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Experiments Find Gene Key to the Human Brain’s Large Size

The single gene identified by the study may be what makes human brains three times larger than our closest great ape relatives at birth

After five weeks of development, a human brain organoid (left) is roughly twice the size of those from a chimpanzee (top right) and a gorilla (bottom right). (S. Benito-Kwiecinski / MRC LMB / Cell)
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Human brains are big, and they get big fast. When we’re born, our noggins contain triple the number of neurons found in the skulls of newborn chimpanzees and gorillas, some of our closest relatives, even though all three species spend about the same amount of time in the womb. Now, new research published last week in the journal Cell identifies a molecular switch that may be key to triggering the human brain’s speedy development, reports Karina Shah for New Scientist.

"This provides some of the first insight into what is different about the developing human brain that sets us apart from our closest living relatives, the other great apes,” says Madeleine Lancaster, a developmental biologist with the United Kingdom’s Medical Research Council and the study’s lead author, in a statement. “The most striking difference between us and other apes is just how incredibly big our brains are."

To compare the development of human brain cells with those of chimpanzees and gorillas, researchers grew tiny clusters of brain cells, called organoids, from stem cells in the lab. As expected, the human brain organoids raced ahead of the great apes.

When the researchers took a closer look at the brain tissue, they found that so-called neural progenitor cells divided more rapidly in the human tissues, reports Ian Sample for the Guardian. These neural progenitor cells are responsible for creating all the different cell types in the brain, including neurons, so having more of them to start with increases “the whole population of brain cells across the entire cortex,” Madeleine Lancaster, a developmental biologist with the United Kingdom’s Medical Research Council and the study’s lead author, tells the Guardian.

Just two days into the experiment, the human brain organoids were already bigger than those of the gorillas and chimpanzees. At five weeks, the human tissues were double the size of their primate counterparts, around 0.15 inches across, per New Scientist.

“This early stage of development is usually very inaccessible,” Lancaster tells New Scientist. “It’s a kind of black box in human biology.” The situation isn’t much different when it comes to our understanding of how brain development occurs in gorillas and chimpanzees. “Apes are an endangered species, so ethically, we wouldn’t want to do experiments at this stage. We usually don’t even know the gorilla is pregnant this early on,” Lancaster tells New Scientist.

To figure out what gave rise to this striking developmental divergence, the researchers looked at which genes were active in the three organoids and when they switched on. This led them to a gene called ZEB2 that turned on sooner in apes than in humans.

In subsequent experiments using the gorilla neural progenitor cells, the researchers found that delaying the effects of ZEB2 caused the gorilla organoid to grow larger. Conversely, when the gene was switched on early in the human organoids they didn’t grow as big and developed more like ape brain tissues.

Speaking with the Guardian, John Mason, a developmental biologist at the University of Edinburgh in Scotland who was not involved in the research, says organoids are a promising tool for studying brain development. “It’s important to understand how the brain develops normally, partly because it helps us understand what makes humans unique and partly because it can give us important insights into how neurodevelopmental disorders can arise,” he tells the Guardian.

“Brain size can be affected in some neurodevelopment disorders,” Mason adds. “For example, macrocephaly is a feature of some autism spectrum disorders, so understanding these very fundamental processes of embryonic brain development could lead to better understanding of such disorders.”

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