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In his 1932 novel Brave New World, Aldous Huxley walks you into a terrifying lab where human embryos and fetuses are being grown in glass containers and genetically engineered to fit into a certain rank of society. It continues to be nightmare fuel for college students everywhere.
Now that we live in an era where science fiction is morphing into science, conceiving artificial embryos sounds like an incarnation of the book—but couldn’t be further from it. Scientists have proven it is possible to synthetically create embryos from stem cells. This is a viable and ethical alternative to studying human or animal embryos, and a new frontier in finding out more about how preimplantation embryos may mutate or fail.
Instead of trying to build a societal hierarchy from human beings born in vitro, researchers Cody Kime, Kiichiro Tomoda and their team from the RIKEN Center for Biosystems Dynamics Research are developing new systems to find out what can go wrong with embryos in their earliest phases and cause early pregnancy loss. They recently published a study in Stem Cell Reports and are optimistic that the glitches of nature can someday be prevented.
"As you can imagine, there is tremendous power, inevitable risk, and serious ethical responsibility, although using cultured cells we can greatly reduce animal experiments. Perhaps one of the best applications is screening genetic mutations that impede fertility and reproduction," Kime told SYFY WIRE. "if those mutations are tolerated in our starting stem cell population, we can initiate reprogramming, and see how those mutations affect the synthetic embryo system. From there, we can get a better picture of how those genes may affect human fertility and improve on treatments."
If organoids (even the brain) can be grown for further research, so can embryoids. The team, whose in vitro synthetic embryo systems (SESs) came from mouse stem cells, was trying to successfully recreate totipotency, meaning that the cells would have everything they needed to develop into a whole organism. Totipotency does not last long in early embryonic cells. Pluripotency, which is the ability to produce some types of necessary cells, but not all, is much easier to achieve with reprogramming. This is still a positive. Dr. Kime wonders if the pluripotent stem cells, might possibly reprogram to be totipotent and form complete embryo.
There are three types of cells that emerge from totipotency: the cells of the actual embryo, the placenta and the amniotic sac. This is such a fleeting state in mammals because the cells in the embryo multiply and polarize fast to turn into one of those three things. Kime and Tomoda didn’t try to do everything at once. The team started by growing pluripotent mouse cells, or epiblast stem cells, responsible for only the fetus. Pluripotent epiblast stem cells are capable of arranging themselves to represent a post-implantation embryo. Hitting the rewind button on those cells with reprogramming might revert them back to the totipotent phase, before they specialized to just the fetus.
"We have seen evidence that something like totipotency may be happening in our reprogramming system, and it arises by taking a later stage embryonic stem cell and treating it with specific natural molecules and nutrients," Kime said. "In a way the cell is ‘tricked’ to reprogram and gain the ability to form the other embryonic lineages."
Reprogramming meant that the scientists would need to be able to tell which genes each cell turned on or off. They used a process called RNA sequencing, which sees how much RNA is and how many sequences of that RNA is in a sample. RNA (ribonucleic acid) tells DNA how to put together different proteins. Sequencing reveals its transcriptome, or everything that makes up RNA, and allows scientists to better understand cells up close. They observed the gene expression in thousands of cells, which told them which cells could be potentially reprogrammed to become totipotent. Hi-res regulation of gene expression could even show what ways cells were changing. In Kime's system, after 5 days of reprogramming, some of the reprogrammed epiblast stem cells (EPISCs) finally got there.
“The analysis revealed that cells resembling all three types of the early embryo were generated by our unique reprogramming system at the same time," he said. "Our analysis showed, in great detail, that our reprogrammed cells had engaged nearly all early embryo cells, while turning off the genes of the cell type they came from. The most important analysis was comparing our reprogrammed cells to real embryonic cells and finding that, across incredibly rich data, our cells were nearly identical."
The breakthrough has given Kime, Tomoda and their team a portal into what was once unthinkable. Because epiblast stem cells are easily reproduced, they can carry out studies on a much larger scale. They will also be able to explore things that would have not been considered ethical otherwise, such as getting a more in-depth look at how reprogramming happens and screening for gene mutations and other things that could cause a pregnancy to terminate itself. So while their work may be venturing into a brave new world, the intent is the total opposite of the sinister motives in Brave New World.
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