In the large-scale research project Human Cell Atlas, an international research consortium is working on mapping all the cells in the human body in detail. While previous publications have focused on individual organs, the consortium has now published for the first time four large tissue-spanning cell atlases, which together comprise over a million individual cells from 33 tissue types. The results show how different cell types convert their genetic material differently, shed light on the properties of immune cells during development from fetus to adult and provide a better understanding of many diseases.
Since its inception in 2016, the Human Cell Atlas (HCA) consortium has been working to map all cell types in the human body. More than 2,300 researchers from 83 countries around the world are involved. All data are published freely accessible so that the results are available as a resource for further research. Previous publications have focused on individual tissues and organs. They have already provided important insights into the structure and functioning of the respective organs. However, cross-tissue analyzes have so far been lacking.
Single cells mapped across tissues
Now, members of the consortium have mapped cells from 33 different tissues in detail. They present their results in four studies published in the journal Science. The first study, for which the Tabula Sapiens Consortium is responsible, a group of more than 150 researchers, provides the most comprehensive cross-tissue cell atlas to date. For their Tabula Sapiens cell atlas, the authors sequenced the transcriptome, i.e. the RNA selected for the production of proteins, from almost 500,000 living cells from 24 different tissues. It provides information about gene activity in cells and tissues.
The special feature: “In order to enable cross-tissue comparisons, we developed an approach in which we examined a large number of organs from the same person,” the authors explain. The donors came from different ethnic groups, were of different ages and had diverse medical backgrounds. “The Tabula Sapiens is a reference atlas that will provide the scientific community with new insights into human biology for many years to come,” says Stephen Quake of Stanford University, one of the leaders of the consortium.
The same genes used differently
Among other things, the authors used the data to show how differently the different cell types implement the genetic program with which they are equipped. “Although the genome is often referred to as the blueprint of an organism, it is perhaps more accurate to describe it as a building block list made up of the different genes that may or may not be used in the different cell types of a multicellular organism,” explain the authors. “Although almost every cell in the body has essentially the same genome, each cell type uses this genome in different ways and expresses a subset of all possible genes.”
Findings about how the same gene can become differently active in different cell types may also help in the future when it comes to better understanding the causes and effects of genetic diseases – an important area of application for cell atlases. In addition, a team led by Gökcen Eraslan from the Broad Institute in Cambridge is presenting a new method in the second Science study that can also be used to map frozen tissue samples at the single-cell level. “Our study opens the way for examinations of tissues from entire patient cohorts at the single-cell level,” says Aviv Regev, one of the two chairs of the HCA consortium. “We were able to create a new route map for multiple diseases by directly relating cells to human disease biology and to disease-prone genes in different tissues.”
Atlas of the Immune Cells
The third and fourth studies take a closer look at immune cells in different tissue types. “Most studies on human immunity focus on cells derived from the blood,” the researchers explain. “But immune cells that colonize peripheral tissue also play an important role in health and disease.” A team led by Cecilia Domínguez Conde from the Wellcome Sanger Institute in Cambridge therefore sequenced the RNA of around 330,000 immune cells from different parts of the body.
“By comparing certain immune cells in different tissues from the same donors, we identified different types of memory T cells in different parts of the body, which could have major implications for the management of infections,” says Conde’s colleague Sarah Teichmann, who co-authored the HCA consortium leads. The researchers also developed a program that can automatically recognize different types of immune cells with the help of machine learning.
Development from fetus to adult
In addition, a team led by Conde’s colleague Chenqu Suo mapped the cells of the developing immune system of fetuses during different stages of pregnancy. “This comprehensive atlas of human immune development reveals tissues involved in the formation of blood and immune cells, which improves our understanding of immune and blood diseases,” says Suo’s colleague Muzlifah Hannifa. “In collaboration with the other studies, it enables the immune system to be mapped from development to adulthood and reveals cell types that are lost during adolescence. It also helps support research in cell engineering and regenerative medicine.”
In an accompanying commentary on the studies, also published in Science, Zedao Liu and Zemin Zhang from Peking University write that the tissue-spanning cell atlases form important reference data sets that can also be used in medical research, for example when it comes to to predict possible side effects of new medicines even before the first clinical studies. “Taken together, these cross-tissue studies bring us closer to building a comprehensive human single-cell atlas,” they write.
Sources: The Tabula Sapiens Consortium, Science, doi: 10.1126/science.abl4896; Gokcen Eraslan (Broad Institute of MIT and Harvard, Cambridge) et al., Science, doi: 10.1126/science.abl4290; Cecilia Domínguez Conde (Wellcome Sanger Institute, Cambridge) et al., Science, doi: 10.1126/science.abl5197; Chenqu Suo (Wellcome Sanger Institute, Cambridge) et al., Science, doi: 10.1126/science.abo0510