‘Mini-brains’ research brings neural development breakthrough

Researchers in Cambridge have identified a key genetic switch that ensures humans develop much bigger brains than apes, an important step in the scientific understanding of neural development.

The team at the MRC Laboratory of Molecular Biology led by Madeline Lancaster made the discovery after comparing so-called mini-brains grown from human, gorilla and chimpanzee stem-cells. Mini-brains, known more formally as cerebral organoids, are pea-sized neural assemblages grown in laboratories that mimic aspects of real brains.

The researchers found that a gene called ZEB2, a master regulator that switches other genes on and off, played a key role in determining brain size. ZEB2 activates later in humans than in apes, allowing more time for stem cells called neural progenitors to multiply and laying the foundation for the larger human brain.

“A delayed change in the shape of cells in the early brain is enough to change the course of development, helping determine the numbers of neurons,” said Lancaster, who in 2013 made the world’s first mini-brain.

“It is remarkable that a relatively simple evolutionary change in cell shape could have major consequences in brain evolution,” she added. “I feel like we’ve really learnt something fundamental about the questions I’ve been interested in for as long as I can remember: what makes us human?”

The findings were reported in the journal Cell on Wednesday.

The Cambridge team made their discovery after examining the early stages of brain development, when general-purpose stem cells are beginning to become specialised neurons — a process that starts about four weeks after conception.

They found that, in early embryos, ZEB2 promotes the conversion of neural progenitors into primitive brain cells known as radial glia. They showed how the cells changed during their transition, as the cylindrical progenitor cells matured into a conical shape and slowed their multiplication.

The transition took five days in gorillas and chimpanzees but seven days in humans, allowing more time for the progenitor cells to multiply. As a result, mini-brains derived from human stem cells grew to become twice as big as the ape ones.

When the researchers delayed the gene’s activity with chemicals in gorilla organoids, they developed more like human ones, growing slower and larger. Conversely, switching on ZEB2 sooner in human mini-brains made them develop more like ape organoids.

Lancaster emphasised that, although ZEB2 was important in making human brains, it interacted with hundreds of other genes that were involved in various stages of neural development — most of them still unknown.

“For example, although ZEB2 is a master regulator, we do not know what turns it on,” Lancaster said.

Other researchers have used organoids to shed light on the next stage of embryonic brain development. Two scientific teams found in 2018 that a quite different group of genes played a critical role in the expansion of radial glia into functioning neurons in humans but not in other primates.

One of those involved in that research, Sofie Salama of the University of California Santa Cruz, emphasised that the findings by Lancaster’s team were an important contribution.

“Research is moving ahead faster than ever but we’re only just beginning to understand what makes the human brain so big, so complex and so capable,” Salama said.