The large size of human brains is down to a combination of evolution and genetics, according to a study by German scientists

Animal studies on great apes have long been banned in Europe for ethical reasons, so German researchers have used so-called organoids – three-dimensional cell structures a few millimetres in size that are grown in the laboratory – as an alternative to animal experiments.

These organoids can be produced from pluripotent stem cells, which then differentiate into specific cell types, such as nerve cells. In this way, the research team was able to produce both chimpanzee and human brain organoids.

Proliferation of brain cells?

Wieland Huttner of the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Germany, one of the three lead authors of the study said: “These organoids allowed us to investigate a central question concerning [the] ARHGAP11B [gene]. In a previous study we were able to show that ARHGAP11B can enlarge a primate brain. However, it was previously unclear whether ARHGAP11B had a major or minor role in the evolutionary enlargement of the human neocortex.”

To clarify this, the ARGHAP11B gene was first inserted into brain ventricle-like structures of chimpanzee organoids. The question was whether the ARGHAP11B gene would lead to the proliferation of those brain stem cells in the chimpanzee brain that are necessary for the enlargement of the neocortex.

Extraordinary mental ability

Michael Heide, the study’s lead author, who is head of the Junior Research Group Brain Development and Evolution at the German Primate Centre (DPZ) and an employee at the MPI-CBG, said: “Our study shows that the gene in chimpanzee organoids causes an increase in relevant brain stem cells and an increase in those neurons that play a crucial role in the extraordinary mental abilities of humans.”

When the ARGHAP11B gene was knocked out in human brain organoids or the function of the ARHGAP11B protein was inhibited, the amount of these brain stem cells decreased to the level of a chimpanzee.

Heide advised: “We were thus able to show that ARHGAP11B plays a crucial role in neocortex development during human evolution.”

Julia Ladewig of the Hector Institute for Translation Brain Research (HITBR) in Germany, the third of the lead authors, added: “Given this important role of ARHGAP11B, it is furthermore conceivable that certain maldevelopments of the neocortex may be caused by mutations in this gene.”

Image: An organoid about 3mm in size made from stem cells of a chimpanzee. The brain stem cells are stained red; brain stem cells that received the ARHGAP11B gene are shown in green. Credit: Jan Fischer