
Getting back to the positive, it’ll be exciting to continue to follow the efforts of Conception and other firms in this space.
References and notes
- Note that IVG also has important potential in research to study human gametes in the lab. It need not be combined with IVF although that is likely to happen to do research on early human embryos.
- The End of Sex, Hank Greely.
- GMO Sapiens, Paul Knoepfler.
- Derivation of human primordial germ cell-like cells in an embryonic-like culture, Nat. Comm.
- Mice with two dads have been created using CRISPR, Jessica Hamzelou over at MIT Tech Review.