The differences in our cells don’t come from differences in the genes themselves: Every cell in your body contains a copy of your distinctive DNA and the 20,000 genes for making proteins it encodes. “The genome is a parts list,” Quake said. “There’s no way to predict which cell types come out of a given genome.”

To distinguish a white blood cell from a muscle cell at the molecular level, scientists have to look at the cell’s RNA. RNA transcripts that are copied from DNA sequences ferry the instructions for building proteins to the ribosome, the cell’s protein construction center. Therefore, RNA transcripts contain the information about which genes are active and expressed in a particular cell.

Using a powerful set of single-cell genomics tools, scientists can read these expression patterns to fingerprint a cell. These tools have matured over the past few years so that scientists can now quickly and efficiently look at tens of thousands or even millions of cells in a single experiment.

“Once that was in place, then there’s nothing stopping you from making an atlas,” Quake said. “It all just kind of cascaded.”

Cell atlases started pouring in. Scientists began by examining the gene expression in individual cells from model organisms like fruit flies and mice. Since then they’ve moved on to humans. Within the last year, maps of blood vessels, tumors, placenta, kidney and intestine, among other tissues, were published in high-profile journals. Many of these atlases not only looked at cell identities, but also mapped out precisely where those cells were located in the tissues — information critical for understanding which cells might be involved with disease.

“The amount of data collection is mind-blowing,” said Elizabeth Rhea, a research assistant professor at the University of Washington who is not involved in any cell atlas effort. She reflected on how rapidly the technologies have advanced: 12 years ago, as a graduate student at Vanderbilt University, Rhea would examine the expression of a single gene in the developing mouse brain and liver. Now “we are able to do that, but for every gene expressed in every cell within a chunk of tissue,” she said.

With each new cell atlas, researchers have had to reckon with how much complexity they were missing before. Reviewing the data sometimes made Angelo feel as if he were looking at endlessly looping videos of fractals, he said. “You keep zooming in” and the pattern goes on indefinitely; the more you uncover, the more you realize there’s more to uncover. “A lot of this is kind of daunting.”

This has proved true for many human organs — especially the brain.

Mind-Blowing Diversity

The complexity of the human brain, in its construction and function, has limited our ability to understand it. Its 86 billion neurons are tiny sparks animating thoughts, perceptions, feelings and important functions throughout the body. Fabian Theis, director of the computational health center at Helmholtz Munich, who works on several atlas efforts but was not involved in the brain atlas, remembers one colleague telling him that the brain is like a separate organism. “It’s like 100 organs meshed into one,” he said.

Claudia Doege, an associate professor of pathology and cell biology at Columbia University, echoed that view. “You need to put a lot of people together to dig through that big mess,” she said.

Doege studies the hypothalamus, an ancient and critical part of the brain that evolved to control basic bodily functions like body temperature, heart rate and hunger. In 2020, she was invited to help interpret brain atlas data collected from hypothalamic tissues — a rare opportunity to probe the infrequently sampled brain region.

It was a “gargantuan task,” said Hannah Glover, a postdoctoral researcher in Doege’s lab. Intermittently cursing at her computer, Glover spent months tearing through literature and reference atlases to identify genes expressed in different regions of the brain and comparing them to the genes found in the newly analyzed hypothalamus.

The analysis revealed “an extreme amount of diversity,” Doege said. They identified more than 350 distinct neuron populations and 19 non-neuron cell populations from 10 different regions within the hypothalamus.

Other research groups working on the brain cell census backed this up. Rebecca Hodge, an assistant investigator at the Allen Institute for Brain Science in Seattle who co-authored several of the new Science papers, also found that most of the cell types were located in evolutionarily ancient parts of the brain.

“That was one of the first descriptions of so much cellular diversity being outside of the cortex,” Hodge said, referring to the much-studied brain region where higher-order functions like critical thinking occur. “It’s scratching the surface, probably, of what the actual cellular diversity is there.”