A mouse with two dads — and a new frontier for biology | Katsuhiko Hayashi
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We are on the brink of a breakthrough in reproductive technology that could allow parents of the same sex to reproduce with DNA from both parents. That's right. But this kind of science wouldn't just help same-sex couples. As biologist Katsuhiko Hayashi presented in 2024, it could also keep biodiversity from extinction. He explains after the break.

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And now, our TED Talk of the day. It is my great pleasure to be here to share some news from biology today with you. So your life and mine start with this. The union of sperm and egg. The fertilization involves sperm from the father and egg from the mother. They meet in the usual way and fertilize the egg, acquire the potential to give rise to the individuals like you and me.

If you trace back your generation, you are derived from your parents, and your parents are derived from your grandparents and so on, in distant past. This perpetuity can only be achieved through what biologists like me call germ cell lineage. These are the only cells that are immortal among more than 200 types of cells in your body. The rest die with you. So these immortal germ cells called gametes are very important.

and we call them germline. In our society, this unbroken line is under threat. The present generations are having children later and later, and the older germ cells are less likely to result in successful fertilization, which leads to the declining birth rate. It's not just the people. Continuous decrease in the reproductive rate of large livestock has resulted in huge economic losses.

Setting aside human needs, there are endangered animals down to a few individuals. How can we preserve them? That is where the assisted reproductive technology offered hope. Since Robert Edwards successfully combined human germ cells in the dish, more than 12 million babies have been born through this technology called in vitro fertilization. However, current assisted reproductive technology can only be applied if sperm and egg can be obtained from the body.

If not, there are no options available. But I would ask now, can we create a germ cell in the dish? So this is the question. So let's start with how the germ cells are formed in the body. After fertilization, fertilized eggs undergo cell divisions and differentiate into the different cell types. As it further develops, original cells of eventual sperm and eggs, known as the primordial germ cell, emerge.

Then these primordial germs are then differentiated into the primary egg, known as the oocyte in the female, or spermatogonia, the precursor of sperm in the male. These egg and sperm mature over time, which is associated with the sexual maturation of individuals. Now imagine if this entire process were to occur outside the body. So my team and I have been focusing on replicating this entire process in the dish

known as in vitro gamma-Agenesis. The key to generating the germ cell in the dish is a type of cells called pluripotent stem cells, because they each have the ability to differentiate into any cell type in the body. Martin Evans showed that such a pluripotent stem cell could be derived from preimplantation embryo in mice, and James Thompson showed it could be done in humans.

Based on these breakthroughs, Shinya Yamanaka showed that any kind of cell in the body could be turned into the pluripotent stem cells simply by expressing a specific set of proteins. These are called induced pluripotent stem cells, and they possess the same potential as those derived from the embryos. By using these pluripotent stem cells, we can hijack the germline

During normal development, cells receive the signal that guides their differentiation into the different cell types. By mimicking light signals, puripotent stem cells can be directed along the pathway to differentiate into the egg and sperm. This has been successfully demonstrated in our laboratory by using mouse puripotent stem cells. By providing appropriate signals, we were able to generate mature egg from mouse puripotent stem cells. Also, to achieve this,

We created a mini-ovary from pluripotent stem cells, allowing the oocytes to mature outside the body. Importantly, eggs produced in a dish are capable of fertilization and giving rise to yet more mice. These look the same as any other mice. They grow up, they eat the food, they breed and live long. But in this case, the genetic mother of these mice is the pluripotent stem cell growing in a dish.

And now, back to the episode. With this in vitro gamma genesis, the process of creating an egg requires only skin cells or other easily collectable cells from the body, even cells and uri. So this means actually this kind of technology can be applied to the various mammalian species, including humans, livestock, or even endangered animals.

Several research groups have successfully produced the primordial germ cells from pre-potent stem cells in all these cases. Notably, our laboratory is actively involved in the depopulation effort for the northern white rhinoceros. Sadly, there are only two females who remain on this planet. We have generated

egg precursors from the northern white rhinoceros in these peregrine stem cells, and they're currently creating a mini-ovary system to mature these precursors into the eggs. But we can go further than that. By using this technology, we can skip the sex-dependent reproduction. Today, germ cells have different shapes and different functions based on the sex. This difference is genetically made by the sex chromosome.

In the human, males have an X and Y chromosome, and females have two X chromosomes. From a genetic viewpoint, this is the only difference between male and female. But in a dish, we can eliminate this difference. So our laboratory succeeded in switching from the XY chromosome to the XX chromosome. How did we do that? Well, we took the skin cells from the male mice and made induced pill-potent stem cells, which have X and Y chromosomes, of course. Then we made a lot of these cells.

In some rare populations, unrequalled segregation of sex chromosomes occurs during cell division, which means some XY chromosomes become one X chromosome that then doubles and becomes two X chromosomes. We picked up a very rare population of these cells that have two X chromosomes, and we made an egg. The egg derived from sex-combated induced buprenorphine stem cells behaves exactly like an egg from traditional females.

We then fertilized sex-combated eggs with sperm, and this gave rise to typical, healthy mice. They grow up, they eat the food they mate, and live long, just like conventional bred mice. The only difference is these are derived from two dots. Looking at the history of reproductive technology like this, technologies developed in the experimental animal like this

can eventually be applied to humans and other animals. Today, the production of eggs in the dish, even from traditional male cells, opens up new possibilities for reproduction in the future. We can create a germ cell in the dish, and they can come from two fathers, two mothers, or perhaps other combinations. Thank you.

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That was Kasuhiko Hayashi speaking at TED 2024. If you're curious about TED's curation, find out more at ted.com slash curation guidelines.

And that's it for today. TED Talks Daily is part of the TED Audio Collective. This episode was produced and edited by our team, Martha Estefanos, Oliver Friedman, Brian Green, Autumn Thompson, and Alejandra Salazar. It was mixed by Christopher Fazi-Bogan. Additional support from Emma Taubner and Daniela Balarezo. I'm Elise Hu. I'll be back tomorrow with a fresh idea for your feed. Thanks for listening.

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