What is the basis of the enormous nerve mass in humans? With the help of “mini-brains” grown in the laboratory, researchers have now gained new insights into why we develop larger brains than chimpanzees and gorillas. According to this, the neural progenitor cells remain active for longer in humans, which is associated with maintaining a cylindrical shape. The researchers were also able to show that a special gene plays a role: by manipulating its activity, they were able to “humanize” the brain organoids of gorillas.
Given the many similarities with our closest relatives in the animal kingdom, there is one crucial difference: Compared to chimpanzees and gorillas, around three times as many neurons are created in the course of human brain development. Scientists have long been interested in the genetic and developmental processes on which this difference is based. A new technique has been available for some years to investigate this question: so-called cerebral organoids, which are grown from stem cells in the Petri dish, offer new ways of investigating brain development in the laboratory. Using certain techniques, it is possible to stimulate the stem cells to develop in a similar way to the natural formation of the brain. This creates structures with cerebral features – “mini-brains”.
By comparing the characteristics of human brain organoids with those grown from chimpanzee stem cells, researchers have already shown differences. There have already been indications that the special neural development in humans has to do with delays. “But in these studies, the comparisons were carried out at stages in which neurogenesis was already in progress,” write Madeline Lancaster’s scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge. The team’s focus was therefore on an earlier phase of development: The researchers set their sights on the processes in the neural precursor cells from which the nerve cells are formed.
An early form in sight
As they explain, this special early form is initially characterized by a cylindrical shape, which presumably makes it easier for them to divide into identical daughter cells with the same shape. The more often the neural progenitor cells multiply at this stage, the more neurons are created later. As the cells mature and slow to multiply, they elongate and form a shape like an elongated ice cream cone, the scientists explain. This was previously known from studies on mice. With them, the neural progenitor cells change from the cylindrical shape to the conical one comparatively quickly, which is accompanied by the slowing down of the reproduction.
With the help of brain organoids, the researchers have now been able to discover how this development takes place in humans, gorillas and chimpanzees. They found that the change in shape of the neural progenitor cells in great apes takes a very long time compared to mice: the transition takes about five days. But with the human brain organoids, the process took about seven days, the scientists report. During the time that they kept their cylindrical shape, the progenitor cells actually divided more frequently and produced more daughter cells for further neuronal development.
According to the researchers, this is also the reason why the human brain organoids become much larger than the monkey organoids – which reflects the characteristics of real brains. “It is becoming apparent that a delayed development of the cells in the early brain, which is associated with a deformation, affects the number of neurons formed,” says Lancaster. “It is noteworthy that a relatively simple evolutionary change in cell shape appears to have major consequences for the development of the brain. This sheds light on what makes us human, ”said Lancaster.
Humanized monkey organoids
In this context, the scientists also went one step further: They gained clues about the genetic mechanisms that underlie the difference in the development of neural progenitor cells. To do this, they compared the gene activity – i.e. which genes are switched on and off – in the human brain organoids with those in the monkey versions. In doing so, they came across a genetic make-up called “ZEB2”, which is switched on earlier in gorilla brain organoids than in the human versions.
To investigate the importance of the gene, they used certain procedures to delay the effect of ZEB2 in the development of the gorilla brain organoids. It was shown that the influence slowed the maturation of the progenitor cells, as a result of which the gorilla brain organoids developed and became larger similar to the human ones. The researchers were also able to show the opposite effect: the earlier activation of the ZEB2 gene in the human progenitor cells promoted a premature transition in the human organoids, so that these developed more like the ape versions.
“The study now provides a new insight into the peculiarities of the developing human brain, which distinguish us from our closest living relatives, the other great apes,” Lancaster sums up the results.
Source: UK Research and Innovation, technical article: Cell, doi: 10.1016 / j.cell.2021.02.050