THE human placenta is riddled with cancer-like patterns of mutations. But the discovery is better news than it might appear: it is helping scientists open a new window on the mysterious world of early human development.
In some ways, the placenta is a forgotten organ. It begins to form shortly after fertilisation from the embryo’s cells and then helps to support the future fetus as it develops before it is discarded at birth.
But it is difficult to study how embryos “decide” which cells are destined for the placenta and which for the fetus. “So far, we’ve been blind to the first split,” says Tim Coorens at the Wellcome Sanger Institute near Cambridge, UK.
Coorens and his colleagues, including his PhD supervisor Sam Behjati, decided to retrace the lineages of cells in full-term placentas to see where they came from.
Their approach relies on the fact that cells naturally accumulate mutations in their DNA and then pass these on when they divide. By comparing patterns of mutations between samples, it is possible to trace cells’ family trees back in time.
The team studied 42 human placentas, taking several small biopsies from each and sequencing the whole genomes of the cells within them.
A key discovery was just how mutated placental tissue can be. Some body cells, such as certain cells lining the colon, are known to have a naturally high rate of mutation, but the placental cells had about five times as many mutations to a single DNA “letter” as even these cells.
The placental tissue also had large numbers of changes involving the addition or loss of chunks of DNA – a form of mutation that is vanishingly rare in most human tissues, but common in certain childhood cancers.
Why such a vital organ should be so cavalier about its genome remains unclear. Its disposability might provide a clue: as it only “lives” for nine months, it doesn’t need to invest precious resources into repairing itself, says Coorens.
The placenta may even benefit the embryo by acting as a sort of dumping ground for potentially problematic cells. By comparing placental samples with samples of umbilical cord, which grows from future fetal cells, Coorens and his colleagues found that a cell’s “decision” to join the placental or fetal lineages happens at the earliest stages of development, even as soon as the first division that turns a fertilised egg into two cells.
The team found evidence in favour of this idea in one of the placentas. It contained cells with three copies of chromosome 10, but the associated umbilical cord had the usual two.
Cell family tree tracing showed that the cells with three copies of the chromosome were directed towards the placenta during some of the first cell divisions following fertilisation.
The work adds to evidence that mammalian embryos push their cells towards particular destinies at a much earlier stage of development than previously thought, says Magdalena Zernicka-Goetz at the California Institute of Technology, whose research in mice first suggested this idea.
“It is incredible for me to see that the same now is found to be the case in the human embryo,” she says.
Reference: bioRxiv, DOI: 10.1101/2021.01.26.428217