NOVA1

Neanderthal brain organoids reveal what makes us human

“The final goal is to catalog the genetic variants that make us human.”

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What’s left of the Neanderthals, our closest extinct relative, is mostly teeth and bones. While they live on in a way within the DNA of all of us, their physical presence is best imagined by examining their skeletal remains. Soft tissue fossils are incredibly rare. And while we’ve found the brains of dinosaurs we have not found the brains of Neanderthals.

Scientists have, however, given us a peak by growing Neanderthal pea-size brain organoids. In 2018, a team led by Alysson Muotri, a geneticist and professor at the UC San Diego School of Medicine, announced they created clusters of lab-grown brain cells containing Neanderthal DNA. The goal, Muotri said at the time, was “to recreate Neanderthal minds.”

Now, they have published data revealing how these 'Neanderthalized' brain organoids behave.

On Thursday, a team, including Muotri, published a study in the journal Science detailing brain organoids they grew with the Neanderthal variant of NOVA1, a gene that influences neurodevelopment and function.

The addition, in turn, caused the organoids to differ from those strictly of the Homo sapien variety: They developed slower, expressed different electrophysical properties, and displayed higher surface complexity.

Muotri tells Inverse it’s fair to say these changes would influence specific abilities. “We know that even small perturbations during early development might have a dramatic impact on human behavior,” he says.

And while it’s premature to say Neanderthals acted in one way or another, the results do add to our understanding of the differences between these extinct humans and us. It’s understood we evolved to be a unique type of human. Cells in a dish may explain why.

What’s new — This study helps explain why modern humans are different from Neanderthals by recreating a potential version of the past.

“This reverse-engineering approach can teach us how the archaic version of the gene behaves in the relevant cell types,” Muotri says.

“By knowing this, we can then create hypotheses on why these differences emerged.”

Genomic analysis comparing the genomes of Neanderthals to a diverse population of modern humans revealed there are 61 protein-coding genes different between the two groups. The study team decided to zero in on the gene NOVA1 because it’s “a master regulator of hundreds of other genes during neurodevelopment,” Muotri says.

The brain organoids with the Neanderthal version of NOVA1 developed uneven surfaces.Muotri Lab/UC San Diego

With the help of CRISPR-Cas9 genome-editing technology, the team replaced the modern human allele of the NOVA1 gene in human pluripotent stem cells with the archaic NOVA1 gene from the Neanderthal genome.

Observations revealed this reintroduction caused changes in “alternative splicing” in genes involved in neurodevelopment, proliferation, and synaptic connectivity. Alternative splicing is a mechanism the nervous system uses to generate complexity and variability, Muorti explains. NOVA1 typically regulates alternative splicing in developing nervous systems.

“The archaic NOVA1 targets these genes to be spliced in different ways, generating new isoforms that we don’t detect in modern humans or will only appear at different stages,” Muorti says.

The organoids looked different too. Modern human brain organoids have a smooth surface, while the archaic versions have uneven surfaces.

Modern human brain organoids, without the archaic version of NOVA1.Muotri Lab/UC San Diego

Brain organoids, for their part, differ from actual brains in important ways. Their gene expression generally mirrors that of a developing brain in utero, but they are not a perfect reproduction of brain cell types, and there is some concern growing organoids can introduce unintended mutations. In a 2019 interview with Inverse, Muotri emphasized brain organoids are human-like — but not exactly human.

But experts suggest they do have the potential to revolutionize medical research when it comes to disease modeling and drug screening. And now, it appears they may revolutionize our understanding of what it means to be human.

Why it matters — These results suggest the modern human version of NOVA1, which likely became a fixed part of Homo sapien DNA after our ancestors diverged from Neanderthals, some 500,000 to 800,000 years ago, was critical to our species’ evolution.

A tray of modern human brain organoids.Muotri Lab/UC San Diego

“The neural network consequence of the archaic NOVA1 is something we are super excited about and what to explore further,” Muotri says.

“This modification seems quite important for the evolution of the human brain. We plan to challenge these organoids to test how adaptable and plastic are these networks.”

What's next — The team is also interested in examining the other 60 protein-coding genes setting apart us from the Neanderthals.

To do so, a multidisciplinary team called the Archealization Center was formed. This team will systematically test the impact of these genes using a variety of organoid models.

“The final goal is to catalog the genetic variants that make us human,” Muorti says.

Abstract: The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of NOVA1. Moreover, levels of synaptic markers and synaptic protein co-associations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in NOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species’ evolution.
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