Researchers have 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, according to a report in Science.
The tissues, made by engineering human stem cells, are far from being true representations of these species’ brains — but they show distinct differences from human organoids, including size, shape and texture. The findings, published on February 11 in Science, could help scientists to understand the genetic pathways that allowed human brains to evolve.
The latest work takes the research further by looking at gene variants that humans lost in evolution. But Camp remains sceptical about the implications of the results, and says the work opens more questions that will require investigation.
Neanderthals are archaic humans that lived from 500,000 years ago to about 11,700 years ago, interbreeding with 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.
Humans are more closely related to Neanderthals and Denisovans than to any living primate, and some 40 per cent of the Neanderthal genome can still be found spread throughout living humans. But researchers have limited means to study these ancient species’ brains — soft tissue is not well-preserved, and most studies rely on inspecting the size and shape of fossilized skulls. Knowing how the species’ genes differ from humans’ is important because it helps researchers to understand what makes humans unique — especially in our brains.
The researchers, led by Alysson Muotri, a neuroscientist at the University of California, San Diego, used the genome-editing technique CRISPR–Cas9 to introduce the Neanderthal and Denisovan form of a gene called NOVA1 into human pluripotent stem cells, which can develop into any cell type. They cultured these to form organoids, clumps of brain-like tissue, up to 5 millimetres across, alongside normal human brain organoids for comparison.
It was immediately clear that the organoids expressing the archaic variant of NOVA1 were different. Human brain organoids are typically smooth and spherical, whereas the ancient-gene organoids had rough, complex surfaces and were smaller. This is probably because of differences in how the cells grow and multiply, say the authors.
To determine which archaic gene to express in the organoids, the researchers compared a library of human genome sequences with near-complete genomes of two Neanderthals and one Denisovan. They found 61 genes for which the human version is consistently different from that in the ancient species. Of these, NOVA1 is involved in forming the brain’s synapses, or nerve junctions, and is associated with neurological disorders when its activity is altered.
The human NOVA1 gene differs from the archaic variant — which still is present in other living primates — by a single base which the researchers edited into the stem cells using CRISPR–Cas9. That difference swaps a single amino acid in the NOVA1 protein made by the archaic organoids.
The differences between the resulting organoids continued at the molecular level. The team found 277 genes that had different activity between the ancient-gene and human organoids; some of those genes are known to affect neuronal development and connectivity. As a result, the archaic organoids contained different levels of synapse proteins and their neurons fired in less orderly patterns than did those in the control tissues. There is also evidence that they matured more quickly, the report said.
