Mini brains genetically altered with CRISPR to be Neanderthal-like

By Ibrahim Sawal

Miniature brains grown in the lab are helping to reveal how modern humans survived when other hominins died out.

Neanderthals and Denisovans are some of our closest relatives. They lived alongside us about 50,000 years ago when modern humans migrated from Africa towards Europe, but they went extinct shortly after we came into contact with them. This might be because modern humans outcompeted and outsmarted them, but it may have just been bad luck.

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Alysson Muotri at the University of California, San Diego, and his colleagues wanted to know more about how our brains differed from these other hominins and whether this could affect survival. The team compared the genomes of modern humans, Neanderthals and Denisovans and found a total of 61 genes that differed.

One gene, neuro-oncological ventral antigen 1 (NOVA1), particularly caught their eye. The gene is specifically active during brain development and influences the developing nervous system. The team found that the modern human NOVA1 gene differed from the Neanderthal and Denisovan version by a single base pair

To find out more, the team grew their own ancient human-like brains. They used CRISPR genome editing to change the modern NOVA1 gene in human stem cells to mimic the Neanderthal and Denisovan version, then prompted the cells to develop into a Neanderthal or Denisovan-like brain organoid – a small, simplified version of the organ consisting of clusters of brain cells in a dish. They did the same with standard human stem cells.

As they matured, the ancient human organoids were smaller in diameter, had a more wrinkled cell surface and their cells multiplied more slowly than the modern human ones. “They are quite distinct from modern humans, suggesting that single base alteration can change brain development,” says Muotri.

This alteration also changed the expression of 277 genes compared with the modern human organoids, and caused 113 alternative splicing events – a process that causes one gene to code for multiple proteins, many of which were linked to brain development and synapse formations.

“The fact that virtually all modern humans now carry the modern version of the gene, strongly suggests that the alteration is a benefit to our species,” says Muotri. “If I might speculate, it might suggest that individuals carrying the Neanderthal NOVA1 alteration have a potential different way to process information,” he says, and this therefore may have affected their survival.

Tony Capra at the University of California, San Francisco, says he is excited about these new methods because it allows us to directly test Neanderthal brains. “As it progresses, we will be able to evaluate how the Neanderthal genome worked in more and more complex and realistic models,” he says.

However, because Muorti and his team used a modern human genome with a single change, Capra says this doesn’t truly reflect the entire Neanderthal or Denisovan genome. “It is unlikely that a single “magic” genetic change produced a dramatic positive change in these traits,” says Capra. He says there are many parts of our genome that contribute to cognition and that evolution may have acted on multiple variants with smaller effects.

Journal reference: Science, DOI: 10.1126/science.aax2537

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