According to biologist and historian Michel Morange, biology has, since around the turn of the millennium, been rediscovering the cell: acknowledging that it’s with the cell, not the gene, that an understanding of life must begin. He’s in good company. “The cell is the fundamental unit of structure, function and organization of living systems,” veteran molecular biologist Sydney Brenner wrote in 2010, while Nobel laureate Paul Nurse calls the cell “the basic functional unit of life” – the smallest entity that is undeniably alive.
This is why the international consortium called the Human Cell Atlas (HCA) is so significant. Founded in 2016 and now comprising more than 3,600 members from more than 100 countries, it is a project with an ambition at least equal to that of the much-trumpeted Human Genome Project: to map out all the cells of the human body. Given that we have fewer than 20,000 protein-encoding genes but around 37 trillion cells, the endeavour is arguably even more daunting.
Of course, not all cells are in the same places from one person to the next. But a key goal of the HCA is to document all of the basic cell types in the body – liver cells, neurons, muscle cells and so on – and to figure out what makes them different and why and how diseases make them dysfunctional. Such information is arguably more relevant medically than is a catalogue of genes, since it is in general with the malfunction of cells that illness begins.
Every one of our cells contains the same genes (except red blood cells, from which the gene-bearing chromosomes are expelled), yet they can be vastly different in shape and function. That’s generally because each cell type has a different suite of genes that are active, being switched on or off mainly by “epigenetic” chemical modifications to the respective parts of the chromosomes.
One of the key objectives of the HCA is to characterise these differences, largely by measuring each cell’s “transcriptional profile”: which genes have been transcribed into the RNA molecules from which their corresponding proteins are constructed.
This has become possible over the past decade or two thanks to a technique called single-cell RNA sequencing (scRNA-seq), the central technology of the HCA. In a recent demonstration of what this technology can now achieve, a paper in Science this month reported a cell-by-cell map of transcriptional profiles for the entire mouse brain.
One of the revelations of scRNA-seq is that there is much more variation among our cells than was previously suspected. Whereas it was once suspected that there were around 200 different types of cell in our bodies, we know there are many thousands – at least 5,000 in the brain alone. (How, and how much, these are distinguished has itself become a matter of intense debate.)
It’s a telling fact that once we mapped out genes we discovered we had considerably overestimated their number, whereas we now see we had considerably underestimated the diversity of human cells.
The first major tranche of publications from the HCA, a collection of more than 40 papers released in late November, unveiled cell maps of the digestive tract from the mouth to the colon, and (for foetuses and infants) of the organ called the thymus, where some of the white blood cells of the immune system are produced.
Among the early fruits of these labours are insights into what causes some cells to alter their states to trigger the inflammation underpinning gut diseases such as coeliac disease (intolerance of gluten) and Crohn’s. Other groups in the consortium are looking at cells of the human skeleton, skin, brain, eyes, and lungs.
While the HCA has been described as a “Google Maps of the human body”, that’s a little misleading. For one thing, cells change over time, not least during the course of development from the early embryo. And there’s no unique way of characterising cells: the transcriptome reveals a lot, but efforts are afoot also to measure single-cell profiles of proteins (the proteome) and metabolic molecules (the metabolome).
Each -ome opens a new window, and each is a reminder that every cell has its own story and that our existence and our health are not about conformance to any gene-based blueprint, but emerge from webs of molecular interactions of mind-boggling complexity.
The real challenge is to understand the principles that, if we are lucky, ensure robust and reliable functioning despite so much potential for failure and breakdown.
