It provides oxygen and nutrients for a growing baby, removes waste products as they build up in its blood, and protects the life of the foetus. Yet the placenta, the temporary organ that cherishes the unborn, is a puzzle. It carries the DNA of the newly formed child but manages to elude immune responses from its genetically distinct mother.
Understanding how the placenta survives and functions is of critical importance in ensuring pregnancies are healthy and viable – and thanks to a remarkable global project, the Human Cell Atlas (HCA), researchers are now uncovering the secrets of its behaviour.
This achievement could have crucial consequences. When problems affect a placenta, conditions such as pre-eclampsia or even miscarriages can happen. Understanding the mechanics of its functioning should help doctors tackle these conditions. Nor is this the only success for the Atlas project, which was launched in 2016 by scientists based in Britain and the United States, a collaboration that has since expanded dramatically and now includes several thousand researchers from institutions around the world.
In addition to their placenta triumphs, these groups are also revealing cellular secrets of the immune system as well as the brain, lungs and other organs. In the process, scientists have discovered thousands of new types of cells, the fundamental unit of life, in humans.
“There are about 37.2 trillion cells in an average human adult, and these come in many different types,” said Aviv Regev of the US biotechnology giant Genentech, and one of the founders of the HCA project. “We knew of several hundred types when we launched the atlas but, since then, we have found several times that number, and the total is rising all the time. We now know of thousands of different cell types in humans.”
In the past, scientists used microscopic observations of tissue to identify different types of cells. This process works for the more common cells. However, some are rare and are easily overlooked, although they can be crucial in ensuring the proper functioning of organs in the body.
To get round that problem, scientists turned to genomics and advanced computational technology to pinpoint individual cells from their genetic signatures. “We call it the resolution revolution,” said the project’s other founder, Sarah Teichmann, who is based at the Wellcome Sanger Institute in Cambridgeshire.
“Thanks to the development of single-cell genomics, we can sequence each individual cell in a tissue sample. It has transformed our ability to study the cellular composition of the human body.”
In the first six years of its existence, researchers working for the HCA sequenced and characterised a total of 117.8 million cells, from 174,600 samples, from 9,551 individuals. Hundreds of new cell types have been revealed this way, with discoveries in the placenta lying in the vanguard of this research.
“The foetus creates the placenta which surrounds and protects it, and establishes communication between itself and its mother’s uterus in which it is developing,” said cellular geneticist Roser Vento-Tormo, who is also at the Wellcome Sanger Institute.
Scientists knew that cells called trophoblasts left the placenta to migrate into the mother’s uterus during pregnancy. There they carry out an inter-cellular conversation that persuades the mother’s immune system to tolerate the foetus growing inside her. But the exact nature of this interchange eluded efforts to decode it. So HCA researchers turned to the techniques of single-cell genomics and used these to analyse more than 70,000 individual cells taken from first trimester pregnancies. This revealed how these cells were interacting with each other and showed how trophoblasts invade the uterus’s lining and cause its tissue to change structure, creating the blood supply for the developing foetus.
“What we have discovered are the messages that those cells are giving to their maternal cells in order for the foetus and placenta to reside peacefully inside the mother,” said Vento-Tormo. The importance of this work was also stressed by Teichmann. “This first HCA of early pregnancy is going to transform our understanding of healthy development. It will also shed light on disorders of pregnancy.”
Other discoveries made by HCA researchers include their pinpointing of a new cell type in the lung. This cell carries a receptor that, when missing, plays a key role in causing cystic fibrosis, one of the west’s most common life-threatening inherited diseases.
“Until then, we did not know that this cell type existed,” added Regev. “We were completely blind to it and thought a different cell type was involved. Knowing the right cell is crucial, of course. It means you can target therapies accurately and effectively. So that has been a very important discovery as well.”
Another example of the potential of HCA research is provided by scientists who were working in early 2020 during the first weeks of the Covid pandemic. They used single-cell genomics to uncover two sets of cells – known as goblet and ciliated cells – in the nose. These were found to have high levels of proteins that the Covid virus uses to get into our bodies. The identification of these cells helped explain the high transmission rate of Covid at a crucially important time.
“Knowing which exact cell types are important for virus transmission provides a basis for developing potential treatments to reduce the spread of the virus,” said Teichman. “It also demonstrates the immense potential of HCA research.”
