A Mouse With Two Dads — and a New Frontier for Biology | Katsuhiko Hayashi | TED

It is my great pleasure to be here to share some news from biology today with you. So your life and mine starts 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 the fertilized egg acquires the potential to give rise to the individuals like you and me. If you trace back your generations, 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 germs, 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. The continuous decrease in the reproductive rate of large livestock has resulted in huge economic losses. Setting aside the human needs, there are endangered animals down to a few individuals. How can we preserve them? That is where the assisted reproductive technology offers hope. Since Robert Edwards successfully combined human germ cells in a dish, more than 20 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 germ cells in a dish? So this is a question. So let's start with how the germ cells form in the body. After fertilization, a fertilized egg undergoes cell divisions and differentiates into the different cell types. As it further develops, original cells, or eventual sperm and egg, known as the primordial germ cells, emerge. These primordial germ cells then differentiate into the primary egg, known as the oocyte, in the female, or spermatogonia, the precursor of the 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 duplicating this entire process in a dish, known as in vitro gametogenesis. The key to generating the germ cells in a 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 Thomson 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 embryos. By using these pluripotent stem cells, we can hijack the germline. During normal development, cells receive a signal that guides their differentiation into the different cell types. By mimicking the right signals, pluripotent 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 pluripotent stem cells. By providing appropriate signals, we were able to generate mature eggs from most pluripotent stem cells. Also to achieve this, we created a mini ovary from pluripotent stem cells, allowing the oocyte to mature outside the body. Importantly, eggs produced in a dish are capable of fertilization and giving rise to yet more mice like these. These looks 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 grown in a dish. With this in vitro gametogenesis, the process of creating an egg requires only skin cells

or other easily collectable cells from the body, even cells in urine. 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 pluripotent stem cells in all these cases. Notably, our laboratory is actively involved in the repopulation effort for the northern white rhinoceros. Sadly, there are only two females who remain on this planet. We have generated the egg precursors from the northern white rhinoceros induced pluripotent stem cells, and are 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 shape and different function based on the sex. This difference is genetically made by the sex chromosome. In the human, males have an X and Y chromosome, and the 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 the switching from the XY chromosome to the X chromosome. How did we do that? Well, we took the skin cells from the male mice, and then made induced pluripotent stem cells, which have X and Y chromosomes, of course. Then we made a lot of these cells. In some rare populations, unequal 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 that very rare population of these cells that have two X chromosomes, and we made an egg. The egg derived from sex-converted induced pluripotent stem cells behaves exactly [like an] egg from traditional females. We then fertilized the sex-converted egg with the sperm, and this gave rise to typical healthy mice like these. They grow up, they eat the food, they mate and live long, just like conventionally bred mice. The only difference is these are derived from two dads. Looking at the history of reproductive technology like this, technologies developed in experimental animals like this can eventually be applied to the human and other animals. Today, the production of egg in a dish, even from traditional male cells, open a new possibility for reproduction in the future. We can create germ cells in a dish, and they can come from two fathers, two mothers or perhaps other combinations. Thank you. (Applause)