So we are writing the atlas of the human body

Imagine having a set of 37,000 billion (37 trillion) different cells, connected in very complex architectures and in continuous dynamic evolution from the point of view of their activities and their functional morphology. Now imagine also that you want to obtain a map of the types and relationships between all the cells in question, one by one, and you want, for the extra cost, to characterize how each cell evolves over time, modifying its biochemistry in response to different stimuli and the passage of time.

What you are imagining is of studying a person’s body at the single cell level, and you are not the only one to imagine it, because it is precisely one of the most ambitious research programs that the world scientific community has ever conceived. Launched in 2018, the Human Biomolecular Atlas program (HuBMAP) aims to map how all cell types are arranged in the human bodyusing different types of technologies to create organ maps at single cell resolution (and, actually, even looking inside individual cells).

60 different institutions and over 400 scientists, once the development of the necessary techniques (often invented from scratch) have been completed, have begun to produce results and the first publications in the latest issue of Nature demonstrate the astonishing quality of the information obtained. These are three articles, each of which illustrates a different technique for characterizing our body at the level of a single cell, with a previously unthinkable detail and dimensional scale.

In a first article, a technique that I know well, having used it myself in its infancy, is used, namely MALDI mass spectrometry directly on tissue, to obtain, cell by cell, the characterization of the proteins at work in each cell at a given instant of time. It’s a bit as if we could take a direct look at the machines that are operating inside each factory in a district that brings together many factories to obtain a series of precisely coordinated processes; but the factories, i.e. the cells, are only a few tens of microns large, and are about 500,000 cells and 588 arteries inside the intact decidua (the maternal membrane in contact with the fetal chorion), obtained from 66 individuals between 6 and 20 weeks of gestation. By following the evolution of the type and quantity of the various proteins involved in working over time, it was possible to observe the process through which the fetus remodels the maternal tissues, activating at precise moments, in precise districts and with a specific sequence a series of molecular steps which lead to the progressive construction of the interface between the unborn child and the mother. This first atlas of the spatio-temporal development of the decidua during pregnancy is not only useful in understanding the mechanisms through which gestation works, with unprecedented detail; it also constitutes a standard, thanks to which it will be possible to study anomalies in the formation of the mother-fetus interface and to clarify etiological perturbations in maternal-fetal tolerance and in some complications of pregnancy.

In a second article, the HuBMAP researchers focused on another type of interface in our body, namely the one between us, our microbiome and our food: the intestine. In this case, the power of a second technique, the most advanced version of single-cell RNA sequencing, was demonstrated by evaluating the organization of individual cells at eight different intestinal sites from tissue from nine donors. The cellular composition of the intestine was extremely site-specific and very varied between different districts, with a considerable complexity of the epithelial subtypes and with different cellular architectures corresponding to the different “neighborhoods” of the factory district of our metaphor. Furthermore, distinct immunological niches are highlighted that are present in the gut, providing further variety in how we interact with our microbiome and our foods along the digestive tract. These results describe the complexity of the cellular composition, regulation and organization of the intestine and serve as an important reference map for understanding human biology and diseases, particularly for future comparisons aimed at demonstrating the disturbance of tissue organization in specific districts (think, for example, of the case of inflammatory bowel diseases).

In a third article, the power of single cell mapping is demonstrated by comparing the status of the same tissue in healthy and diseased donors. Analyzing over 400,000 nuclei and whole cells from 45 healthy reference kidney and 48 patient samples resulted in a high-resolution cell atlas of 51 major cell types, including rare and previously undescribed cell populations. Again, both RNA profiles and active regulatory factors were obtained for each cell, so that their spatial distribution was mapped on the whole kidney. In sick subjects, the nephrons (i.e. the functional units of the kidney made up of Malpighian corpuscles and renal tubules, involved in blood plasma filtration and the formation of preurine) were found to be altered at the cellular level in at least 28 different ways and locations, in correspondence with alterations of the renal cycle, adaptation and repair of damage and degenerative states (related, for example, to inflammation). Once the “molecular signatures” of these pathological states were obtained, it was possible to reconstruct the detailed map of each lesion, both at an anatomical and functional level, while large-scale 3D imaging analysis (approximately 1.2 million cellular communities examined) provided the molecular correlates of the active immune responses. These analyzes defined biological pathways relevant to the time course and lesion niches, including signatures underlying epithelial repair that, when altered, correspond to a decline in renal function.

Three techniques, three investigations and three different tissues: this is the first taste of what is yet to come, and which will allow us to obtain the first physical and functional map, cell by cell, of a healthy person, but also its alterations in different states (physiological or pathological), allowing an unprecedented understanding of our body’s health and disease.

The number of cells in a human body is orders of magnitude higher than that of visible galaxies in our universe; mapping their positions, connections and their states over time represents the most ambitious goal that the modern biomedical research program has ever imagined, to establish the scale connection that exists between that immense multitude of molecular machines that make up our chemistry, the cells within which they function, and finally the tissues and organs that anatomy atlases tell us about.