Researchers concentrate how a single gene alteration may have isolated modern humans from extinct hominins

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• Source: University of California San Diego Health


• Date: 16 Feb,2021

As a professor of pediatrics and molecular and cellular medicine at University of California San Diego School of Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and what goes wrong in neurological disorders. For nearly as long, he has also been curious about the evolution of the human brain -; what changed which makes us so different from preceding Neanderthals and Denisovans, our nearest evolutionary relatives, now extinct?

Evolutionary studies rely heavily on two tools -; genetics and fossil analysis -; to research how a species changes over time. But neither approach can reveal much about brain development and function since brains do not fossilize, Muotri said. There’s absolutely not any physical record to research.

So Muotri decided to attempt stem cells, a tool not often applied in evolutionary reconstructions. Stem cells, the self-renewing precursors of other cell types, can be used to build brain organoids -;”mini brains” in a laboratory dish. Muotri and colleagues have pioneered the use of stem cells to compare humans to other primates, such as chimpanzees and bonobos, but until today a comparison with extinct species wasn’t thought possible.

Mimicking an alteration they discovered in one gene, the researchers used stem cells to engineer”Neanderthal-ized” brain organoids.

One of those altered genes -; NOVA1 -; captured Muotri’s attention because it’s a master gene regulator, affecting many other genes during early brain development. The researchers utilized CRISPR gene editing to engineer contemporary human stem cells with the Neanderthal-like mutation in NOVA1. They then coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized brain organoids.

It’s fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired. We don’t know exactly how and when in our evolutionary history that change occurred. But it seems to be significant, and could help explain some of our modern capabilities in social behavior, language, adaptation, creativity and use of technology.”

Alysson R. Muotri, Study Senior Author, Director, UC San Diego Stem Cell Program and Member, Sanford Consortium for Regenerative Medicine

Brain organoids are small clusters of brain cells formed by stem cells, but they are not exactly brains (for one, they lack connections to other organ systems, such as blood vessels). Muotri’s team has optimized the brain organoid-building process to achieve coordinated electric oscillatory waves like those produced by the human brain.

The Neanderthal-ized mind organoids looked very different than modern human mind organoids, even to the naked eye. They had a distinctly different form. Peering deeper, the team found that contemporary and Neanderthal-ized brain organoids also differ in the way their cells proliferate and how their synapses -; the connections between neurons -; form. The proteins involved in synapses differed. And electrical impulses displayed higher activity at earlier stages, but did not synchronize in networks in Neanderthal-ized mind organoids.

According to Muotri, the neural network changes in Neanderthal-ized brain organoids parallel how newborn non-human primates acquire new abilities more rapidly than human newborns.

“This study focused on just one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when every, or a combination of two or more, are altered,” Muotri said.

“We’re excited about this new combination of stem cell biology, neuroscience and paleogenomics. The ability to apply the comparative approach of modern people to other extinct hominins, like Neanderthals and Denisovans, using brain organoids carrying ancestral genetic variants is a totally new field of study.”

To continue this work, Muotri has teamed up with Katerina Semendeferi, professor of anthropology at UC San Diego and study co-author, to co-direct the new UC San Diego Archealization Center, or ArchC.

“We will combine and incorporate this awesome stem cell work with anatomic comparisons from several species and neurological conditions to make downstream hypotheses about brain functioning of our extinct relatives,” Semendeferi stated. “This neuro-archealization approach will complement attempts to understand the thoughts of our ancestors and close relatives, like the Neanderthals.”