Scientists apply bar codes to cells Each cell has its own pattern Algorithm reveals new cell types
A new ground-breaking technology known as single-cell RNA sequencing allows scientists to read active genes from hundreds of thousands of cells, all at once. And special DNA ‘bar codes’ make it possible to trace every single active gene back to a cell.
Brain researcher Ed Lein is surprised at the results of an analysis of brain cells taken from the exterior layer of a cerebral cortex. Together with his colleagues from the Allen Institute in Seattle, USA, he has just examined the brains of two dead people. The analysis identified all the familiar types of brain cells, but also a cell type that they had never seen before. Eager to observe the unknown cell with their own eyes, the scientists get behind their microcope to see a round cell body from which a wealth of thin ramifications protrude. The shape reminds them of a rosehip, so the cell is named a rosehip cell.
The new discovery was made in cooperation with scientists from the US and Europe, and is one of the first to be made in connection with a new global project known as the Human Cell Atlas. The project aims to map out all cells of the human body, aiming to thereby revolutionise our surprisingly sparse knowledge about cellular activity. Some 1500 scientists from 62 nations are participating in the project, and they have already identified a series of previously unknown cell types, and have drawn up detailed maps for several of our organs.
The new breakthroughs have revealed the cells behind the incurable disease of cystic fibrosis, and how cancer cells attack otherwise promising immune therapy. The project now paves the way for new types of treatment which leverage these diseases’ hidden weaknesses. The human body includes a huge variety of cell types, each looking different, each carrying out its series of tasks. Red blood cells are full of the protein haemoglobin, which they need to carry oxygen about the blood. Nerve cells have long threads and many links with their neighbours, ensuring quick and efficient communication. Fat cells can be more than 200 times larger than red blood cells, as they store fat as energy reserves.
The variation of cell types in the body is all the more remarkable when you consider that they all have exactly the same DNA. However, the cells express the DNA in different ways, bringing different proteins into play. A brain cell expresses genes that are responsible for the formation of neuro-transmitters such as dopamine and serotonin. Those genes, on the other hand, are of no use to immune cells, which require genes for the production of substances which assist in defense against infection. So, every cell type has its own pattern of active and inactive genes that determine both its unique shape and its particular range of functions.
Over the past 150 years, scientists have identified some 200 different cell types based on their shapes and their locations in the body. But in recent decades, new methods have allowed us to see exactly which genes the cells express, and there is every indication that the body’s cells can be divided into many more types – perhaps thousands of them.
Until recently, however, even sophisticated genetic methods have not allowed scientists to unravel this confusion of cells in our bodies. They could either study a few cells at a time, or they could identify the genes that were active in a particular organ, without learning which cells expressed what. But new technology has changed that. Today, scientists can analyse a sample consisting of hundreds of thousands of cells, and still identify the gene activity in every single one of them. One of the cornerstones of the Human Cell Atlas project is a method known as singlecell RNA sequencing, or scRNA-seq. Within the past 10 years this technique has become so sophisticated that scientists can simultaneously measure the gene activity in all cells of a tissue sample, and this technique is now helping to map the human body. The method analyses the RNA molecule contents of all cells. When a cell expresses a gene, it will
first translate it into an RNA sequence, and that is subsequently translated into a protein. The RNA hence reflects the active genes of the cell.
If the cells included only two or three genes, it would have been relatively easy to categorise them according to gene activity. But with 20,000+ genes, there are so many possible combinations that scientists needed newly-developed algorithms to handle the large quantities of data. The algorithms use the data to place each cell in a kind of coordinate system with 20,000+ dimensions – one dimension for every gene – and then depending on the genes’ activity level, the cell gets allocated its place in the coordinate system. Cells that are close together in the system have similar patterns of gene activity, and so can be placed wthin the same cell type. The algorithm identifies related groups of cells in the coordinate system, giving scientists a general impression of the cell types present in the tissue.
And this is the manner of presentation which has now led to the discovery of several new cell types, and of subgroups within familiar cell types.
New cells can suggest treatment
Ed Lein’s rosehip cell was one of the first discoveries from the Human Cell Atlas. It is a nerve cell, but unlike many other nerve cells, it slows down electric signals instead of passing them on. It contributes to the control of which messages reach their destination – an important role to ensure that the brain does not drown in unnecessary signals.
However, the rosehip cell is not the only new cell type revealed by the Human Cell Atlas – and probably not the most important either. Ionocytes in the lungs might prove to be an even more vital discovery. Ionocytes express higher levels of a gene known as CFTR than any other cells in the body. CFTR plays the main role in cystic fibrosis – a genetic disease suffered by more than 70,000 people worldwide. The gene codes for a protein that carries water and chloride ions in and out of cells, and it is involved in the secretion of slime in the lungs. People with a mutation of the gene produce an overly thick layer of slime in the lungs, and suffer from potentially lethal breathing problems.
Years of intensive research into the disease have not produced a cure, but the discovery of ionocytes bodes well for the future. Scientists have long believed that the production of the CFTR protein was carried out by a series of well-known airway cells. However, the new discovery shows that by far the most CFTR is expressed in the ionocytes, and these make up only about 1% of the airway cells. This knowledge makes possible brand new cystic fibrosis treatments in which scientists can aim directly for the ionocytes in an effort to achieve normal CFTR activity levels in people born with the disease.
Map solves a pregnancy mystery
The Human Cell Atlas goes beyond the identification of new cell types. One of the project’s most important aims is to draw up detailed maps of the cells within the individual organs and tissues, to find out how the different cells cooperate.
In one of the project’s studies, scientists looked at the tissue that links mother and embryo during the first weeks of pregnancy. At this time, the embryo’s placenta is attached to the womb via a slimy layer produced in the womb: decidua. So far, our knowledge about this layer has been very limited. Scientists knew that cells from the embryo communicate and mix with the mother’s cells in the decidua and that the layer is extremely important in the early stages of pregnancy. But exactly where the interaction between the mother’s cells and the embryo took place was a mystery. Normally, the immune system attacks unfamiliar cells, but during pregnancy the mother’s immune system is kept in check despite another human occupying her body.
After the Human Cell Atlas’ mapping out of some 70,000 decidua cells, analyses revealed new types of cells and information regarding their interactions. Three types of