Organoids show how human brains become massive compared with other primates

March 24, 2021
New discoveries point to a very different evolution pattern for the human brain. (S.Benito-Kwiecinski/MRC LMB/Cell)

New discoveries point to a very different evolution pattern for the human brain. (S.Benito-Kwiecinski/MRC LMB/Cell)

By using miniature brains artificially grown from stem cells, researchers have for the first time identified how the human brain manages to grow several times larger than those of other large primates.

Their study, published March 24 in Cell, uncovered a key molecular switch that triggers human brains to develop triple the number of neurons of chimps or gorillas, despite much of their developmental biology being the same.

"By studying the evolution of ape brain development, we are gaining insight into what makes the human brain unique," said first author Silvia Benito-Kwiecinski, a postdoctoral researcher at the MRC Laboratory of Molecular Biology in England. "This study further highlights how small changes in the regulation and timing of the expression of genes can have major consequences for diversity between species."

One of the most unusual aspects of human biology is the size of the brain, which dwarfs that of other intelligent primates. Humans' massive brains provide a huge cognitive advantage over much of the animal kingdom and are instrumental in the ability to develop advanced societies.

"The most pronounced difference that sets the human brain apart from other apes is the size of our brains, containing roughly [three times] more neurons than other hominids (great apes), our closest living relatives," Benito-Kwiecinski said.

Benito-Kwiecinski explained to The Academic Times that neurons are generated in the brain by a class of cells called neural progenitor cells, so any differences in the number of neurons between one species and another must come down to differences in the behavior of these cells at an early phase of development.

Neural progenitor cells start off in a cylindrical shape, allowing fast multiplication in the early phases of development. Later, the cells elongate, changing shape as they slow down their reproduction. The longer this transition takes, the more neurons in the fully developed brain.

Studies have already identified differences in the progression of human progenitor cells between humans and distantly related animals like mice, but conducting these types of studies in non-human primates is much more difficult due to ethical concerns.

"This pre-neurogenic stage has been inaccessible, as it occurs so early in fetal development that human tissue is difficult to come across and, given the protected status of apes, it is unethical and impossible to study fetal ape tissue," Benito-Kwiecinski said. "This means that this period of hominid brain development is somewhat of a black box, which organoids offer a window into."

This window is one that has been used frequently in recent years. Artificially grown organoids, or miniature organs, have allowed researchers to conduct better and more ethical research into many areas of human biology, including embryos, thyroids and even human tear glands.

The MRC Laboratory of Molecular Biology produced the first brain organoids in 2013, a project led by Madeline Lancaster, the senior author on the new study. This time, Lancaster and her team grew brain organoids from human, chimpanzee and gorilla stem cells, and observed how long the transition between the different neural progenitor cell phases took.

They found that in gorillas and chimpanzees, this transition takes a long time, occurring over approximately five days, compared with just a few hours for simpler animals like mice.

However, for the human cells, the transition took even longer, around seven days. This extra time of uninhibited growth in the cylindrical phase accounts for the huge difference in total neuron count in fully developed brains.

The team also investigated the genetic mechanism behind the transition in cell shape by comparing the gene expression between the different brain organoids during development. They identified differences in a gene called ZEB2, which expressed sooner in the gorilla organoids, suggesting that its activation causes neuron development to slow down sooner. Mutations in this gene are also known to cause a developmental disability called Mowatt-Wilson syndrome.

"The delayed expression of ZEB2 in humans may be a key contributor to human brain expansion, and these findings may also be important to understanding the large range of neurodevelopmental symptoms that arise in humans with mutations in ZEB2," Benito-Kwiecinski said.

To confirm the relationship between ZEB2 and the developmental timeline of neurons, the team delayed the effects of this gene in the gorilla organoids, finding that this resulted in slower development of larger organoids.

The researchers would next like to "go upstream" with their research and look at the mechanisms controlling the expression of the gene itself, taking one more step toward solving the riddle of human brain evolution.

"It's remarkable that a relatively simple evolutionary change in cell shape could have major consequences in brain evolution," Lancaster said. "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 study, "An early cell shape transition drives evolutionary expansion of the human forebrain," published March 24 in Cell, was authored by Silvia Benito-Kwiecinski, Stefano L. Giandomenico, Magdalena Sutcliffe, Paula Freire-Pritchett, Iva Kelava, Kate McDole and Madeline A. Lancaster, MRC Laboratory of Molecular Biology; Erlend S. Riis, University of Cambridge; Stephanie Wunderlich and Ulrich Martin, Hannover Medical School; and Gregory A. Wray, Duke University. 

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