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It’s one of the defining attributes of the human being: Compared to our closest primate relatives, we have incredibly large brains.
Now, scientists have clarified the reasons for the difference by collecting cells from humans, chimpanzees and gorillas and turning them into brain masses in the laboratory.
Tests on the tiny “brain organoids” reveal a hitherto unknown molecular switch that controls brain growth and makes the human organ three times larger than the brains of great apes.
Flip the switch and the human brain loses its growth advantage, while the great ape brain can be grown larger like a human’s.
“What we see is a very, very early difference in cellular behavior that allows the human brain to grow larger,” said Dr. Madeleine Lancaster, a developmental biologist at the Laboratory for Molecular Biology at the Medical Research Council in Cambridge. “We can account for almost the entire difference in size.”
The healthy human brain usually reaches about 1,500 cm.3 in adulthood, about three times the size of 500 cm3 gorilla brain or 400cm3 chimpanzee brain. But figuring out why has been fraught with difficulties, especially since the development of the human brain and of the great apes cannot be easily studied.
In an effort to understand the process, Lancaster and his colleagues collected cells, often left over from medical tests or operations, from humans, gorillas and chimpanzees, and reprogrammed them into stem cells. They then grew these cells in a way that encouraged them to become brain organoids – tiny lumps of brain tissue a few millimeters wide.
After several weeks, the human brain organoids were by far the largest of the lot, and close examination revealed why. In human brain tissue, so-called neural progenitor cells, which then produce all brain cells, divide more than those in great ape brain tissue.
Lancaster, whose study is published in Cell, added: “You have an increase in the number of those cells, so once they switch to produce the different brain cells, including neurons, you have more to start with, so you get a increase in the entire population of brain cells throughout the cortex. “
Mathematical modeling of the process showed that the difference in cell proliferation occurs so early in brain development that it ultimately leads to nearly doubling the number of neurons in the adult human cerebral cortex compared to that of the great apes.
The researchers went on to identify a gene that is crucial to the process. Known as Zeb2, it is later activated in human tissue, allowing cells to divide further before maturing. The tests showed that delaying the effects of Zeb2 made gorilla brain tissue grow larger, while activating it earlier in human brain organoids made them grow larger like those of apes.
John Mason, a professor of molecular neural development at the University of Edinburgh, who was not involved in the research, said he highlighted the power of organoids for studying brain development.
“It is important to understand how the brain normally develops, partly because it helps us understand what makes humans unique and partly because it can give us important information about how neurodevelopmental disorders can arise,” he said.
“Brain size can be affected in some neurodevelopmental disorders, for example macrocephaly is a feature of some autism spectrum disorders, so understanding these fundamental processes of embryonic brain development could lead to a better understanding of these disorders “he added.
