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When attached to a plate, brain organoid neurons (yellow) spread out among other cells called astrocytes (blue).

Muotri Lab/University of California, San Diego

Neanderthal-inspired ‘minibrains’ hint at what makes modern humans special

What is it about DNA that makes the human brain “human?” Seeking to understand how our complex brains evolved, researchers have now switched a single human gene out for its Neanderthal counterpart in brain tissue grown in a lab dish. Changes to the resulting organoid reveal the role this gene may have played in ancient—and modern—brain development.

“This is amongst the first studies of its kind to investigate how specific changes in the DNA of modern humans influences brain development,” says Debra Silver, a developmental neurobiologist at Duke University who was not involved with the work. Although past work has used similar approaches to examine the differences between the brains of humans and other primates, the new work looks at an even closer relative, where differences are expected to be more subtle.

Neanderthals are archaic humans that lived from 500,000 years ago to about 11,700 years ago, interbreeding with our species, Homo sapiens, for much of that time. Their brains were about as big as ours, but anthropologists think they must have worked incredibly differently, because in those hundreds of thousands of years, Neanderthals never achieved the sophisticated technology and artistry humans have.

To explore what differences might exist, neuroscientist Alysson Muotri at the University of California (UC), San Diego, and his team first compared the genomes of modern humans with those of Neanderthals and Denisovans—another archaic human—reconstructed from excavated bones. They found 61 genes for which modern humans all had one version and the archaic humans had another. 

His team then used the gene-editing tool CRISPR on stem cells derived from human skin cells to modify a gene, NOVA1, known to regulate the activity of other genes during early brain development. Switching out just one DNA base turned that gene into a Neanderthal NOVA1. Next, the researchers grew little clusters of brain cells called organoids, with and without the Neanderthal version, and compared them. Organoids are a far cry from real brains, and those with a single Neanderthal gene can by no means be considered fully “Neanderthal” organoids, cautions Madeline Lancaster, a developmental biologist at the Medical Research Council’s Laboratory of Molecular Biology.

These brain organoids carry a Neanderthal gene.

Muotri Lab/University of California, San Diego

Nonetheless, changing that one gene altered the organoid’s growth, appearance, and electrical activity, Muotri and his colleagues report today in Science. The modified organoid matured faster, yielding an uneven, complex surface instead of a smooth one. Its electrical activity revved up more quickly than that of its counterpart, and the connections between nerves, the synapses, depended on slightly different versions and interactions of key proteins. What’s more, the electrical impulses were not as synchronized as in the fully modern human organoid. “It looks almost like anything they could [test] showed a difference,” says Arnold Kriegstein, a developmental neurobiologist at the UC San Francisco School of Medicine.

The results, which held up in tests using human stem cells derived from a different donor’s skin cells, “tell us their brains probably worked in a different way than [ours] do,” Muotri says.

Researchers are excited but cautious about these results. “It is amazing that by changing a single amino acid in a single protein, one creates an effect that is visible even in how the organoids look in the microscope,” says Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology. But because organoids represent only the earliest stages of development, “it’s difficult to know how [the changes] would manifest in a more mature brain,” Kriegstein says.

Although they can be powerful, organoids “are a difficult tool,” adds Wolfgang Enard, an evolutionary geneticist at Ludwig Maximilian University of Munich. They can be tricky to grow and their characteristics are often hard to replicate across batches.

But Muotri is undaunted. Now that they have the protocol nailed down, he and other UC San Diego researchers have launched a center to expand their study of archaic human gene variants. Having teased out the effects of one Neanderthal gene, they’re ready to tackle the other 60.