Let’s take a trip back in time, to when you were just made up of a single cell. The sperm from your father and the egg from your mother will have just fused, forming a single-celled zygote. This zygote is now going to keep multiplying to form many cells, marking the start of embryonic development.
At some point, this mass of cells, making up the early embryo, will have implanted in your mother’s womb and begun to grow bigger. The cells will also have started to differentiate, transforming into all the different kinds of cells that make up who we are – skin, muscles, nerves, etc. Over time, the cells will also have developed into heart, lungs, the brain, and so forth. Finally, a whole nine months later, you will have been born, as a fully formed human baby.
In the early stages of the human embryo, before it has implanted in the mother’s womb, the cells arrange themselves in a particular way. A blob of cells gathers towards one side of the embryo and the other cells arrange themselves around this blob. This blob is called the inner cell mass. It contains cells with the ability to make all the other types of cells in the human body – i.e. the cells in this blob are pluripotent. Since a whole human body takes shape from this blob, scientists are naturally very interested in studying it in detail.
One way that scientists study cells is by looking at the kinds of proteins the genes in the cells can make. That is, they look at gene expression data. With this, they can see which genes are on or off in each of the cells they study.
The inner cell mass
In 2016, Manvendra Singh, then a graduate student with Zsuzsanna Izsvak at the Max Delbrück Center for Molecular Medicine in Berlin, reanalysed previously published gene expression data from an early human embryo, and was surprised.
Among the cells of the inner cell mass, he found a new group of cells that hadn’t been seen before. These cells were non-committed: they did not become a part of the later stages of the embryo. They seemed to get eliminated early on in development, compared to the other inner cell mass cells, which went on to make the developing embryo. What are these dying cells in the developing human embryo, and why do they die so young?
A 2014 study from Dr. Izsvak’s lab had shown that human embryonic stem cells express a gene called HERVH, a virus-like gene that’s important in maintaining pluripotency. Based on his analysis of the gene expression data in 2016, Dr. Singh found that most of the inner cell mass cells also express HERVH – but not the non-committed cells that eventually die.
“We found that, in the inner cell mass, the real pluripotent stem cells, they are marked by HERVH. There is also a separate group of cells that are not committing to any lineage, which are dying and eliminated out of development,” Dr. Singh said. Collaborators in the University of Spain verified these results and found these dying cells in fertilised embryos (in the lab).
Jumping genes
Dr. Singh and the team continued working on this new non-committed cell type in the lab, but they didn’t use human embryos. Instead, they used human embryonic stem-cell lines – cells that could mimic the early stages of the human embryo. They found that the non-committed cells, which don’t express HERVH, actually express transposons, a.k.a. “jumping genes”, dangerous little pieces of DNA that can insert themselves into different regions of the genome, damaging it and leading to cell death. The DNA damage caused by the transposons leads to these cells dying out early.
Initially, at the beginning of development, all the cells of the inner cell mass express these potentially dangerous transposons, but very soon, most of the cells express HERVH. Through a series of experiments, the researchers found that HERVH actually ends up protecting the cells from the damage inflicted by the jumping genes, kickstarting a protective mechanism that prevents the transposons from getting expressed in most cells. But some cells – the non-committed ones – don’t express HERVH, and are killed off by the uncontrolled transposon activity.
These findings were recently published in the journal PLoS Biology.
‘A selection arena’
“It’s an interesting paper because it attempts to see the invisible, a transient cell population doomed to elimination,” said Cedric Feschotte, a professor in Molecular Biology and Genetics in Cornell University and Dr. Singh’s subsequent postdoctoral advisor. “The existence of this cell population could have been easily overlooked because of the death of the cells.”
The authors call the early human embryo a ‘selection arena’: where the cells that survive express HERVH and the cells that don’t become damaged and die. Just like different animals compete to survive in the wild, it appears that even early cells in the developing human embryo play a carefully coordinated game to decide which cells win or lose the race to survive.
“The cells [expressing HERVH] are the winners, and that’s why we call it an arena, they are able to control them [transposable elements],” said Dr. Izsvak. “By the end of the game, we have a battlefield, we have the ‘good’ cells that will form the embryo, and the ‘bad’ cells will be destroyed by cell death.”
HERVH itself is also a transposon but without the ability to jump. Instead, it plays a protective role. “One family of transposons protects our early embryonic cells from dying, which were dying because of another set of transposons which are mutagenic, which causes DNA damage,” Dr. Singh added. “Life and death are both owed to two families of transposons, and I think that is very exciting.”
A small price to pay
In the early embryo, when the cells form the inner cell mass and other cells surround it, the latter eventually form the placenta. The placenta is a structure that attaches to the wall of the uterus, near the developing fetus, and helps move oxygen and nutrients from the mother to it.
Dr. Singh found that the cells that form the placenta also express transposon activity that could cause DNA damage. But somehow, even though these cells don’t express the protective HERVH, they are more tolerant of the transposons, and don’t die.
But it comes at a cost: cells of the placenta are different from other cells of the baby. Dr. Singh said “it will be discarded after childbirth, so the cost of the placenta is least to the organism.”
Scientists already know that HERVH plays a role in the pluripotency of stem cells, so it already has major implications for regenerative medicine. Based on their results, the authors also suggest that it could play a role in the fitness of the early embryo.
As HERVH is expressed in the “good” cells, it follows that healthier embryos should ideally have more of these good cells and less of the non-committed cells. The authors speculate that perhaps reducing transposon activity in the early embryo could affect its fitness, with implications for infertility treatment and in-vitro fertilisation techniques.
Rohini Subrahmanyam is a freelance journalist.
