The Human Brain Has a Dizzying Array of Mystery Cells

An international team of scientists has mapped the human brain in much finer resolution than ever before. The brain atlas, a $375 million effort started in 2017, has identified more than 3,300 types of brain cells, an order of magnitude more than was previously reported. The researchers have only a dim notion of what the newly discovered cells do.

The results were described in 21 papers published on Thursday in Science and several other journals.

Ed Lein, a neuroscientist at the Allen Institute for Brain Science in Seattle who led five of the studies, said that the findings were made possible by new technologies that allowed the researchers to probe millions of human brain cells collected from biopsied tissue or cadavers.

“It really shows what can be done now,” Dr. Lein said. “It opens up a whole new era of human neuroscience.”

Still, Dr. Lein said that the atlas was just a first draft. He and his colleagues have only sampled a tiny fraction of the 170 billion cells estimated to make up the human brain, and future surveys will certainly uncover more cell types, he said.

Biologists first noticed in the 1800s that the brain was made up of different kinds of cells. In the 1830s, the Czech scientist Jan Purkinje discovered that some brain cells had remarkably dense explosions of branches. Purkinje cells, as they are now known, are essential for fine-tuning our muscle movements.

Later generations developed techniques to make other cell types visible under a microscope. In the retina, for instance, researchers found cylindrical “cone cells” that capture light. By the early 2000s, researchers had found more than 60 types of neurons in the retina alone. They were left to wonder just how many kinds of cells were lurking in the deeper recesses of the brain, which are far harder to study.

With funding from the National Institutes of Health, Dr. Lein and his colleagues set out to map the brain by inspecting how brain cells activated different genes. At least 16,000 genes are active in the brain, and they are turned on in different combinations in different types of cells.

The researchers collected brain tissue from several sources, including people who had recently died and those who were undergoing brain surgery.

When studying fresh brain tissue, the scientists attached glass tubes to the surface of individual cells to eavesdrop on their electrical activity, injected dye to make out their structure and finally sucked out the nuclei from the cells to inspect them more closely.

Rather than carrying out these procedures by hand, the researchers designed robots to work efficiently through the samples. The robots have inspected more than 10 million human brain cells so far, Dr. Lein estimated.

Bottom row: Drawings of neurons known as double bouquet cells, isolated from tissue biopsies during brain surgery. Double bouquet cells serve to prevent other neurons from sending out too many signals. Top row: Electrical activity recorded from each neuron.Credit…Allen Institute for Brain Science

Some of the newly identified cells were found in layers of cerebral cortex on the brain’s outer surface. This region is essential for complex mental tasks such as using language and making plans for the future.

But the new studies reveal that much of the brain’s diversity lies outside of the cerebral cortex. A vast number of the cell types uncovered in the project lie in the deeper regions of the brain, such as the brain stem that leads to the spinal cord.

The researchers found many new types of neurons, cells that use electric signals and chemicals to process information. But neurons make up only about half the cells in the brain. The other half are far more mysterious.

Astrocytes, for example, appear to nurture neurons so that they can keep working properly. Microglia serve as immune cells, attacking foreign invaders and pruning some of the branches on neurons to improve their signaling. And the researchers found many new types of these cells as well.

The researchers used some of the same methods to study the brains of chimpanzees and other species. By comparing the results among species, the researchers investigated how the human brain evolved to be different from those of other primates.

Previous studies had suggested that the human brain might be distinctive thanks in part to having evolved new kinds of cells. But the researchers were surprised to find that all of the cell types in human brains matched up with those found in chimpanzees and gorillas, our closest living relatives.

Within those cells, researchers discovered a few hundred genes that became either more or less active in humans than in other apes. Many of those genes are close to genetic switches that turn genes on or off.

Dr. Bakken and his colleagues found that a number of the genes that make humans distinct are involved in building the connections between neurons, known as synapses.

“It’s really the connections — how these cells are talking to each other — that makes us different from the chimpanzees,” said Trygve Bakken, a neuroscientist at the Allen Brain Institute who worked on the primate studies.

Megan Carey, a neuroscientist at the Champalimaud Center for the Unknown in Portugal who was not part of the brain atlas project, said that the research provided a staggering amount of new data for researchers to use in future studies. “I think this is a tremendous success story,” she said.

Yet she also cautioned that understanding how the human brain works would not be a matter of simply cataloging each and every part down to its finest details. Neuroscientists will also have to step back and look at the brain as a self-regulating system.

“There will be answers in this data set that will help us get closer to that,” Dr. Carey said. “We just don’t know which ones they are yet.”

Adam Hantman, a neuroscientist at the University of North Carolina who was not involved in the study, said that the atlas would be a big help for some kinds of research, like tracing the development of the brain. But he questioned whether a catalog of cell types would elucidate complex behavior.

“We want to know what the orchestra is doing,” he said. “We don’t really care what this one violinist is doing at this one moment.”

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