A new study is the first to identify how human brains grow much larger, with three times as many neurons, compared to the brains of chimpanzees and gorillas. The study, led by researchers at the Medical Research Council (MRC) Molecular Biology Laboratory in Cambridge, UK, identified a key molecular switch that can make organoids in the brain of monkeys grow like human organoids, and vice versa.
The study, published in the journal Cell, compared “brain organoids” – 3D tissues made from stem cells that model early brain development – which were cultured from human stem cells, gorillas and chimpanzees.
Similar to real brains, organoids in the human brain have grown much larger than organoids from other monkeys.
Dr Madeline Lancaster, of the MRC Molecular Biology Lab, who led the study, said: “This gives a first glimpse into what is different in the developing human brain that sets us apart from our closest living relatives, the other great apes. . The most striking difference between us and other apes is how incredibly large our brains are. “
During the early stages of brain development, neurons are made by stem cells called neural progenitors. These progenitor cells initially have a cylindrical shape that allows them to easily divide into identical daughter cells of the same shape.
The more neural progenitor cells multiply at this stage, the more neurons there will be later.
As cells mature and slow to multiply, they lengthen, forming a shape similar to a stretched ice cream cone.
Previously, research on mice had shown that their neural progenitor cells matured in a conical shape and slowed their multiplication within hours.
Now, brain organoids have allowed researchers to discover how this development occurs in humans, gorillas and chimpanzees.
They found that in gorillas and chimpanzees this transition takes time, lasting about five days.
Human progenitors were further delayed in this transition, taking about seven days. Human progenitor cells have retained their cylindrical shape longer than other monkeys, and during this time they divide more frequently, producing more cells.
This difference in the speed of transition from neural progenitors to neurons means that human cells have more time to multiply. This could be largely responsible for the approximately three times the number of neurons in the human brain than in the brains of gorillas or chimpanzees.
Dr Lancaster said: “We have found that a delayed change in cell shape early in the brain is enough to change the course of development, helping to determine how many neurons are being made.
“It is remarkable that a relatively simple evolutionary change in cell form can have major consequences for the evolution of the brain. I feel like we have really learned something fundamental about the questions that interest me since then. as long as I can remember – what makes us human. “
To uncover the genetic mechanism behind these differences, the researchers compared the expression of genes – which genes are turned on and off – in organoids in the human brain compared to other monkeys.
They identified differences in a gene called “ZEB2”, which was activated earlier in organoids in the gorilla brain than in human organoids.
To test the effects of the gene in gorilla progenitor cells, they delayed the effects of ZEB2. This slowed down the maturation of progenitor cells, causing organoids in the gorilla’s brain to develop more similar to humans – slower and larger.
Conversely, activating the ZEB2 gene earlier in human progenitor cells favored a premature transition in human organoids, so that they developed more like monkey organoids.
The researchers note that organoids are a model and, like all models, do not fully replicate real brains, especially mature brain functions. But for fundamental questions about our evolution, this brain tissue in a dish offers unprecedented insight into key stages in brain development that would be impossible to study otherwise.
Dr Lancaster was part of the team that created the first brain organoids in 2013.
This study was funded by the Medical Research Council, the European Research Council and Cancer Research UK.